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2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement

Developed in collabration with the American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance

      Abbreviations and Acronyms:

      AR (aortic regurgitation), AS (aortic stenosis), AVA (aortic valve area), AVR (aortic valve replacement), CAD (coronary artery disease), CMR (cardiac magnetic resonance), COPD (chronic obstructive pulmonary disease), CT (computed tomography), EF (ejection fraction), EOA (effective orifice area), EuroSCORE (European system for cardiac operative risk evaluation), LV (left ventricular), LVOT (left ventricular outflow pact), MDCT (multidetector computed tomography), NCDR (National Cardiovascular Data Registry), PARTNER (Placement of Aortic Transcatheter Valve trial), PH (pulmonary hypertension), RV (right ventricular), SOURCE (SAPIEN Aortic Biosprosthesis European Outcome registry), STS (Society of Thoracic Surgeons), TAVR (transcatheter aortic valve replacement), TEE (transesophageal echocardiogram), TTE (transthoracic echocardiography), VARC (Valve Academic Research Consortium)

      Preamble

      This document has been developed as an Expert Consensus Document (ECD) by the American College of Cardiology Foundation (ACCF), American Association for Thoracic Surgery (AATS), Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons in collaboration with the American Heart Association (AHA), American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Failure Society of America, Society of Cardiovascular Computed Tomography, Society of Cardiac Magnetic Resonance, Society of Cardiovascular Anesthesiologists, and Mended Hearts. ECDs are intended to inform practitioners, payers, and other interested parties of the opinion of ACCF and document cosponsors concerning evolving areas of clinical practice and/or technologies that may be widely available or may be new to the practice community. Topics chosen for coverage by ECDs are so designed because the evidence base, the experience with technology, and/or clinical practice are not considered sufficiently well developed to be evaluated by the formal ACCF/AHA Practice Guidelines process. Often the topic is the subject of considerable ongoing investigation. Thus, the reader should view the ECD as the best attempt of the ACCF and document cosponsors to inform and guide clinical practice in areas where rigorous evidence may not yet be available or evidence to date is not widely applied to clinical practice. When feasible, ECDs include indications or contraindications. Some topics covered by ECDs will be addressed subsequently by the ACCF/AHA Practice Guidelines Committee.
      To avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the writing committee, all members of the writing committee, as well as peer reviewers of the document, are asked to disclose all current health care–related relationships, including those existing 12 months before initiation of the writing effort. The ACCF Task Force on Clinical Expert Consensus Documents (TF CECD) reviews these disclosures to determine what companies make products (on market or in development) that pertain to the document under development. Based on this information, a writing committee is formed to include a majority of members with no relevant relationships with industry or other entity (RWI), led by a chair with no relevant RWI. Authors with relevant RWI are not permitted to draft or vote on text or recommendations pertaining to their RWI. RWI is reviewed on all conference calls and updated as changes occur. Author and peer reviewer RWI pertinent to this document are disclosed in Appendices 1 and 2, Appendices 1 and 2, respectively. Additionally, to ensure complete transparency, authors’ comprehensive health care–related disclosure information—including RWI not pertinent to this document—is available online (see Online Appendix 3). Disclosure information for the ACCF TF CECD is also available online at www.cardiosource.org/ACC/About-ACC/Leadership/Guidelines-and-Documents-Task-Forces.aspx, as well as the ACCF disclosure policy for document development at www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/Relationships-With-Industry-Policy.aspx.
      The work of the writing committee was supported exclusively by the ACCF without commercial support. Writing committee members volunteered their time to this effort. Conference calls of the writing committee were confidential and attended only by committee members.
      Robert A. Harrington, MD, FACC
      Chair, ACCF Task Force on Clinical Expert Consensus Documents

      1. Introduction

      1.1 Document Development Process

      1.1.1 Writing Committee Organization

      The Writing Committee consisted of a broad range of members representing 12 societies and the following areas of expertise: cardiothoracic surgery, interventional cardiology, general cardiology, geriatric cardiology, echocardiography, cardiac anesthesiology, cardiac computed tomography (CT), cardiac magnetic resonance (CMR), cardiac nursing, heart failure, neurology, valvular heart disease, structural heart disease, and the consumer perspective. Geographic distribution of members crossed most U.S. time zones and included international representation. Members with expertise using this new and emerging technology and those with expertise in their content area, but not in the procedure discussed herein, served on the committee to provide appropriate balance of perspectives.
      This writing committee met the College’s disclosure requirements for relationships with industry as described in the Preamble. Important to note, if an author works in an institution that serves as a TAVR trial site but has no direct relationship with the trial sponsor or other relevant company (that produces [competing] products or services discussed in this document) or institutional relationship as defined by the ACCF Disclosure Policy for Document Development, the trial site information was not deemed relevant to this writing effort and is not included in the table of relevant author disclosures (Appendix 1). For example, if an author works in an institution where TAVR is performed, but he/she: (1) does not personally perform the procedure; or (2) performs the procedure but has no direct relationship to the trial (eg, principal investigator, investigator, steering committee member, consultant) and does not oversee funds related to the trial, then the relationship is not included in the table of relevant disclosures. In these situations, these relationships do not even need to be disclosed. However, in the spirit of full disclosure, this information is recorded in the online disclosure table containing all author health care relationships.

      1.1.2 Document Development and Approval

      The Writing Committee convened by conference call and e-mail to finalize the document outline, develop the initial draft, revise the draft per committee feedback, and ultimately sign off on the document for external peer review. All participating organizations participated in peer review, resulting in 48 reviewers representing 1087 comments. Comments were reviewed and addressed by the writing committee. A member of the ACCF TF CECD served as lead reviewer to ensure that all comments were addressed adequately. Both the Writing Committee and TF CECD approved the final document to be sent for board review. The ACCF Board of Trustees, AATS Council, SCAI Board of Directors, and STS Board of Directors reviewed the document, including all peer review comments and Writing Committee responses, and approved the document in January 2012. The AHA, ASE, EACTS, HFSA, Mended Hearts, SCA, SCCT, and SCMR endorsed the document in January 2012. This document is considered current until the TF CECD revises or withdraws it from publication.

      1.2 Purpose of This Document

      Transcatheter aortic valve replacement (TAVR) offers new and potentially transformational technology for patients with severe aortic valvular stenosis who are either extremely high-risk candidates or inoperable for surgical aortic valve replacement (AVR) or who are inoperable by virtue of associated comorbidities. In the future, this technology may be utilized in lower risk surgical candidates. An estimated 40,000 patients have received TAVR worldwide. Multiple single and multicenter registries, and a single randomized trial, have documented favorable outcomes using a wide spectrum of endpoints, including survival, symptom status, quality of life, and need for repeat hospitalization. The implementation of TAVR into the flow of patient care is complex, involving consideration of several key factors such as clinical site selection, operator and team training and experience, patient selection and evaluation, procedural performance and complication management, and postprocedural care. Collaborative stakeholder involvement is required in the management of this high-risk patient population with extensive coexistent medical conditions. A previously published document by ACCF and STS identified a high-level series of issues to be addressed regarding this technology.
      • Holmes Jr., D.R.
      • Mack M.J.
      Transcatheter valve therapy a professional society overview from the American College of Cardiology Foundation and the Society of Thoracic Surgeons.
      This current collaborative expert consensus document, which involves 12 professional societies, addresses these issues in greater detail with the intent to examine the current state of the evidence, facilitate the integration of this technology into the armamentarium of therapeutic options for patients with aortic valvular stenosis, and to enable responsible adoption and diffusion of this promising technology. This document has focused on published data; it must be remembered that there is only 1 single completed randomized trial, although others are in progress or planned; much of the data in this expert consensus document is based upon information from studies and registries, both surgical and TAVR, which are frequently retrospective and include self-reported clinical events rather than adjudicated events.

      2. Background and Historical Aspects

      The most common cause of valvular aortic stenosis (AS) in adults is calcification of a normal trileaflet or congenital bicuspid valve.
      • Roberts W.C.
      • Ko J.M.
      Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation.
      • Selzer A.
      Changing aspects of the natural history of valvular aortic stenosis.
      • Stephan P.J.
      • Henry III, A.C.
      • Hebeler Jr., R.F.
      • et al.
      Comparison of age, gender, number of aortic valve cusps, concomitant coronary artery bypass grafting, and magnitude of left ventricular-systemic arterial peak systolic gradient in adults having aortic valve replacement for isolated aortic valve stenosis.
      Calcific AS is characterized by lipid accumulation, inflammation, fibrosis, and calcification
      • Ghaisas N.K.
      • Foley J.B.
      • O’Briain D.S.
      • et al.
      Adhesion molecules in nonrheumatic aortic valve disease: endothelial expression, serum levels and effects of valve replacement.
      • Otto C.M.
      • Kuusisto J.
      • Reichenbach D.D.
      • et al.
      Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis Histological and immunohistochemical studies.
      and is common in the United States. It typically presents in older individuals (ie, >75 years) in contrast to bicuspid AS, which presents a decade or more earlier. Rheumatic AS, uncommon in the Western world, occurs due to fusion of the commissures with scarring and calcification of the cusps, and retraction of the leaflets resulting in the valve being both regurgitant and stenotic.

      2.1 Pathophysiology and Clinical Course

      In adults with valvular AS, the obstruction develops gradually, typically over many years during which the left ventricle (LV) adapts to the systolic pressure overload with progressive concentric hypertrophy that results in diastolic dysfunction,
      • Stephan P.J.
      • Henry III, A.C.
      • Hebeler Jr., R.F.
      • et al.
      Comparison of age, gender, number of aortic valve cusps, concomitant coronary artery bypass grafting, and magnitude of left ventricular-systemic arterial peak systolic gradient in adults having aortic valve replacement for isolated aortic valve stenosis.
      • Peterson K.L.
      • Tsuji J.
      • Johnson A.
      • et al.
      Diastolic left ventricular pressure-volume and stress-strain relations in patients with valvular aortic stenosis and left ventricular hypertrophy.
      • Spann J.F.
      • Bove A.A.
      • Natarajan G.
      • et al.
      Ventricular performance, pump function and compensatory mechanisms in patients with aortic stenosis.
      reduced coronary reserve,
      • Carabello B.A.
      • Paulus W.J.
      Aortic stenosis.
      • Marcus M.L.
      • Doty D.B.
      • Hiratzka L.F.
      • et al.
      Decreased coronary reserve: a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries.
      myocardial ischemia,
      • Koyanagi S.
      • Eastham C.L.
      • Harrison D.G.
      • et al.
      Increased size of myocardial infarction in dogs with chronic hypertension and left ventricular hypertrophy.
      and eventually, depressed contractility resulting in LV systolic dysfunction.
      • Gunther S.
      • Grossman W.
      Determinants of ventricular function in pressure-overload hypertrophy in man.
      • Krayenbuehl H.P.
      • Hess O.M.
      • Ritter M.
      • et al.
      Left ventricular systolic function in aortic stenosis.
      • Carabello B.A.
      • Green L.H.
      • Grossman W.
      • et al.
      Hemodynamic determinants of prognosis of aortic valve replacement in critical aortic stenosis and advanced congestive heart failure.
      Ultimately, in some patients, heart failure or sudden death occurs. Typically, patients with AS are free from cardiovascular symptoms (ie, angina, syncope, and heart failure) until late in the course of the disease. However, once symptoms manifest, the prognosis is poor, with the interval from the onset of symptoms to the time of death being approximately 2 years in patients with heart failure, 3 years in those with syncope, and 5 years in those with angina.
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      Gardin et al. reported that among symptomatic patients with moderate-to-severe AS treated medically, mortality rates after the onset of symptoms were approximately 25% at 1 year and 50% at 2 years,
      • Gardin J.M.
      • Kaplan K.J.
      • Meyers S.N.
      • et al.
      Aortic stenosis: can severity be reliably estimated noninvasively?.
      with approximately 50% of deaths being sudden. In the elderly high-risk patients in the PARTNER (Placement of Aortic Transcatheter Valve) trial who were treated medically (Cohort B), the survival at 1 year was only 50%.
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      The natural history of AS has changed since the publication of the seminal paper by Morrow and colleagues in 1968.
      • Morrow A.G.
      • Roberts W.C.
      • Ross Jr., J.
      • et al.
      Obstruction to left ventricular outflow Current concepts of management and operative treatment.
      The original data were derived largely from patients with rheumatic AS or AS due to a bicuspid aortic valve, with an average age of death of 63 years. On the contrary, patients being considered for TAVR on a trileaflet valve present much later in life, typically in their late 70s or older, and have dominantly fibrocalcific AS. Although now occurring later in life, the onset of symptoms still heralds a rapid decline with medical therapy alone.
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.

      2.2 Diagnosis

      2.2.1 Echocardiography Versus Catheterization

      Assessment of the severity of stenosis does not differ in TAVR patients compared with the general AS population, and decisions should therefore be based upon established guidelines.
      • Baumgartner H.
      • Hung J.
      • Bermejo J.
      • et al.
      Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice.
      Although invasive cardiac catheterization has historically been the standard for quantification of AS, this function has been largely replaced by echocardiography.
      • Popovic A.D.
      • Thomas J.D.
      • Neskovic A.N.
      • et al.
      Time-related trends in the preoperative evaluation of patients with valvular stenosis.
      Echocardiographic diagnosis is made by the observation of a calcified valve with restricted leaflet opening by two-dimensional (2D) echocardiography with quantification of the peak and mean AV gradient made by applying the simplified Bernoulli equation (Δp = 4v2) to the maximal velocity recorded through the aortic valve by continuous-wave Doppler. Multiple imaging windows (apical 4-chamber and long-axis, right parasternal, suprasternal notch, and subcostal views) should be obtained to assure acquisition of the maximal velocity and to avoid angle-related errors. Although aortic valve area (AVA) can be measured by planimetry, it is more accurately assessed by application of the continuity equation, using pulsed-wave Doppler in the left ventricular outflow tract (LVOT) and continuous-wave Doppler across the valve. Severe stenosis is defined in the guidelines as a peak velocity >4.0 m/s (corresponding to a peak gradient of 64 mm Hg), a mean gradient >40 mm Hg, OR valve area <1.0 cm2 when LV systolic function is normal. To account for patient size, the valve area is often indexed to body surface area, with 0.6 cm2/m2 considered to be the threshold for severe AS. An important exception is when the gradient suggests less severe stenosis than the valve area, most commonly due to low stroke volume, either in dilated ventricles with low ejection fraction (EF) or small ventricles with normal EF. In this setting, a dobutamine stress study (maximum stress dose 20 mcg/kg/min), may be helpful. If the maximum jet velocity rises over 4 m/s with the dobutamine-induced increase in stroke volume whereas the AVA remains less than 1.0 cm2, then the valve is truly severely stenotic. On the other hand, if stroke volume increases with little rise in gradient (causing valve area to increase substantially), then the AS is only mild to moderate in severity, and the LV dysfunction is due to causes other than AS.
      • Blais C.
      • Burwash I.G.
      • Mundigler G.
      • et al.
      Projected valve area at normal flow rate improves the assessment of stenosis severity in patients with low-flow, low-gradient aortic stenosis: the multicenter TOPAS (Truly or Pseudo-Severe Aortic Stenosis) study.
      • Grayburn P.A.
      Assessment of low-gradient aortic stenosis with dobutamine.
      • Monin J.L.
      • Monchi M.
      • Gest V.
      • et al.
      Aortic stenosis with severe left ventricular dysfunction and low transvalvular pressure gradients: risk stratification by low-dose dobutamine echocardiography.
      Occasionally, the AVA appears larger than the elevated gradient would suggest, usually due to elevated stroke volume from aortic regurgitation (AR), anemia, fever, or hyperthyroidism. Sometimes, though, it reflects a technical error in applying the continuity equation, when the blood accelerates within the LVOT due to an upper septal bulge, which may result in an overestimation of valve area. To avoid this, one can try to measure the LVOT area at the point of maximal velocity, though the geometry is often quite distorted in this region, making estimation of the LVOT area difficult. Alternatively, one can use the LV stroke volume (from 2D or three-dimensional [3D] measurements of the LV, ideally with contrast infusion) or right ventricular (RV) stroke volume (from RV outflow tract) as the input into the continuity equation. Dividing this stroke volume by the time velocity integral of the AV continuous-wave Doppler will also yield the AVA, independent of any distortion in the LVOT.
      Despite the convenience and wide-spread applicability of transthoracic echocardiography (TTE), there are occasions when invasive measurements are needed, such as in patients with a discrepancy between clinical and echocardiographic assessments. In such cases, catheterization should generally be performed with dual catheters, 1 placed in the LV, the other in the proximal aorta to obtain simultaneous pressure measurements and obtain the most accurate assessment of the gradient. Infusion of dobutamine may allow assessment of low-output, low-gradient AS in the catheterization laboratory.
      • Nishimura R.A.
      • Grantham J.A.
      • Connolly H.M.
      • et al.
      Low-output, low-gradient aortic stenosis in patients with depressed left ventricular systolic function: the clinical utility of the dobutamine challenge in the catheterization laboratory.
      Other adjunctive testing used in quantifying AS includes transesophageal echocardiography (TEE),
      • Shanewise J.S.
      • Cheung A.T.
      • Aronson S.
      • et al.
      ASE/SCA guidelines for performing a comprehensive intraoperative multiplane transesophageal echocardiography examination: recommendations of the American Society of Echocardiography Council for Intraoperative Echocardiography and the Society of Cardiovascular Anesthesiologists Task Force for Certification in Perioperative Transesophageal Echocardiography.
      CT scanning (dynamic or gated during systole),
      • Greenland P.
      • Bonow R.O.
      • Brundage B.H.
      • et al.
      ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography).
      and CMR.
      • Hundley W.G.
      • Bluemke D.A.
      • Finn J.P.
      • et al.
      ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents.

      2.2.2 Stress Testing

      The presence or absence of symptoms should guide the management of AS patients, yet in many cases, this important clinical benchmark is difficult to establish, owing to the subjective nature of the symptoms and comorbid conditions such as chronic lung disease in this patient population. In general, stress testing is contraindicated when symptoms are present because of the potential for complications in these patients. However, in patients with equivocal symptoms, stress testing, and in particular stress echocardiography, can be very helpful.
      • Lancellotti P.
      • Lebois F.
      • Simon M.
      • et al.
      Prognostic importance of quantitative exercise Doppler echocardiography in asymptomatic valvular aortic stenosis.
      Simple determination of functional capacity may help show limitations of which a patient may be unaware. Isolated echocardiographic (ECG) changes during the stress test without symptoms or change in blood pressure should not be interpreted as a positive indicator of severe AS. Other potential markers for AS severity include signs of LV dysfunction on exercise echo or a rise in left atrial or right ventricular pressure.
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • et al.
      2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease).
      • Vahanian A.
      • Baumgartner H.
      • Bax J.
      • et al.
      Guidelines on the management of valvular heart disease: the Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology.

      2.3 Special Considerations

      2.3.1 Symptom Status

      With severe, symptomatic, calcific AS, AVR is the only effective treatment that improves symptoms and prolongs survival.
      • Connolly H.M.
      • Oh J.K.
      • Orszulak T.A.
      • et al.
      Aortic valve replacement for aortic stenosis with severe left ventricular dysfunction Prognostic indicators.
      • Kvidal P.
      • Bergstrom R.
      • Horte L.G.
      • et al.
      Observed and relative survival after aortic valve replacement.
      These results are partly dependent on LV function. In the setting of LV dysfunction caused by afterload mismatch, survival is still improved, although improvement in LV function and resolution of symptoms might be incomplete after AVR. Age itself is a risk factor for adverse outcome, but it is not a contraindication to AVR even in the very elderly.
      • Kolh P.
      • Kerzmann A.
      • Honore C.
      • et al.
      Aortic valve surgery in octogenarians: predictive factors for operative and long-term results.
      • Litmathe J.
      • Feindt P.
      • Kurt M.
      • et al.
      Aortic valve replacement in octogenarians: outcome and predictors of complications.

      2.3.2 Associated Coronary Artery Disease

      In patients with moderate AS, who are undergoing coronary artery bypass graft surgery (CABG), AVR should be performed at the time of revascularization irrespective of symptoms related to moderate AS.
      • Pereira J.J.
      • Balaban K.
      • Lauer M.S.
      • et al.
      Aortic valve replacement in patients with mild or moderate aortic stenosis and coronary bypass surgery.
      • Smith W.T.
      • Ferguson Jr., T.B.
      • Ryan T.
      • et al.
      Should coronary artery bypass graft surgery patients with mild or moderate aortic stenosis undergo concomitant aortic valve replacement? A decision analysis approach to the surgical dilemma.
      There are no data to support performing AVR for mild AS at the time of CABG. Patients undergoing surgical AVR with significant stenoses (>50% to 70% stenosis) in major coronary arteries should be treated with concomitant CABG. Options in patients with combined AS and CAD continue to grow with the use of hybrid procedures where PCI is followed by valve surgery. It is possible that such a strategy could be performed in the setting of TAVR.
      • Adams D.H.
      • Chikwe J.
      • Filsoufi F.
      • et al.
      The year in cardiovascular surgery.
      • Byrne J.G.
      • Leacche M.
      • Unic D.
      • et al.
      Staged initial percutaneous coronary intervention followed by valve surgery (“hybrid approach”) for patients with complex coronary and valve disease.

      2.3.3 Associated Lesions—AR, MR, Pulmonary Hypertension, TR

      Patients with severe AS often have additional associated significant valvular heart disease. Treatment of these lesions in patients undergoing AVR should be undertaken using standard criteria. However, treatment of associated valvular lesions may increase the risk of AVR.
      • He G.W.
      • Acuff T.E.
      • Ryan W.H.
      • et al.
      Aortic valve replacement: determinants of operative mortality.
      A special circumstance is that of pulmonary hypertension (PH) either primary or secondary (reactive or related to increased LV end-diastolic pressure). Both conditions may increase the risk of AVR and must be taken into consideration in the risk/benefit ratio.
      PH can be present in patients with severe AS, either from the transmission of increased LV diastolic and/or left atrial pressures, associated mitral regurgitation (MR), or from a secondary increase in pulmonary vascular tone. The prevalence of PH in patients with AS is undefined, varying widely on the definition used and the population studied.
      • Pai R.G.
      • Varadarajan P.
      • Kapoor N.
      • et al.
      Aortic valve replacement improves survival in severe aortic stenosis associated with severe pulmonary hypertension.
      • Kapoor N.
      • Varadarajan P.
      • Pai R.G.
      Echocardiographic predictors of pulmonary hypertension in patients with severe aortic stenosis.
      Clinically, PH associated with critical AS portends a poor prognosis and is associated with an increased risk of sudden cardiac death.
      • McHenry M.M.
      • Rice J.
      • Matlof H.J.
      • et al.
      Pulmonary hypertension and sudden death in aortic stenosis.
      Consistent with the surgical valve implant experience, PH after TAVR is a predictive factor for both early (30-day) and late (1-year) mortality, similar in risk to major access site complications and renal insufficiency.
      • Pai R.G.
      • Varadarajan P.
      • Kapoor N.
      • et al.
      Aortic valve replacement improves survival in severe aortic stenosis associated with severe pulmonary hypertension.
      • Rodes-Cabau J.
      • Webb J.G.
      • Cheung A.
      • et al.
      Transcatheter aortic valve implantation for the treatment of severe symptomatic aortic stenosis in patients at very high or prohibitive surgical risk: acute and late outcomes of the multicenter Canadian experience.
      • Ben-Dor I.
      • Goldstein S.A.
      • Pichard A.D.
      • et al.
      Clinical profile, prognostic implication, and response to treatment of pulmonary hypertension in patients with severe aortic stenosis.
      • Cam A.
      • Goel S.S.
      • Agarwal S.
      • et al.
      Prognostic implications of pulmonary hypertension in patients with severe aortic stenosis.
      • Khandhar S.
      • Varadarajan P.
      • Turk R.
      • et al.
      Survival benefit of aortic valve replacement in patients with severe aortic regurgitation and pulmonary hypertension.
      • Zuern C.S.
      • Eick C.
      • Rizas K.
      • et al.
      Prognostic value of mild-to-moderate pulmonary hypertension in patients with severe aortic valve stenosis undergoing aortic valve replacement.
      The presence of PH makes patients more susceptible to any hemodynamic and electrical instability related to the procedure and may increase the risk of postprocedural complications. In addition, PH may result in right heart failure and severe tricuspid regurgitation (TR), both of which complicate management and increase risks.
      In the setting of severe AS and PH several treatment strategies have been used.
      • McLaughlin V.V.
      • Archer S.L.
      • Badesch D.B.
      • et al.
      ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association.
      Persistently elevated left-sided cardiac filling pressures increase the risk of pulmonary edema when challenged with a pulmonary vasodilator. Pulmonary vasodilators, such as nitric oxide, prostacylin, and sildenafil, have been administered during and following cardiac surgery with improved hemodynamic effects.
      • Santini F.
      • Casali G.
      • Franchi G.
      • et al.
      Hemodynamic effects of inhaled nitric oxide and phosphodiesterase inhibitor (dipyridamole) on secondary pulmonary hypertension following heart valve surgery in adults.
      • Fattouch K.
      • Sbraga F.
      • Bianco G.
      • et al.
      Inhaled prostacyclin, nitric oxide, and nitroprusside in pulmonary hypertension after mitral valve replacement.
      • Trachte A.L.
      • Lobato E.B.
      • Urdaneta F.
      • et al.
      Oral sildenafil reduces pulmonary hypertension after cardiac surgery.
      However, their overall clinical utility in improving late survival in the surgical population and their role in TAVR remains unclear. Further investigation is needed to determine the optimal procedural and periprocedural management of patients with AS and PH undergoing TAVR.

      2.3.4 Low Gradient–Low EF

      As mentioned, the combination of overt congestive heart failure and low aortic valve gradient is relatively common. This may be a consequence of excessive afterload (despite left ventricular hypertrophy [LVH]) or reduced contractile function
      • Huber D.
      • Grimm J.
      • Koch R.
      • et al.
      Determinants of ejection performance in aortic stenosis.
      likely due to increased myocardial fibrosis.
      • Herrmann S.
      • Stork S.
      • Niemann M.
      • et al.
      Low-gradient aortic valve stenosis myocardial fibrosis and its influence on function and outcome.
      When there is overt heart failure due to low forward flow and a low transvalvular gradient (mean gradient ≤30 mm Hg), both mechanisms may be present. Because of reduced contractility in the low-flow/low-gradient AS patient, prognosis with surgical AVR is adversely affected with operative mortality as high as 20%. However the 5-year survival is still reported to be better in patients treated surgically.
      • Tribouilloy C.
      • Levy F.
      • Rusinaru D.
      • et al.
      Outcome after aortic valve replacement for low-flow/low-gradient aortic stenosis without contractile reserve on dobutamine stress echocardiography.
      • Quere J.P.
      • Monin J.L.
      • Levy F.
      • et al.
      Influence of preoperative left ventricular contractile reserve on postoperative ejection fraction in low-gradient aortic stenosis.
      When the primary reason for poor LV performance is excessive afterload, the prognosis following surgical AVR is usually good.
      • Carabello B.A.
      • Green L.H.
      • Grossman W.
      • et al.
      Hemodynamic determinants of prognosis of aortic valve replacement in critical aortic stenosis and advanced congestive heart failure.
      In general, patients with low gradient, low EF who have the best prognosis are those with inotropic reserve (shown by an increase in stroke volume with dobutamine infusion), who have limited coronary disease and a mean gradient that although low, still exceeds 20 mm Hg.
      • Tribouilloy C.
      • Levy F.
      • Rusinaru D.
      • et al.
      Outcome after aortic valve replacement for low-flow/low-gradient aortic stenosis without contractile reserve on dobutamine stress echocardiography.

      2.3.5 Basal Septal Hypertrophy—Outflow Tract Gradients

      Although infrequent, proximal septal bulging with LVOT obstruction may present unique issues in the presence of AS. While this can be readily addressed during AVR via myomectomy, such an approach would not be possible with TAVR. Thus, careful preprocedural echocardiographic screening is recommended to specifically avoid this scenario in patients being considered for TAVR.

      3. Current Treatment Options

      3.1 Surgical AVR

      AVR is the only effective treatment considered a Class I recommendation by ACCF/AHA and ESC guidelines in adults with severe symptomatic AS.
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • et al.
      2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease).
      • Vahanian A.
      • Baumgartner H.
      • Bax J.
      • et al.
      Guidelines on the management of valvular heart disease: the Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology.
      Not only does it offer symptomatic relief, the operation improves long-term survival. Since 1960, when AVR was first introduced, advancement in prosthetic technology including improved hemodynamics, durability and thromboresistance, and techniques in cardiac surgery such as cardioplegia, management of the small aortic root, resection of associated subvalvular disease, and replacement of associated aortic aneurysm have resulted in improvements in both operative and long-term results.

      3.1.1 Valve Type

      Current AVR options include mechanical, bioprosthetic, and in specific situations homograft and autograft techniques. Each has their advantages and drawbacks, but the trend in some centers in the recent era has been toward tissue valve replacement in a majority of patients because of improved durability and the lack of requirement for anticoagulation therapy.

      3.1.1.1 Mechanical Valves

      Mechanical valves are now extremely durable, have excellent hemodynamics, and are minimally thrombogenic with adequate anticoagulation. Current anticoagulation is mostly based on Vitamin K antagonists. Newer agents such as oral direct thrombin inhibitors and factor Xa inhibitors have been studied in other patient populations, mainly atrial fibrillation, and have been found to be associated with decreased bleeding risk and minimum drug or food interaction.
      • Kolh P.
      • Wijns W.
      • Danchin N.
      • et al.
      Guidelines on myocardial revascularization.
      They have not been well studied in patients with AVR. With warfarin there is a risk of serious thromboembolism of approximately 0.5% a year and a similar risk of major hemorrhage annually.
      • Toole J.M.
      • Stroud M.R.
      • Kratz J.M.
      • et al.
      Twenty-five year experience with the St Jude medical mechanical valve prosthesis.
      Mechanical valves are typically preferred in younger patients given their reliable long-term durability.

      3.1.1.2 Bioprosthetic Valves

      Compared with mechanical valves, bioprosthetic valves do not require anticoagulation with warfarin, and thus have a lower risk of bleeding. However, long-term durability varies substantially with age for these valves. Structural valve degeneration leading to symptoms or reoperation, commonly associated with calcification of the biologic leaflets, occurs at an average of 10 to 12 years in younger patients and 15 to 18 years in older patients. Actuarial freedom from reoperation following implant of a modern bioprosthetic valves is approximately 95% at 5 years, 90% at 10 years, but drops to 70% at 15 years.
      • Braunwald E.
      Aortic valve replacement: an update at the turn of the millennium.
      Thus, bioprosthetic valves are generally preferred in older patients who are unlikely to tolerate bleeding risk associated with anticoagulation treatment and in whom a 15-year durability is reasonable. In patients with bioprosthetic valves, if prosthetic dysfunction occurs, TAVR may play an important role in solving the clinical issues in the future.

      3.1.2 Procedural Hazards

      Current data from the Society of Thoracic Surgeons (STS) registry documents a mortality that is under 3% for all patients undergoing AVR. As with any procedure, operative mortality is strongly correlated with the severity of the disease and comorbidity of patients. The operative risks can be estimated with online risk calculators from the STS (http://209.220.160.181/STSWebRiskCalc261/) and the European System for Cardiac Operative Risk Evaluation (www.euroscore.org).
      • Nashef S.A.
      • Roques F.
      • Hammill B.G.
      • et al.
      Validation of European System for Cardiac Operative Risk Evaluation (EuroSCORE) in North American cardiac surgery.
      • Shroyer A.L.
      • Coombs L.P.
      • Peterson E.D.
      • et al.
      The Society of Thoracic Surgeons: 30-day operative mortality and morbidity risk models.
      In selected patients with minimal comorbidity, mortality and major morbidity are under 1% each in many centers. In general, perioperative stroke rates are 1.5% (with major life-debilitating stroke being somewhat less) and other major complications are relatively rare. Renal failure, pulmonary failure, and gastrointestinal complications are not common. As older, more frail patients with extensive comorbidities undergo AVR, the risk of death and morbidity as well as length of hospitalization increases significantly.
      Society of Thoracic Surgeons national cardiac surgery database.
      • O’Brien S.M.
      • Shahian D.M.
      • Filardo G.
      • et al.
      The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 2—isolated valve surgery.
      In addition to comorbidity, preoperative functional performance is also a maker of postoperative morbidity/mortality.
      A recent study reviewed the results of high-risk surgical AVR in 4 centers with significant experience. The patients were a mean age of 76 and the mean STS predicted risk of mortality was 16.3%. Complications included stroke in 4.4%, new permanent pacemaker in 5%, multisystem organ failure in 6.9%, pneumonia in 7.5%, and dialysis in 8.2%. Postoperative length of stay was 12.6 days and in-hospital mortality was 16.4%. One-, 3- and 5-year survival was 70.9%, 56.8%, and 47.4%. This study was performed between 2002 and 2007 in 4 centers before participation in the PARTNER Trial commenced and therefore serves as a reasonable baseline for comparing the results of TAVR.
      • Thourani V.H.
      • Ailawadi G.
      • Szeto W.Y.
      • et al.
      Outcomes of surgical aortic valve replacement in high-risk patients: a multiinstitutional study.

      3.1.3 Patient Selection

      Patient selection for AVR for AS is well outlined by ACCF/AHA and ESC guidelines.
      • Vahanian A.
      • Baumgartner H.
      • Bax J.
      • et al.
      Guidelines on the management of valvular heart disease: the Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology.
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • et al.
      ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease).
      Problems arise when the clinicians and patients note significant symptoms and significant structural disease that are complicated by the presence of significant comorbidity. Although current STS risk score and EuroSCORE give information concerning short-term operative risks and benefits, they are not able to predict symptom resolution, quality-of-life improvement, or return to independent living.

      3.1.3.1 Use of STS and euroscore Models in Patient Selection for Conventional AVR

      Although a number of risk algorithms for cardiac surgery have been developed, the STS and logistic EuroSCORE are the most commonly used. Although both are accurate in low-risk patients, accuracy is less in higher-risk subsets. These 2 scores include different covariates. The logistic EuroSCORE is based on 12 covariates derived from 14,799 patients undergoing all types of cardiac operations (mostly coronary bypass) in 8 European countries in 1995. On the other hand, the STS risk predictor is based on 24 covariates derived from 67,292 patients undergoing isolated AVR only in the United States over a relatively more contemporary period between 2002 and 2006. The STS model is the standard most commonly used in the United States.

      3.1.3.2 Patient Risk of AVR

      Information from the STS National Database shows that the operative mortality for isolated AVR has declined from 3.4% in 2002 to 2.6% today (http://www.sts.org/sites/default/files/documents/20112ndHarvestExecutiveSummary.pdf). The most important preoperative patient risk factors are the need for emergency surgery, the presence of endocarditis, and a history of previous cardiac surgery. The present models do not include some risk factors that may be particularly important in the prediction of outcomes for very high-risk populations including frailty, PH, porcelain aorta, and the presence of hepatic dysfunction, although all have been added to a recent upgraded version.
      • Melby S.J.
      • Moon M.R.
      • Lindman B.R.
      • et al.
      Impact of pulmonary hypertension on outcomes after aortic valve replacement for aortic valve stenosis.
      • Sundermann S.
      • Dademasch A.
      • Praetorius J.
      • et al.
      Comprehensive assessment of frailty for elderly high-risk patients undergoing cardiac surgery.
      It should be emphasized that risk models serve as 1 aspect of patient selection, but need to be considered in concert with clinical judgment and the other methods of risk assessment. In the final analysis, patient risk and benefit is determined, not by statistical models, but by the experience, knowledge, and expertise of the physicians charged with rendering care.

      3.1.3.2.1 Specific Surgical Risks

      3.1.3.2.1.1 Stroke

      Although ischemic stroke can result from many causes after AVR, a major concern is the role of thromboembolism. The risks of thromboembolism are usually greater in the first few days and months after bioprosthetic AVR implantation before the sewing ring of the prosthesis is endothelialized
      • Heras M.
      • Chesebro J.H.
      • Fuster V.
      • et al.
      High risk of thromboemboli early after bioprosthetic cardiac valve replacement.
      ; risks after mechanical AVR continue. The risk of stroke within 30 days among 67,292 cases of AVR in the STS Registry was 1.5%; this data set was used to develop a model for predicting 30-day stroke risk.
      • O’Brien S.M.
      • Shahian D.M.
      • Filardo G.
      • et al.
      The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 2—isolated valve surgery.
      Within the STS database among 108,687 AVR operations between 1996 through 2006, the risk of in-hospital permanent stroke decreased 21% from 1.7% to 1.3%.
      • Brown J.M.
      • O’Brien S.M.
      • Wu C.
      • et al.
      Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons National Database.
      It is important to note, however, that independent neurological assessment was not done in these patients, so the actual stroke incidence in these patients may be underestimated. Overall, embolic stroke risks are greater with mechanical valves, which require long-term oral anticoagulation, than with bioprosthetic valves, which have a 0.7% per year risk of thromboembolism in patients with normal sinus rhythm without warfarin anticoagulation.
      • Bloomfield P.
      • Wheatley D.J.
      • Prescott R.J.
      • et al.
      Twelve-year comparison of a Bjork-Shiley mechanical heart valve with porcine bioprostheses.
      Of note, many AVR patients are older, with other comorbid cardiac conditions that increase stroke risk, including atrial fibrillation, cardiomyopathy, and carotid stenosis or aortic arch atheroma.
      • Goldstein L.B.
      • Bushnell C.D.
      • Adams R.J.
      • et al.
      Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      However, even carefully selected octogenarians can safely undergo AVR with a 2% incidence of stroke.
      • Kolh P.
      • Kerzmann A.
      • Honore C.
      • et al.
      Aortic valve surgery in octogenarians: predictive factors for operative and long-term results.
      • Ferrari E.
      • Tozzi P.
      • Hurni M.
      • et al.
      Primary isolated aortic valve surgery in octogenarians.
      Because of the risk of stroke, the 2006 ACC/AHA guidelines for the management of patients with valvular heart disease include a variety of recommendations regarding the use of antithrombotic therapy to reduce thromboembolism risk after AVR.
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • et al.
      ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease).
      The choice of antithrombotic agents include warfarin with target international normalized ratios (INRs) typically in the range from 2.0 to 4.0 depending on the specific prosthesis, aspirin 75 mg to 325 mg per day, and clopidogrel 75 mg per day, as well as combinations. Recommendations depend upon the type of valve, timing after surgery, presence or absence of risk factors such as atrial fibrillation, and ability of the patient to take warfarin or aspirin.
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • et al.
      ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease).
      Given the greater risk of thromboembolism, particularly stroke, which usually occurs within the first 72 hours post-procedure, many centers start heparin (target aPTT 55 s to 70 s) as soon as the risk of surgical postoperative bleeding is acceptable, which is usually within 48 hours of surgery. Heparin can be discontinued when warfarin therapy reaches a therapeutic INR usually above 2.0.
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • et al.
      ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease).

      3.1.3.2.1.2 Other Complications

      Aside from other surgical complications of renal, hepatic, neurological, and pulmonary disease compromise, a major risk of conventional AVR is sternal wound infection. In most centers, this risk is under 1% for deep infection, but the risk of any type of infection is still present and particularly increased in patients with diabetes, obesity, smoking, immunosuppressive therapy, and prior radiation therapy. With the advent of negative pressure wound therapy and continued advances in surgical technique, these risks are now rarely fatal, but remain morbid. Blood requirement after valve replacement can lead to hepatitis C, human immunodeficiency virus, or other viral infection. These transfusion-acquired infections are now extremely rare due to transfusion guidelines and systems precautions.

      3.1.3.3 Prohibitive Risk, Extreme Risk, Inoperability

      Despite substantial contemporary experience with successful AVR in elderly patients, multiple series have documented that 30% to 40% of patients with severe AS do not undergo surgery owing to advanced age, LV dysfunction, multiple coexisting conditions, and patient preference or physician recommendation.
      • Bach D.S.
      • Cimino N.
      • Deeb G.M.
      Unoperated patients with severe aortic stenosis.
      • Bach D.S.
      • Siao D.
      • Girard S.E.
      • et al.
      Evaluation of patients with severe symptomatic aortic stenosis who do not undergo aortic valve replacement: the potential role of subjectively overestimated operative risk.
      • Dua A.
      • Dang P.
      • Shaker R.
      • et al.
      Barriers to surgery in severe aortic stenosis patients with Class I indications for aortic valve replacement.
      • Iung B.
      • Baron G.
      • Butchart E.G.
      • et al.
      A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on Valvular Heart Disease.
      • Iung B.
      • Cachier A.
      • Baron G.
      • et al.
      Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery?.
      • Varadarajan P.
      • Kapoor N.
      • Bansal R.C.
      • et al.
      Clinical profile and natural history of 453 nonsurgically managed patients with severe aortic stenosis.
      The definitions used to describe patient populations considered for TAVR vary; for example, prohibitive risk would describe a patient in whom the procedure could be performed from a technical standpoint but would be associated with prohibitively high morbidity and mortality.
      • Bouma B.J.
      • van Der Meulen J.H.
      • van Den Brink R.B.
      • et al.
      Variability in treatment advice for elderly patients with aortic stenosis: a nationwide survey in the Netherlands.
      Inoperability might identify a patient group in whom technical success would not be possible; for example, no vascular access. Different trials have used these terms for patient enrollment; for example, the CoreValve Trial identifies extreme risk, whereas the PARTNER (Placement of AoRtic TraNscathetER Valve) Trial used the term inoperable. For this document, we prefer the term prohibitive risk. This includes some patients in whom surgery might be deemed unsuitable based on the physician’s assessment of the patient’s risk for surgery; whereas in others, the surgeon may decide that the operation cannot be performed successfully because of technical considerations. Assessment of inoperability is also driven by surgeon and institutional experience and thus varies. The incidence of patients undergoing AVR with an STS predicted risk of mortality >5% is low but vary significantly amongst institutions and may be related to volume and referral patterns. Experience with such patients is pivotal for TAVR teams. Referral to such team and another opinion/consultation is crucial before deeming a patient inoperable. Whereas practice guidelines have been developed to assist physicians and surgeons in determining appropriate use of treatment options,
      • Vahanian A.
      • Baumgartner H.
      • Bax J.
      • et al.
      Guidelines on the management of valvular heart disease: the Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology.
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • et al.
      ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease).
      there are, however, no specific recommendations for defining inoperability. Current ACCF/AHA guidelines acknowledge that special considerations are required for the management of advanced elderly patients with AS, since age-related and comorbid conditions commonly exist in patients in their 80s and 90s even though AVR is technically feasible even in this group.
      • Brown J.M.
      • O’Brien S.M.
      • Wu C.
      • et al.
      Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons National Database.
      • Varadarajan P.
      • Kapoor N.
      • Bansal R.C.
      • et al.
      Survival in elderly patients with severe aortic stenosis is dramatically improved by aortic valve replacement: results from a cohort of 277 patients aged > or =80 years.
      In the absence of literature evidence and guidelines recommendations, the determination of inoperability in any given patient depends on the judgment of the medical team. It is generally agreed that patients with limited life expectancy due to concurrent conditions such as malignancy, dementia, primary liver disease, chronic obstructive pulmonary disease (COPD), among others, are not appropriate for AVR. Frailty and related conditions of debility and deconditioning are known to result in inability to recover from major heart surgery such as AVR, despite operative survival and hospital discharge.
      • Sundermann S.
      • Dademasch A.
      • Praetorius J.
      • et al.
      Comprehensive assessment of frailty for elderly high-risk patients undergoing cardiac surgery.
      These conditions can potentially contribute to increased surgical mortality and morbidity in the elderly.
      • Mihaljevic T.
      • Nowicki E.R.
      • Rajeswaran J.
      • et al.
      Survival after valve replacement for aortic stenosis: implications for decision making.
      Inoperability from the surgeon’s judgment may result from technical considerations that preclude safe performance of AVR, such as prior mediastinal irradiation, porcelain aorta or severe periannular calcification, severe aortic atheromatous disease, prior cardiac operations, among others including the internal mammary artery crossing the midline. Although infrequent, aortic valve bypass with a LV apex-to-descending aortic conduit has been used in some patients with severe AS judged to be inoperable via a mediastinal approach and cardiopulmonary bypass.
      • Gammie J.S.
      • Brown J.W.
      • Brown J.M.
      • et al.
      Aortic valve bypass for the high-risk patient with aortic stenosis.
      In summary, a substantial percentage of patients with AS are judged to be inoperable for surgery based primarily on the physician’s or surgeon’s determination of operative risk and survivability. Although some patients may be found to be inoperable for technical and surgical reasons, most inoperable patients are felt to be too ill from associated comorbid conditions.

      3.2 Alternatives to AVR

      3.2.1 Medical Therapy

      There are no proven medical treatments to prevent or delay the disease process in the aortic valve leaflets. However, evaluation and modification of cardiac risk factors is important in patients with aortic valve disease to prevent concurrent coronary artery disease (CAD). The association of AS with risk factors similar to those associated with atherosclerosis
      • Ghaisas N.K.
      • Foley J.B.
      • O’Briain D.S.
      • et al.
      Adhesion molecules in nonrheumatic aortic valve disease: endothelial expression, serum levels and effects of valve replacement.
      • Otto C.M.
      • Kuusisto J.
      • Reichenbach D.D.
      • et al.
      Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis Histological and immunohistochemical studies.
      had suggested that intervention may be possible to slow or prevent disease progression in the valve leaflet,
      • Palta S.
      • Pai A.M.
      • Gill K.S.
      • et al.
      New insights into the progression of aortic stenosis: implications for secondary prevention.
      • Rajamannan N.M.
      • Otto C.M.
      Targeted therapy to prevent progression of calcific aortic stenosis.
      but prospective, randomized, placebo-controlled trials failed to demonstrate a benefit of statins in reducing the progression of aortic valve stenosis.
      Longer-term palliative medical management of symptomatic AS may be appropriate for patients who are either not candidates for aortic valve surgery due to comorbidities or in patients who refuse AVR. The overall goal of medical therapy is to treat coexisting cardiovascular conditions, and treat superimposed diseases that often exacerbate the disease process. Patients should be educated about the effects of sodium intake, change in weight, and other factors that may lead to clinical decompensation. Medical therapy should be judicious and include treating concurrent cardiovascular conditions such as correction of anemia and fever, and preventative measures such as pneumococcal or influenza vaccination. Given the severe hypertrophy, optimizing hemodynamics by maintaining sinus rhythm may help with symptom stabilization.
      Even with optimal care, adults with severe symptomatic inoperable AS will have exacerbations of symptoms and frequent hospitalizations. Palliative care should include end-of-life discussions and counseling as appropriate. Counseling is also indicated regarding true risk of AVR, and the importance of accurate risk prediction cannot be overemphasized. Many patients may refuse surgery based on misunderstood operative risk.

      3.2.2 Balloon Aortic Valvuloplasty

      First reported in 1986,
      • Cribier A.
      • Savin T.
      • Saoudi N.
      • et al.
      Percutaneous transluminal valvuloplasty of acquired aortic stenosis in elderly patients: an alternative to valve replacement?.
      balloon aortic valvuloplasty was considered to be a less invasive and safe alternative to AVR, particularly in high surgical risk patients with multiple medical comorbidities. Although balloon aortic valvuloplasty results in immediate hemodynamic improvement with a significant decrease in transvalvular gradients resulting in larger valve area, it does not result in sustained clinical improvement because of high recurrence rates; restenosis or recoil of the aortic valve usually occurs within 6 months. Patients treated with balloon aortic valvuloplasty alone have shown poor prognosis, with survival rates of 50% at 1 year, 35% at 2 years, and 20% at 3 years.
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      • Ben-Dor I.
      • Pichard A.D.
      • Satler L.F.
      • et al.
      Complications and outcome of balloon aortic valvuloplasty in high-risk or inoperable patients.
      • Lieberman E.B.
      • Bashore T.M.
      • Hermiller J.B.
      • et al.
      Balloon aortic valvuloplasty in adults: failure of procedure to improve long-term survival.
      • Otto C.M.
      • Mickel M.C.
      • Kennedy J.W.
      • et al.
      Three-year outcome after balloon aortic valvuloplasty Insights into prognosis of valvular aortic stenosis.
      In addition, serious complications due to balloon aortic valvuloplasty occur in 15% to 25% of patients.
      • Ben-Dor I.
      • Pichard A.D.
      • Satler L.F.
      • et al.
      Complications and outcome of balloon aortic valvuloplasty in high-risk or inoperable patients.
      Percutaneous balloon aortic valvuloplasty Acute and 30-day follow-up results in 674 patients from the NHLBI Balloon Valvuloplasty Registry.
      • Ben-Dor I.
      • Maluenda G.
      • Looser P.M.
      • et al.
      Outcomes of concomitant percutaneous coronary intervention and balloon aortic valvuloplasty.
      Balloon aortic valvuloplasty, therefore, should not be used as a substitute for AVR in patients who are candidates for surgical AVR. Even as a palliative treatment, balloon aortic valvuloplasty data suggest that there is much uncertainty regarding improved longevity or quality of life after the procedure with a mean duration of symptom improvement of only 1 year.
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • et al.
      ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease).
      • Hara H.
      • Pedersen W.R.
      • Ladich E.
      • et al.
      Percutaneous balloon aortic valvuloplasty revisited: time for a renaissance?.
      There has been no significant difference in long-term survival demonstrated between patients undergoing balloon aortic valvuloplasty and those undergoing medical therapy alone.
      • Otto C.M.
      • Mickel M.C.
      • Kennedy J.W.
      • et al.
      Three-year outcome after balloon aortic valvuloplasty Insights into prognosis of valvular aortic stenosis.
      Although balloon aortic valvuloplasty as a stand-alone treatment is not recommended,
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • et al.
      ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease).
      Percutaneous balloon aortic valvuloplasty Acute and 30-day follow-up results in 674 patients from the NHLBI Balloon Valvuloplasty Registry.
      • Ben-Dor I.
      • Maluenda G.
      • Looser P.M.
      • et al.
      Outcomes of concomitant percutaneous coronary intervention and balloon aortic valvuloplasty.
      it may still be used in contemporary practice as a bridge to subsequent AVR (both Class IIb, Level of Evidence C recommendation).
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • et al.
      2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease).
      • Ben-Dor I.
      • Pichard A.D.
      • Satler L.F.
      • et al.
      Complications and outcome of balloon aortic valvuloplasty in high-risk or inoperable patients.
      • Ussia G.P.
      • Capodanno D.
      • Barbanti M.
      • et al.
      Balloon aortic valvuloplasty for severe aortic stenosis as a bridge to high-risk transcatheter aortic valve implantation.
      In the current era of TAVR, there has been increased interest in balloon aortic valvuloplasty. In this setting, balloon aortic valvuloplasty may be used to assess whether there is initial clinical improvement, in which case, then the patient may be a candidate for TAVR.

      4. Transcatheter Aortic Valve Replacement

      4.1 Background and History

      Given the increased mortality and morbidity of AVR surgery for high-risk patients and the poor long-term results of balloon aortic valvuloplasty, there has been interest in the development of a percutaneously delivered aortic heart valve.
      • Chiam P.T.
      • Ruiz C.E.
      Percutaneous transcatheter aortic valve implantation: assessing results, judging outcomes, and planning trials: the interventionalist perspective.
      As early as 1992, investigators evaluated stent-based porcine bioprostheses delivered to various aortic sites in animal models.
      • Andersen H.R.
      • Knudsen L.L.
      • Hasenkam J.M.
      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.
      This early work culminated in 2000 with implantation of a percutaneous heart valve in a 12-year-old patient with a failing right ventricular to pulmonary arterial conduit that had been placed 8 years previously for the treatment of pulmonary atresia and ventricular septal defect. This initial seminal experience was followed in 2002 by the first human TAVR using the antegrade approach to implant a balloon expandable equine pericardial leaflet stent valve.
      • Cribier A.
      • Eltchaninoff H.
      • Bash A.
      • et al.
      Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description.
      Since that early experience, there have been multiple iterations and a number of new designs.

      4.2 Device Description

      At the present time, the most data available for TAVR are based upon 2 specific devices—the Sapien valve (Figure 1) Edwards Life Sciences, Inc, Irvine, Calif) and the CoreValve (Figure 2) (Medtronic, Inc, Minneapolis, Minn). The most recent iteration of the former is a trileaflet bovine pericardial valve mounted with a tubular slotted balloon-expandable stent composed of a cobalt chromium alloy. The Sapien valve is available in 23-mm and 26-mm sizes in the United States and 23-mm, 26-mm, and 29-mm sizes in Europe. The initial devices required a 22- or 24-French sheath for delivery of the prosthesis. Recent iterations (NovaFlex) have decreased this to 18-French. The first and second generations of this device have been tested in randomized controlled trials for both transfemoral and transapical implantation.
      Figure thumbnail gr1
      Figure 1Sapien valve.
      Source: Edwards Lifesciences.
      Figure thumbnail gr2
      Figure 2CoreValve. The Medtronic CoreValve System is currently limited to investigational use in the United States.
      Source: Medtronic, Inc.
      The second device (CoreValve) is comprised of 3 porcine pericardial tissue leaflets mounted in a self-expanding nitinol frame. It is available in 3 sizes—26 mm, 29 mm, and 31 mm. This valve has also continued to iterate, with the initial devices being 25-French, but now 18-French delivery sheaths are used. This valve has only been used by a retrograde approach—either via transfemoral, subclavian, or direct aortic access.
      A wide range of new devices has been tested with some first-in-man experiences. These devices have been characterized by smaller size, the ability to reposition or even recapture the device after deployment if an optimized device position is not obtained initially, and, modular prosthetic elements to design in situ more optimal conformance to the natural valve and aortic annulus among others.
      Specific anatomic issues must be considered in device design. These include the rigid structure of the pattern of valvular calcification and aortic annulus, and the need for as full apposition as possible to the annulus in an attempt to minimize periprosthetic leak which, given sometimes eccentric, bulky calcification, may be difficult. The close proximity to the coronary ostia, the width and height of the sinuses, the membranous ventricular septum with the His bundle and the anterior leaflet of the mitral valve are also important anatomical considerations. In addition, the size and degree of severity of peripheral arterial disease are all factors that could limit catheter size. Other issues include avoidance of central prosthetic leak, leaflet durability, hemodynamic performance, ability to treat both tricuspid and bicuspid valve anatomy, surfaces designed to minimize thrombogenicity, and the need to optimally position the devices and retrieve and reposition when necessary.
      • Chiam P.T.
      • Ruiz C.E.
      Percutaneous transcatheter aortic valve implantation: evolution of the technology.
      Fundamental issues for all current and future devices are hemodynamic results, valve durability, and residual or new aortic regurgitation (AR). The initial hemodynamic performance of TAVR valves must be similar or superior to that obtained with surgical AVR. This is crucial because high residual transprosthetic gradients result in less symptomatic improvement and poorer regression of left ventricular mass.
      • Dalmau M.J.
      • Gonzalez-Santos J.M.
      • Blazquez J.A.
      • et al.
      Hemodynamic performance of the Medtronic Mosaic and Perimount Magna aortic bioprostheses: five-year results of a prospectively randomized study.
      These transprosthetic gradients are a function of prosthetic size as well as the specific type of prosthesis and can result in patient–prosthesis mismatch. Typical immediate postprocedural gradients after surgical AVR range from 8 mm Hg to 12 mm Hg, whereas the AV area or effective orifice area (EOA) ranges from 1.4 to 1.9 cm2. As documented below in the PARTNER trial, the valve hemodynamics of the TAVR early on are approximately 10% better than the specific surgical aortic prostheses used in that trial.
      There are only limited clinical data on the durability of TAVR valves—up to 2 years—in the PARTNER trial and up to 5 years in other registry experiences. Although the absolute number of patients is small, there have been no reports of structural valve deterioration. The fundamental clinical need for durability may depend in part on the specific patient population. In the PARTNER trial, the mean age at implant was 83 years, and serious comorbidities were frequent. In this setting, the need for durability of 20 years is less important than if the patient selection criteria are broadened to include patients in their early to mid 60s who have isolated AS without comorbid conditions. In this latter group, the TAVR valve must have at least equivalent clinical durability to currently available surgically implanted valves.

      4.3 Current State of the Evidence

      4.3.1 Registry Experience

      Registry data provide important information for assessing the role of TAVR in a large number of patients who are not eligible for randomized controlled trials because of strict selection criteria. Several multicenter registries, including Edwards Lifesciences and Medtronic CoreValve (Table 1, Table 2), have reported early and late outcomes with TAVR. However, patient selection criteria varied amongst the different registries; standardized definitions for clinical events such as those described by the Valve Academic Research Consortium (VARC)
      • Leon M.B.
      • Piazza N.
      • Nikolsky E.
      • et al.
      Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium.
      were not used; and endpoints were not prospectively adjudicated using a blinded clinical event committee.
      Table 1Edwards Sapien transcatheter heart valve registries
      CharacteristicREVIVE, REVIVAL, PARTNER EU (N = 222)SOURCE registry (TF) (N = 920)France registry (N = 1137)Belgium registry (N = 303)Canada registry (TF) (N = 162)
      Demographics
      Age (y)8382838383
      Female (%)5556494644
      EuroSCORE (mean, %)2624232926
      NYHA functional class III/IV (%)8976758093
      Aortic valve area (cm2)0.590.700.670.600.63
      Mean gradient (mm Hg)4549484748
      Prior CABG (%)2615192030
      Ejection fraction (%)5152535055
      Outcomes
      30-day mortality (%)10.47.57.889.5
      1-y mortality (%)2418.9NRNRNR
      Stroke (%)3.33.53.55.03.0
      Major vascular complications (%)27.911.311.3NR13.1
      Permanent pacemaker (%)1.86.78.54.03.6
      Data are derived from the Edwards Lifesciences briefing document for the U.S. Food and Drug Administration (FDA) Circulatory Devices Advisory Panel meeting on TAVR on July 21, 2011 (http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/CirculatorySystemDevicesPanel/ucm240575.htm).
      CABG, Coronary artery bypass graft; NR, not reported; NYHA, New York Heart Association; TF, transfemoral.
      Table 2Medtronic CoreValve transcatheter heart valve registries
      CharacteristicTamburino et al
      • Tamburino C.
      • Capodanno D.
      • Ramondo A.
      • et al.
      Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis.
      (N = 663)
      Milan
      • Godino C.
      • Maisano F.
      • Montorfano M.
      • et al.
      Outcomes after transcatheter aortic valve implantation with both Edwards-SAPIEN and CoreValve devices in a single center: the Milan experience.
      (N = 61)
      French
      • Eltchaninoff H.
      • Prat A.
      • Gilard M.
      • et al.
      Transcatheter aortic valve implantation: early results of the FRANCE (FRench Aortic National CoreValve and Edwards) registry.
      (N = 66)
      Spanish
      • Avanzas P.
      • Munoz-Garcia A.J.
      • Segura J.
      • et al.
      Percutaneous implantation of the CoreValve self-expanding aortic valve prosthesis in patients with severe aortic stenosis: early experience in Spain.
      (N = 108)
      UK/Ireland
      • Moynagh A.M.
      • Scott D.J.
      • Baumbach A.
      • et al.
      CoreValve transcatheter aortic valve implantation via the subclavian artery: comparison with the transfemoral approach.
      (N = 288)
      UK
      • Moat N.E.
      • Ludman P.
      • de Belder M.A.
      • et al.
      Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) registry.
      (N = 452)
      German
      • Zahn R.
      • Gerckens U.
      • Grube E.
      • et al.
      Transcatheter aortic valve implantation: first results from a multi-centre real-world registry.
      (N = 588)
      Buellesfeld et al
      • Buellesfeld L.
      • Gerckens U.
      • Schuler G.
      • et al.
      2-year follow-up of patients undergoing transcatheter aortic valve implantation using a self-expanding valve prosthesis.
      (N = 126)
      Demographics
      Age (y)827982.578.68181.381.481.9
      Female (%)564751.554.6NR4855.857.1
      EuroSCORE (mean, %)2326.624.7162218.120.823.4
      NYHA functional class III/IV (%)71.56974.658.47473.988.274.6
      Mean gradient (mm Hg)52544655NRNR48.746.8
      Outcomes
      Procedural success (%)9898.492.698.197.598.2NR72.6
      30-day mortality (%)5.92.215.17.44.75.812.415.2
      1-y mortality (%)1518.4
      6-month survival,
      NR17.7NR21.7NR38.1
      2-year survival.
      Stroke (%)2.52.24.50.04.24.02.8NR
      Major vascular complications (%)2.021.37.55.69.06.24.0NR
      Permanent pacemaker (%)19.126.125.735.22624.442.526.2
      N, Number; NR, not reported; NYHA, New York Heart Association.
      6-month survival,
      ∗∗ 2-year survival.
      CoreValve system real-world clinical experience to date is comprised of multiple registries from several participating national sites.
      • Avanzas P.
      • Munoz-Garcia A.J.
      • Segura J.
      • et al.
      Percutaneous implantation of the CoreValve self-expanding aortic valve prosthesis in patients with severe aortic stenosis: early experience in Spain.
      • Buellesfeld L.
      • Gerckens U.
      • Schuler G.
      • et al.
      2-year follow-up of patients undergoing transcatheter aortic valve implantation using a self-expanding valve prosthesis.
      • Eltchaninoff H.
      • Prat A.
      • Gilard M.
      • et al.
      Transcatheter aortic valve implantation: early results of the FRANCE (FRench Aortic National CoreValve and Edwards) registry.
      • Godino C.
      • Maisano F.
      • Montorfano M.
      • et al.
      Outcomes after transcatheter aortic valve implantation with both Edwards-SAPIEN and CoreValve devices in a single center: the Milan experience.
      • Moynagh A.M.
      • Scott D.J.
      • Baumbach A.
      • et al.
      CoreValve transcatheter aortic valve implantation via the subclavian artery: comparison with the transfemoral approach.
      • Tamburino C.
      • Capodanno D.
      • Ramondo A.
      • et al.
      Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis.
      • Zahn R.
      • Gerckens U.
      • Grube E.
      • et al.
      Transcatheter aortic valve implantation: first results from a multi-centre real-world registry.
      • Moat N.E.
      • Ludman P.
      • de Belder M.A.
      • et al.
      Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) registry.
      These study sizes range from 61 to 663 patients, with a combined clinical patient experience of nearly 2350 patients that includes follow-up of up to 2 years. (See Table 2 for details.)

      4.3.1.1 Demographics

      Table 1, Table 2 summarize the major patient characteristics for the Sapien and CoreValve family of registries, respectively. The patients selected for entry are elderly (average age typically over 80 years), with symptomatic severe AS (mean gradient ≥45 mm Hg), significant comorbidities, and an average EuroSCORE of ≥23 (Sapien) and >16 (CoreValve),
      • Avanzas P.
      • Munoz-Garcia A.J.
      • Segura J.
      • et al.
      Percutaneous implantation of the CoreValve self-expanding aortic valve prosthesis in patients with severe aortic stenosis: early experience in Spain.
      • Buellesfeld L.
      • Gerckens U.
      • Schuler G.
      • et al.
      2-year follow-up of patients undergoing transcatheter aortic valve implantation using a self-expanding valve prosthesis.
      • Eltchaninoff H.
      • Prat A.
      • Gilard M.
      • et al.
      Transcatheter aortic valve implantation: early results of the FRANCE (FRench Aortic National CoreValve and Edwards) registry.
      • Godino C.
      • Maisano F.
      • Montorfano M.
      • et al.
      Outcomes after transcatheter aortic valve implantation with both Edwards-SAPIEN and CoreValve devices in a single center: the Milan experience.
      • Moynagh A.M.
      • Scott D.J.
      • Baumbach A.
      • et al.
      CoreValve transcatheter aortic valve implantation via the subclavian artery: comparison with the transfemoral approach.
      • Tamburino C.
      • Capodanno D.
      • Ramondo A.
      • et al.
      Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis.
      • Zahn R.
      • Gerckens U.
      • Grube E.
      • et al.
      Transcatheter aortic valve implantation: first results from a multi-centre real-world registry.
      indicating a significant risk with conventional AVR. However, unlike the PARTNER trial, all of these registries used the EuroSCORE risk prediction system for defining high risk and inoperability. EuroSCORE is generally not regarded as valid in high-risk patients for surgical AVR, and surgeon input as to operability was not required in these registries. As a result, the registry results are difficult to interpret because it is unclear whether the patients who were enrolled in these registries were truly “inoperable” versus “high-risk.”
      • Zahn R.
      • Gerckens U.
      • Grube E.
      • et al.
      Transcatheter aortic valve implantation: first results from a multi-centre real-world registry.
      • Thomas M.
      • Schymik G.
      • Walther T.
      • et al.
      Thirty-day results of the SAPIEN aortic Bioprosthesis European Outcome (SOURCE) Registry: a European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve.

      4.3.1.2 Outcomes

      4.3.1.2.1 Procedural Success and Hazards

      In the SOURCE (SAPIEN Aortic Biosprosthesis European Outcome) registry, procedural success rate (defined as 1 valve implanted, AR <2+, and patient left procedure room alive) was 93% for transfemoral TAVR and 92% for transapical TAVR. The procedural success rate reported for CoreValve is >92% except for 1 study that enrolled very high-risk patients.
      • Buellesfeld L.
      • Gerckens U.
      • Schuler G.
      • et al.
      2-year follow-up of patients undergoing transcatheter aortic valve implantation using a self-expanding valve prosthesis.
      Significant variations between registries were not observed in terms of deployment, relief of obstruction and avoidance of significant AR.
      • Zahn R.
      • Gerckens U.
      • Grube E.
      • et al.
      Transcatheter aortic valve implantation: first results from a multi-centre real-world registry.
      • Thomas M.
      • Schymik G.
      • Walther T.
      • et al.
      Thirty-day results of the SAPIEN aortic Bioprosthesis European Outcome (SOURCE) Registry: a European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve.

      4.3.1.2.2 Early and Late Morbidity and Mortality

      The early and late major outcomes with Sapien and CoreValve registries are summarized in Table 1, Table 2. The early morbidity of TAVR includes strokes, coronary occlusion, pacemaker implantation, vascular complications, renal failure, cardiac rupture and tamponade, bleeding, aortic dissection, and death. The overall risk of any 30-day major complication ranges from 20% to over 40%. Early mortality ranges from an in-hospital rate of 5% to 8% and a 30-day mortality rate from 8% to 10%. In the SOURCE registry, the incidence of a major bleeding event was significantly greater among patients undergoing transapical versus transfemoral TAVR (3.9% vs 2.3%), whereas the incidence of vascular access-related complications was significantly higher among patients having transfemoral TAVR (major—11.3% vs 2.0%; minor—10.4% vs 1.0%).
      • Zahn R.
      • Gerckens U.
      • Grube E.
      • et al.
      Transcatheter aortic valve implantation: first results from a multi-centre real-world registry.
      • Thomas M.
      • Schymik G.
      • Walther T.
      • et al.
      Thirty-day results of the SAPIEN aortic Bioprosthesis European Outcome (SOURCE) Registry: a European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve.
      • di Marco F.
      • Gerosa G.
      Percutaneous aortic valve replacement: which patients are suitable for it? A quest for a controlled use.
      • ElBardissi A.W.
      • Shekar P.
      • Couper G.S.
      • et al.
      Minimally invasive aortic valve replacement in octogenarian, high-risk, transcatheter aortic valve implantation candidates.
      • Higgins J.
      • Ye J.
      • Humphries K.H.
      • et al.
      Early clinical outcomes after transapical aortic valve implantation: a propensity-matched comparison with conventional aortic valve replacement.
      Permanent pacemaker placement is reported in between 1.8% up to 8.5% of patients with Sapien and 19.1% to 42.5% with the CoreValve; renal failure in under 3%; and stroke in 1% to 5%. Registry data reflect an overall mortality rate at 1 year of 19% to 24%. In the SOURCE registry, more than half (51.6%) of deaths up to 1 year had a noncardiac etiology and were related to baseline comorbidities.
      • Zahn R.
      • Gerckens U.
      • Grube E.
      • et al.
      Transcatheter aortic valve implantation: first results from a multi-centre real-world registry.
      • Thomas M.
      • Schymik G.
      • Walther T.
      • et al.
      Thirty-day results of the SAPIEN aortic Bioprosthesis European Outcome (SOURCE) Registry: a European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve.
      The recent UK TAVR Registry included 452 Medtronic CoreValve implantations.
      • Moat N.E.
      • Ludman P.
      • de Belder M.A.
      • et al.
      Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) registry.
      In this group, standardized data forms were used and audited. Procedural success was achieved in 98.2% in this high-risk group of patients who had a baseline logistic EuroSCORE of 18.1%. Thirty-day mortality was 5.8%, and 1- and 2-year mortality was 21.7% and 23.9%, respectively. In-hospital stroke occurred in 4% of patients and myocardial infarction in 1.1%. A permanent pacemaker was required in 24.4% (compared with 7.4% with Sapien). Rates of moderate to severe postimplant AR were 17.3% (compared with 9.6% with Sapien). Mortality rates at all time points were significantly lower among patients treated via a transfemoral route as compared with nontransfemoral routes (>85% transapical). In this study, LV function, the presence of moderate/severe AR, and COPD, but not vascular access site, were independent predictors of mortality.

      4.3.1.2.3 Quality of Life in Registries

      Quality of life is a key patient-centered outcome. Although death is the lowest possible functional status, for many, survival marked by reduced physical function or independence may be worse than death. The PARTNER EU Registry is a multicenter study of the early European experience in TAVR. Patients undergoing TAVR by transapical or transfemoral approach were followed to 12 months for symptoms by New York Heart Association (NYHA) functional class, and heart failure–related quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire.
      • Lefevre T.
      • Kappetein A.P.
      • Wolner E.
      • et al.
      One year follow-up of the multi-centre European PARTNER transcatheter heart valve study.
      All patients improved, with no significant differences in NYHA functional class improvement noted between transapical or transfemoral approaches.
      Several single-center registries have added additional information on quality of life using disease-specific or general surveys (Short Form-36 Health Questionnaire, Short Form-12 Health Questionnaire, Kansas City Cardiomyopathy Questionnaire, Minnesota Living with Heart Failure Questionnaire) and on symptoms (NYHA functional class, and 6-minute walk). Improvements following TAVR in vitality, physical functioning, and general and mental health scores have been identified with physical function demonstrating the greatest improvement. Patients who do not experience improvement are more likely to have comorbidities that contribute to continued symptoms and impair quality of life, such as COPD and reduced EF (Table 3).
      Table 3Quality of life and symptom assessment in TAVR registries
      Study populationNYHA functional class6-Minute walkQuestionnaireOther
      PARTNER EU Registry; Lefevre et al (multicenter; N = 130 Sapien)
      • Lefevre T.
      • Kappetein A.P.
      • Wolner E.
      • et al.
      One year follow-up of the multi-centre European PARTNER transcatheter heart valve study.
      Improved class at 1 year in 84.5% of patients (85% NYHA functional class III/IV at baseline, 15% NYHA functional class at 1 year); changes noted at 30 days were sustainedNRKCCQ improvement at 1 year in 72.7% (P < .0002)Small improvement in EQ-5D was not significant
      Buellesfeld et al (multicenter; N = 126 CoreValve)
      • Buellesfeld L.
      • Gerckens U.
      • Schuler G.
      • et al.
      2-year follow-up of patients undergoing transcatheter aortic valve implantation using a self-expanding valve prosthesis.
      Improved in 80% at 30 days; 74% at 2 years (in 50% by 1 level, in 20% by 2 or more levels)NRNRNR
      Krane et al (single-center registry; N = 99 TAVR)
      • Krane M.
      • Deutsch M.A.
      • Bleiziffer S.
      • et al.
      Quality of life among patients undergoing transcatheter aortic valve implantation.
      More class I/II at 3 months (NYHA functional class III/IV from 98% to 2% at 3 months)NRImproved SF-36 PF general health and vitality pre/post at 3 months (all P < .01). No change mental health.85% would do TAVR again
      Ussia et al (single-center registry; N = 57 TAVR)
      • Ussia G.P.
      • Mule M.
      • Barbanti M.
      • et al.
      Quality of life assessment after percutaneous aortic valve implantation.
      More class I/II (average 1.8 NYHA functional class improvement) at 5 months (P < .001)NRSF-12; Improved (P < .001) physical and mental component scores, return to population norms, greatest change in PFNR
      Bekeredjian et al (single-center registry; N = 87 TAVR)
      • Bekeredjian R.
      • Krumsdorf U.
      • Chorianopoulos E.
      • et al.
      Usefulness of percutaneous aortic valve implantation to improve quality of life in patients >80 years of age.
      Improved class (average of 1.7 NYHA functional class improvement) at 6 months (P < .001)NRSF-36 Improved physical and mental component scores, greatest change in PF70% average decrease in NT-proBNP levels of 4000 ng/L (P < .0001)
      Gotzmann et al (single-center registry; N = 44 TAVR)
      • Gotzmann M.
      • Hehen T.
      • Germing A.
      • et al.
      Short-term effects of transcatheter aortic valve implantation on neurohormonal activation, quality of life and 6-minute walk test in severe and symptomatic aortic stenosis.
      Decrease of percentage of NYHA functional class III/IV from 90% to 16% at 30 daysImproved walk time at 30 daysMLHFQ; Improved HF-related QOLLower average decrease in BNP levels of 400 pg/mL (P < .005) and 25% increase in 6-minute walk time (P < .005)
      BNP, Brain natriuretic peptide; EQ-5D, EuroQol Five Dimensions; HF, heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; LOS, length of stay; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NR, not reported; NYHA, New York Heart Association; PF, physical function; QOL, quality of life; SAVR, surgical aortic valve replacement; SF-12, Short Form 12 Health Questionnaire; SF-36, Short Form 36 Health Questionnaire; TAVR, transcatheter aortic valve replacement.

      4.3.1.2.4 Learning Curve

      Each registry has identified a procedural learning curve, but the exact definition of this curve and a clear method to decrease it are not yet clearly reported. This curve has important components such as patient selection, anesthesia, improvement in the equipment over time, and technical decision making regarding valve deployment. The SOURCE registry enrolled 1038 (Cohort 1) and 1306 patients (Cohort 2) undergoing TAVR procedures over 2 sequential years. Age and EuroSCORE were not significantly different between the 2 cohorts. Compared with the first year of experience, valve malposition (1.6% vs 1.2%), and vascular access complications (2.1% vs 1.8%) were not significantly lower in the second year. However, reductions in the rates of postprocedure AR >2+ (4.5% vs 2.1%, P = .011) and conversion to open surgery (3.7% vs 1.5%, P = .0315) were improved.
      • Zahn R.
      • Gerckens U.
      • Grube E.
      • et al.
      Transcatheter aortic valve implantation: first results from a multi-centre real-world registry.
      • Thomas M.
      • Schymik G.
      • Walther T.
      • et al.
      Thirty-day results of the SAPIEN aortic Bioprosthesis European Outcome (SOURCE) Registry: a European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve.
      • Wendler O.
      • Walther T.
      • Schroefel H.
      • et al.
      The SOURCE registry: what is the learning curve in trans-apical aortic valve implantation?.
      Overall 30-day and 1-year survival was similar in both cohorts despite higher number of patients with heart failure and mitral regurgitation enrolled in Cohort 2.
      In summary, the registries demonstrate in high-risk patients that TAVR may be deployed with a high degree of procedural success, predictable risk of stroke, device-dependent high risk of pacemaker implantation (particularly with CoreValve), and a 30-day mortality rate that seems potentially acceptable in a debilitated and ill patient population. Importantly, TAVR seems to alleviate AS to a similar degree as surgical AVR and patients tend to return to Class I or II symptoms with substantial improvements in quality of life.
      Future registries should be designed to include contemporary (ie, VARC) definitions of procedural and quality-of-life outcomes and utilize an independent clinical events committee when possible to standardize event reporting. Longer-term follow-up studies are needed to demonstrate the continued durability of TAVR in the high-risk and inoperable patients.

      4.3.2 Randomized Controlled Trial

      4.3.2.1 PARTNER Trial Design

      The PARTNER trial (Figure 3) was a prospective, unblinded, randomized, controlled, multicenter pivotal trial evaluating the safety and effectiveness of the Edwards Sapien THV transcatheter aortic valve; 2 distinct populations were enrolled—inoperable, or Cohort B, and high-risk operable, or Cohort A. Potential candidates were presented on a national conference call for approval for treatment. Randomization was stratified based on operability for AVR surgery and within cohorts by vascular access for transfemoral delivery. Patients who were considered high surgical risk and eligible for transfemoral access were stratified into Cohort A and randomized to treatment (transfemoral AVR) or control (surgical AVR). Cohort A patients who were not eligible for transfemoral access were evaluated as candidates for transapical delivery and, if appropriate, randomized to treatment (transapical AVR) or control (surgical AVR). Nonsurgical candidates were stratified into Cohort B and randomized to treatment (transfemoral AVR) or control (“standard” therapy). Inoperability was formally defined as “>50% predicted probability of mortality or serious irreversible complication by 30 days by 1 cardiologist and 2 cardiothoracic surgeons.”
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      Cohort B patients who did not meet the criteria for transfemoral delivery were not enrolled in the study because transapical delivery was deemed too risky in Cohort B (Figure 3). Of the 3105 patients screened, a total of 1057 subjects (34%) were enrolled at 25 sites in 2 arms—699 patients in Cohort A and 358 patients in Cohort B. There were 2 co-primary endpoints for the inoperable cohort: (1) freedom from death over the duration of the trial with all patients followed for at least 1 year from randomization; and (2) hierarchical composite of death and recurrent hospitalization. In the high-risk cohort, the primary endpoint was freedom from all-cause death at 1 year. Prespecified secondary endpoints included rate of death from cardiovascular causes, NYHA functional class, the rate of repeat hospitalization due to valve-related or procedural-related clinical deterioration, the distance covered during a 6-minute walk test, valve performance (assessed by echocardiography), and the rates of myocardial infarction, stroke, acute kidney injury, vascular complications, and bleeding. All patients were followed during the index hospitalization; at 30 days, 6 months, and 1 year; and yearly thereafter.

      4.3.2.2 Demographics and Other Baseline Characteristics

      The mean age was about 83 years in Cohort B and 84 in Cohort A; slightly more patients were female (53.6%) in Cohort B, and slightly more patients were male (57.2%) in Cohort A; and most were Caucasian (Table 4). Over 92% in both cohorts were NYHA functional class III or IV, and 60% of patients in both cohorts had undergone prior CABG or PCI. Overall, the groups were balanced in most baseline characteristics in Cohort A; however, there were some imbalances in Cohort B.
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      Patients in both cohorts had relatively preserved LV systolic function.
      Table 4Demographic and other baseline characteristics of the PARTNER trial (Cohort B data first)
      CharacteristicCohort BCohort A
      TAVR (N = 179)Standard Rx (N = 179)P valueTAVR (N = 348)AVR (N = 351)P value
      Demographics
      Age (y)83.1 ± 8.683.2 ± 8.3.9583.6 ± 6.884.5 ± 6.4.07
      Male (%)45.846.9.9257.856.7.82
      STS score11.2 ± 5.811.9 ± 4.8.2111.8 ± 3.311.7 ± 3.5.61
      Logistic EuroSCORE26.4 ± 17.230.4 ± 19.1.0429.3 ± 16.529.2 ± 15.6.93
      NYHA functional class III or IV (%)92.293.9.6894.394.0.79
      O2-dependent COPD (%)21.225.7.389.27.1.34
      Frailty (%)18.128.0915.617.6.58
      Porcelain aorta (%)1911.2.050.61.1.69
      Chest wall radiation (%)8.98.41.000.90.91.00
      Chest wall deformity (%)8.45.0.2900.31.00
      Echocardiographic characteristics
      AV area (cm2)0.6 ± 0.20.6 ± 0.2.970.7 ± 0.20.6 ± 0.2.13
      Mean AV gradient (mm Hg)44.5 ± 15.743.0 ± 15.3.3942.7 ± 14.643.5 ± 14.3.45
      Mean LV EF (%)53.9 ± 13.151.1 ± 14.3.0652.5 ± 13.553.3 ± 12.8.45
      Cohort B includes only nonsurgical candidates in whom “inoperability” was formally defined as greater than 50% predicted probability of mortality or serious irreversible complication by 30 days by 1 cardiologist and 2 cardiothoracic surgeons.
      Cohort A includes patients determined to be at high operative risk defined as predicted operative mortality of ≥15% and/or an STS risk score of ≤10%. The STS risk algorithm is based on the presence of coexisting illnesses in order to predict 30-day operative mortality. Data are derived from the Edwards Lifesciences’ briefing document for the U.S. FDA Circulatory Devices Advisory Panel meeting on TAVR on July 21, 2011 (http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100041b.pdf) and may show some discrepancies compared with the published manuscripts.
      AV, Aortic valve; AVR, aortic valve replacement; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; Rx, therapy; STS, Society of Thoracic Surgeons; TAVR, transcatheter aortic valve replacement.
      Patients in Cohort B had greater frequency of coexisting conditions that contributed to the surgeons’ determination of inoperability, including an extensively calcified (porcelain) aorta (15.1%), chest-wall deformity or prior chest-wall irradiation (13.1%), oxygen-dependent respiratory insufficiency (23.5%), and frailty, according to prespecified criteria (23.1%).

      4.3.2.3 PARTNER Trial Results

      In the inoperable Cohort B patients with symptomatic severe AS, TAVR substantially reduced all-cause mortality by nearly 50% and the composite of all-cause mortality and repeat hospitalization by 55% compared with standard therapy at 1-year follow-up (Table 5). In addition, all key secondary endpoints including patient function significantly improved at 30 days and 1 year. TAVR was associated with an increased risk for stroke and procedure-related adverse events such as bleeding and vascular complications. Sensitivity analyses of patients as they were treated all favored TAVR. Overall, the benefit from TAVR in inoperable patients with symptomatic severe AS greatly exceeds the risk.
      Table 5Major outcomes at 30 days and 1 year in Cohort B of the PARTNER trial
      Characteristic30 days1 year
      TAVR (N = 179)Standard Rx (N = 179)P valueTAVR (N = 179)Standard Rx (N = 179)P value
      All-cause death (%)5.02.8.4130.749.7<.001
      All-cause death or rehospitalization (%)11.212.3.7443.670.4<.001
      Event-free MACCE (%)90.594.4NR65.447.1.003
      All stroke (%)7.31.7.0211.24.5.03
      Major stroke (%)5.61.1.048.43.9.12
      All-cause death or major stroke (%)
      All-cause death or major stroke was not a predefined endpoint.
      8.43.9.1233.050.3.001
      Major vascular complications (%)16.81.1<.000117.32.2<.0001
      Major bleeding (%)20.63.9<.000128.414.4<.001
      Pacemaker insertion (%)3.45.0.604.57.8.27
      Echocardiographic endpoints
      AV area (EOA) (cm2)1.5 ± 0.40.8 ± 0.2<.00011.6 ± 0.50.7 ± 0.32<.0001
      Mean AV gradient (mm Hg)11.1 ± 6.633.0 ± 12.5<.000112.5 ± 10.344.4 ± 15.7<.0001
      Cohort B includes only nonsurgical candidates in whom “inoperability” was formally defined as greater than 50% predicted probability of mortality or serious irreversible complication by 30 days by 1 cardiologist and 2 cardiothoracic surgeons.
      Data are based on Edwards Lifesciences’ briefing document for the U.S. FDA Circulatory Devices Advisory Panel meeting on TAVR on July 21, 2011 (http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100041b.pdf), and may show some discrepancies compared with the published manuscripts.
      AV, Aortic valve; EOA, effective orifice area; MACCE, major adverse cardiac and cerebrovascular events; NR, not reported; Rx, therapy; TAVR, transcatheter aortic valve replacement.
      All-cause death or major stroke was not a predefined endpoint.
      In the high-risk Cohort A patients, TAVR was noninferior to AVR for all-cause mortality at 1 year (24.2% vs 26.8%, hazard ratio: 0.93, 95% confidence interval: 0.71 to 1.22, P = .001 for noninferiority) (Table 6). AVR mortality at 30 days (6.5%) was lower than expected operative mortality (11.8%). Whether this discrepancy can be attributed to chance alone (ideal outcomes with expert surgeons within the idealized environment of a randomized trial) or due to “calibration drift” as surgical outcomes improve over time is not clear. All neurological events (30-day major stroke, 3.8% vs 2.1%) and vascular complications (30-day, 11.1% vs 3.2%) were more frequent with TAVR. By contrast, major bleeding and new-onset atrial fibrillation were more frequent with AVR. Improvements in echocardiographic findings were similar in both groups, although paravalvular regurgitation was increased with TAVR. The data from this cohort further support TAVR as an acceptable alternative to surgical AVR in selected high-risk operable patients.
      Table 6Major outcomes at 30 days and 1 year in Cohort A of the PARTNER trial
      Characteristic30 Days1 Year
      TAVR (N = 348)Surgical AVR (N = 351)P valueTAVR (N = 348)Surgical AVR (N = 351)P value
      Clinical outcomes
      All-cause death (%)3.46.5.0724.226.8.44
      All-cause death or rehospitalization (%)7.29.7.2434.635.9.73
      All stroke (%)5.52.4.048.34.3.04
      Major stroke (%)3.82.1.205.12.4.07
      All-cause death or major stroke (%)
      All-cause death or major stroke was not a predefined endpoint.
      6.98.2.5226.528.0.68
      Major vascular complications (%)17.03.8<.0118.04.8<.01
      Major bleeding (%)9.319.5<.0114.725.7<.01
      Atrial fibrillation (%)8.616.0<.0112.117.1.07
      Pacemaker insertion (%)3.83.6.895.75.0.68
      Echocardiographic endpoints
      AV area (EOA) (cm2)1.7 ± 0.51.5 ± 0.4.0011.6 ± 0.51.4 ± 0.5.002
      Mean AV gradient (mm Hg)9.9 ± 4.81.8 ± 5.0.1610.2 ± 4.311.5 ± 5.4.008
      Cohort A includes patients determined to be at high operative risk defined as predicted operative mortality of ≥15% and/or an STS risk score of ≥10%. The STS risk algorithm is based on the presence of coexisting illnesses in order to predict 30-day operative mortality.
      AV, Aortic valve; AVR, aortic valve replacement; EOA, effective orifice area; TAVR, transcatheter aortic valve replacement.
      All-cause death or major stroke was not a predefined endpoint.
      Of note, the 30-day mortality (generally thought to be procedure-related) in Cohort A (3.4%) and Cohort B (5.0%) was lower than the published SOURCE registry mortality (8.5%), despite a relatively lower-risk patient population enrolled in the latter (1-year mortality of 30.7% in Cohort B, 22.2% in Cohort A, and 18.9% in SOURCE). This arguably raises questions about the generalizability of the randomized trial data to clinical practice.

      4.3.2.3.1 Quality of Life

      The quality-of-life results from Cohort B arm, the inoperable cohort, TAVR patients had improvement in the 6-minute walk performance compared with baseline (P = .002), whereas standard therapy patients did not (P = .67).
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      In addition, TAVR patients were less symptomatic (New York Heart Association class), had reduced hospitalization stay, and improved physical functioning compared with standard therapy. In the high-risk cohort, both New York Heart Association class and 6-minute walk test favored TAVR at 30 days, but the differences were not significant at 1 year. TAVR patients had shorter index hospitalization length of stay (8 vs 12 days, P < .001). Quality of life as assessed by disease-specific measures (Kansas City Cardiomyopathy Questionnaire [KCCQ]) and by general health-related quality of life (Short Form-12 Health Questionnaire) improved at 1, 6, and 12 months in the TAVR group and were significantly higher than in the control arm (P < 0.001). This supports that general and disease-specific quality of life are improved with TAVR to 1 year over standard care among inoperable patients
      • Reynolds M.R.
      • Magnuson E.A.
      • Lei Y.
      • et al.
      Health-related quality of life after transcatheter aortic valve replacement in inoperable patients with severe aortic stenosis.
      (Table 7). The quality of life results from the Cohort A arm of the PARTNER trial were presented in November 2011. The preliminary conclusions were that among patients with severe AS who were at high risk for standard valve replacement, both surgical and transcatheter AVR resulted in substantial improvement in disease-specific and generic health-related quality-of-life assessment over 1-year follow-up, including KCCQ Summary Scale, SF-12 Physical, and SF-12 Mental tests. The benefits were greater at earlier time points in the transfemoral TAVR group and were equivalent at 1 year.

      Cohen DJ. Health-related quality of life after transcatheter vs. surgical aortic valve replacement in high-risk patients with severe aortic stenosis. Results from the PARTNER trial (Cohort A). Presented at: TCT 2011; November 10, 2011; San Francisco, CA.

      Table 7Quality of life and symptom assessment in TAVR trials
      Study populationNYHA functional class6-Minute walkQuestionnaireOther
      PARTNER B (trial) TAVR vs placebo (multicenter; N = 358)
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      • Reynolds M.R.
      • Magnuson E.A.
      • Lei Y.
      • et al.
      Health-related quality of life after transcatheter aortic valve replacement in inoperable patients with severe aortic stenosis.
      More class I, II with TAVR at 1 year (74.8% vs 42.0%)TAVR improved walk time pre/post at 1 year; no change in no-TAVR groupKCCQ; marked improvement with TAVR at 1 year; SF12; improvement in physical and mental HRQOL with TAVRTAVR had fewer rehospitalizations at 1 year
      PARTNER A (trial) TAVR vs SAVR (multicenter; N = 699)
      • Smith C.R.
      • Leon M.B.
      • Mack M.J.
      • et al.
      Transcatheter versus surgical aortic-valve replacement in high-risk patients.
      More class I, II with TAVR at 30 days; no difference between TAVR and SAVR at 1 yearTAVR improved walk time at 30 days compared with SAVR; no difference between TAVR and SAVR at 1 yearNRShorter LOS with TAVR
      HRQOL, Health-related quality of life; KCCQ, Kansas City Cardiomyopathy Questionnaire; LOS, length of stay; NR, not reported; QOL, quality of life; SAVR, surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement.

      4.3.2.3.2 Continued-Access Protocol

      Upon completion of the randomized PARTNER trial, patients have been allowed to have access to TAVR under a continued-access protocol. Enrollment in the randomized continued-access cohort was initiated following completion of the enrollment for PARTNER cohort B trial. From March to September 2009, 91 inoperable patients were enrolled—41 were randomized to TAVR and 50 to standard care. Both short-term (30 days) and long-term (6 months to 1 year) results have been reported (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/CirculatorySystemDevicesPanel/UCM262935.pdf). However, between-group analyses were not conducted due to the small sample size. Enrollment in nonrandomized continued-access cohort was initiated in September 2009 after both cohorts of PARTNER had completed randomized enrollment. Over 600 patients with transfemoral TAVR are being followed currently in this cohort.

      4.3.2.4 TAVR-Specific Clinical Issues

      4.3.2.4.1 Stroke

      Stroke is one of the major adverse events associated with TAVR. Standardized criteria for the definition of stroke endpoints for TAVR clinical trials have been published by the VARC (Table 8). The incidence of stroke depends on the assessment technique used for ascertainment. In the PARTNER Cohort A, the risk of clinically apparent “major” stroke defined as modified Rankin score ≥2 was 3.8% at 30 days and 5.1% at 1 year among the TAVR group compared with 2.1% and 2.4%, respectively, in the surgical group.
      • Smith C.R.
      • Leon M.B.
      • Mack M.J.
      • et al.
      Transcatheter versus surgical aortic-valve replacement in high-risk patients.
      In the PARTNER Cohort B, the stroke risk was 5% with TAVR compared with 1.1% with standard therapy at 30 days and 8.4% versus 3.9% at 1 year.
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      Using magnetic resonance imaging-diffusion weighted imaging (MRI-DWI) studies, the incidence of cerebral ischemic lesions post-TAVR has been reported to be as high as 68% to 84% in some studies, although clinically apparent stroke was reported in >4% of cases.
      • Rodes-Cabau J.
      • Dumont E.
      • Boone R.H.
      • et al.
      Cerebral embolism following transcatheter aortic valve implantation: comparison of transfemoral and transapical approaches.
      • Kahlert P.
      • Knipp S.C.
      • Schlamann M.
      • et al.
      Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation: a diffusion-weighted magnetic resonance imaging study.
      • Arnold M.
      • Schulz-Heise S.
      • Achenbach S.
      • et al.
      Embolic cerebral insults after transapical aortic valve implantation detected by magnetic resonance imaging.
      • Ghanem A.
      • Muller A.
      • Nahle C.P.
      • et al.
      Risk and fate of cerebral embolism after transfemoral aortic valve implantation: a prospective pilot study with diffusion-weighted magnetic resonance imaging.
      Thus, the clinical significance of these new CMR-defined lesions post-TAVR is not clear.
      Table 8Stroke
      Stroke diagnostic criteria
      Rapid onset of a focal or global neurological deficit with at least 1 of the following: change in level of consciousness, hemiplegia, hemiparesis, numbness or sensory loss affecting 1 side of the body, dysphasia or aphasia, hemianopia, amaurosis fugax, or other neurological signs or symptoms consistent with stroke
      Duration of a focal or global neurological deficit ≥24 h; OR <24 h, if therapeutic intervention(s) were performed (eg, thrombolytic therapy or intracranial angioplasty); OR available neuroimaging documents a new hemorrhage or infarct; OR the neurological deficit results in death
      No other readily identifiable nonstroke cause for the clinical presentation (eg, brain tumor, trauma, infection, hypoglycemia, peripheral lesion, pharmacological influences)
      Patients with nonfocal global encephalopathy will not be reported as a stroke without unequivocal evidence based upon neuroimaging studies.
      Confirmation of the diagnosis by at least 1 of the following:
       Neurology or neurosurgical specialist
       Neuroimaging procedure (MR or CT scan or cerebral angiography)
       Lumbar puncture (ie, spinal fluid analysis diagnostic or intracranial hemorrhage)
      Stroke definitions
      Transient ischemic attack:
       New focal neurological deficit with rapid symptom resolution (usually 1 to 2 h), always within 24 h
       Neuroimaging without tissue injury
      Stroke: (diagnosis as above, preferably with positive neuroimaging study)
       Minor—modified Rankin score <2 at 30 and 90 days
      Modified Rankin score assessments should be made by qualified individuals according to a certification process. If there is discordance between the 30- and 90-day Modified Rankin scores, a final determination of major versus minor stroke will be adjudicated by the neurology members of the clinical events committee.
       Major—modified Rankin score ≥2 at 30 and 90 days
      Reprinted with permission from Leon et al.
      • Leon M.B.
      • Piazza N.
      • Nikolsky E.
      • et al.
      Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium.
      CT, Computed tomography; MR, magnetic resonance.
      Patients with nonfocal global encephalopathy will not be reported as a stroke without unequivocal evidence based upon neuroimaging studies.
      Modified Rankin score assessments should be made by qualified individuals according to a certification process. If there is discordance between the 30- and 90-day Modified Rankin scores, a final determination of major versus minor stroke will be adjudicated by the neurology members of the clinical events committee.
      Most stroke cases are due to thromboembolism from the valve site or due to atherothrombotic emboli originating from ulcerative plaque in the great vessels such as the aortic arch. Such particles can be dislodged during catheter manipulation and embolize to the carotids or vertebrals to cause occlusions of distal intracerebral branch arteries. Other potential causes include hypotension associated with rapid ventricular pacing or hemodynamic instability during the procedure, and rarely due to aortic dissection complicating TAVR. It is important to recognize that many patients who have AS may also have other causes for an ischemic stroke such as age, hypertension, diabetes, or other cardiac conditions, including atrial fibrillation, which is a potent risk factor for cardioembolic stroke.
      • Goldstein L.B.
      • Bushnell C.D.
      • Adams R.J.
      • et al.
      Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      Differentiating the cause of the stroke is not always easy, but most trials and registries define strokes within 30 days of an interventional procedure as attributable to the procedure. After 30 days, other comorbid risk factors may account for stroke, which might, therefore, not be attributable to the prosthetic valve. Diagnostic evaluations are needed to assess the neck and cerebral vessels, cardiac function, and other potential causes of stroke in order to differentiate the stroke subtype and embark on the best treatment to prevent a recurrent stroke.
      • Furie K.L.
      • Kasner S.E.
      • Adams R.J.
      • et al.
      Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      • Gutsche J.T.
      • Cheung A.T.
      • McGarvey M.L.
      • et al.
      Risk factors for perioperative stroke after thoracic endovascular aortic repair.
      Nearly two thirds of the strokes related to TAVR at 1 year occurred within the first 30 days in PARTNER Cohort B (13/20), suggesting that most events were likely procedure-related.
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      The incidence of stroke may lessen as patient selection becomes more refined, delivery systems improve in their profile, and embolic protection devices and protocol-driven antithrombotic regimens are routinely used during TAVR.

      4.3.2.4.2 Conduction Defects

      Atrioventricular conduction disturbances after TAVR are associated with many patient-related and procedural-related factors, including preoperative comorbid status, the degree and bulkiness of aortic valve and annular calcification, interventricular septal thickness, pre-existing electrocardiogram abnormalities, the depth of prosthesis implantation, and the profile of the implanted prosthesis.
      • Bleiziffer S.
      • Ruge H.
      • Horer J.
      • et al.
      Predictors for new-onset complete heart block after transcatheter aortic valve implantation.
      • Piazza N.
      • Onuma Y.
      • Jesserun E.
      • et al.
      Early and persistent intraventricular conduction abnormalities and requirements for pacemaking after percutaneous replacement of the aortic valve.
      Unlike conventional AVR, where there may be localized trauma due to decalcification of the annulus and/or suture placement in the proximity of the AV node or the bundles, TAVR may cause conduction abnormalities through mechanical impingement of the conduction system by the prosthesis.
      The incidence of new left bundle-branch block and complete heart block after TAVR ranges from 14% to 83% and 19% to 22%, respectively. Patients with pre-existing right bundle-branch block may be at the highest risk for the development of complete heart block and the need for subsequent pacing.
      • Koos R.
      • Mahnken A.H.
      • Aktug O.
      • et al.
      Electrocardiographic and imaging predictors for permanent pacemaker requirement after transcatheter aortic valve implantation.
      The majority of conduction abnormalities occur prior to actual valve implantation, with 46% occurring during balloon aortic valvuloplasty, 25% during balloon/prosthesis positioning and wire-crossing of the aortic valve, and the remaining 29% during prosthesis expansion.
      • Nuis R.J.
      • Van Mieghem N.M.
      • Schultz C.J.
      • et al.
      Timing and potential mechanisms of new conduction abnormalities during the implantation of the Medtronic CoreValve System in patients with aortic stenosis.
      The incidence of complete heart block requiring permanent pacemaker implantation has been higher with the CoreValve (19.2% to 42.5%) than with the Sapien valve (1.8% to 8.5%), potentially due to its larger profile and extension low into the LV outflow tract. In the most recent UK Registry, pacemakers were implanted in 24.4% of patients receiving the CoreValve.
      Overall, permanent pacemaker implantation rates with the CoreValve, but not Sapien valve, are higher than conventional surgical AVR rates of 1% to 10%. The need for permanent pacemaker implantation occurs early postprocedure and rarely after hospital discharge. The need for permanent pacemaker implantation has no effect on survival, both early at 30 days postprocedure and late at 1 year.
      • D’Ancona G.
      • Pasic M.
      • Unbehaun A.
      • et al.
      Permanent pacemaker implantation after transapical transcatheter aortic valve implantation.
      Continuous postoperative electrocardiogram monitoring should be performed in all patients early after TAVR procedures. Patients with pre-existing or new conduction abnormalities and those receiving the CoreValve device may require longer monitoring.

      4.3.2.4.3 Vascular Complications

      Vascular complications are the most frequent adverse outcome of TAVR and are especially common with transfemoral approach.
      • Wenaweser P.
      • Pilgrim T.
      • Roth N.
      • et al.
      Clinical outcome and predictors for adverse events after transcatheter aortic valve implantation with the use of different devices and access routes.
      These complications relate to the large-caliber sheaths necessary for device deployment, as well as severe atherosclerosis of the arteries, which is common.
      • Kahlert P.
      • Al-Rashid F.
      • Weber M.
      • et al.
      Vascular access site complications after percutaneous transfemoral aortic valve implantation.
      Center/operator experience, the degree and location of vascular calcification, vascular tortuosity, and sheath-to artery ratio are predictors of major vascular complication.
      • Kahlert P.
      • Al-Rashid F.
      • Weber M.
      • et al.
      Vascular access site complications after percutaneous transfemoral aortic valve implantation.
      • Hayashida K.
      • Lefevre T.
      • Chevalier B.
      • et al.
      Transfemoral aortic valve implantation new criteria to predict vascular complications.
      Major vascular complications are classified in accordance with the definitions provided by the VARC and include aortic dissection, perforation, rupture, or bleeding requiring significant blood transfusions, or additional percutaneous or surgical intervention.
      • Leon M.B.
      • Piazza N.
      • Nikolsky E.
      • et al.
      Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium.
      Incidence of major vascular complications ranges from 2% to 26% with transfemoral access and is related to vessel size, tortuosity, and degree of aortoiliac occlusive disease and from 5% to 7% with transapical access.
      • Godino C.
      • Maisano F.
      • Montorfano M.
      • et al.
      Outcomes after transcatheter aortic valve implantation with both Edwards-SAPIEN and CoreValve devices in a single center: the Milan experience.
      • Tamburino C.
      • Capodanno D.
      • Ramondo A.
      • et al.
      Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis.
      • Thomas M.
      • Schymik G.
      • Walther T.
      • et al.
      Thirty-day results of the SAPIEN aortic Bioprosthesis European Outcome (SOURCE) Registry: a European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve.
      • Lefevre T.
      • Kappetein A.P.
      • Wolner E.
      • et al.
      One year follow-up of the multi-centre European PARTNER transcatheter heart valve study.
      • Kodali S.K.
      • O’Neill W.W.
      • Moses J.W.
      • et al.
      Early and late (one year) outcomes following transcatheter aortic valve implantation in patients with severe aortic stenosis (from the United States REVIVAL trial).
      Subclavian access may represent an alternative approach in some patients in whom transfemoral or transapical direct aortic access cannot be utilized. Subclavian artery injury is rare with such access although transient brachial plexus neuropathy has been reported with this approach.
      • Modine T.
      • Obadia J.F.
      • Choukroun E.
      • et al.
      Transcutaneous aortic valve implantation using the axillary/subclavian access: feasibility and early clinical outcomes.
      As delivery systems improve in their profile, the incidence of these complications will lessen.
      • Wenaweser P.
      • Pilgrim T.
      • Roth N.
      • et al.
      Clinical outcome and predictors for adverse events after transcatheter aortic valve implantation with the use of different devices and access routes.
      • Nuis R.J.
      • Piazza N.
      • Van Mieghem N.M.
      • et al.
      In-hospital complications after transcatheter aortic valve implantation revisited according to the valve academic research consortium definitions.
      Of note, left subclavian arterial access for TAVR may not be appropriate in patients with prior CABG with left internal thoracic arterial graft because temporary interruption of blood flow in the left internal thoracic artery may cause coronary insufficiency.

      4.3.2.4.4 Patient Preferences

      Informed consent requires the patient and/or support system be appropriately informed of the procedure benefits and risks, possess personal decision-making capacity, and ultimately be able to make a voluntary decision. Older adults often rely on trusted physicians, family, or friends to participate and guide medical decision making at the point of medical care. A central goal in this interaction is the exchange of relevant, detailed information about treatment strategies delivered in terminology that is understood by the patient and family. This patient-centric educational effort is essential in providing the patient and family information to facilitate interaction with the health care team, and promote personalized decision making for each patient. It is important to remember that risk tolerance and patient expectations vary across many patient populations. Thus, a thorough review of personalized risk/benefit profile is essential for each patient undergoing an invasive procedure.

      4.3.2.4.5 Benefit/Risk Assessment

      The complex task of balancing the benefit and risk of TAVR depends upon accurate information regarding prognosis for survival, morbidity, and expected quality of life. Ideally, an accurate validated model that predicts both in-hospital and long-term outcome should guide this analysis, help educate patients and their families, and effectively manage safety tradeoffs and health care expenditure. Such a model would include some assessment of the relative role of severe AS versus comorbidity (eg, COPD in the etiology of symptoms such as dyspnea). Although several risk models have been developed for prognostication after cardiac surgery, they are limited by modest performance with regards to discriminatory ability, calibration, and face validity. It is not clear whether these models for conventional cardiac surgery are similarly predictive of outcome of patients being considered for TAVR. An additional important issue relates to the lack of a formal assessment of other aspects of treatment risk and benefit (eg, gait, cognition, frailty) in these risk models. Thus, better performing risk models are needed that include a wide spectrum of prognostic variables using contemporary data in relevant populations for a TAVR-specific risk algorithm.
      In TAVR candidates, the benefits of avoidance of sternotomy and cardiopulmonary bypass with its attendant complications and prolonged recovery/hospitalization by applying TAVR appear to come at the price of potentially serious vascular and technical complications and increased hazards of stroke and paravalvular AR (Figure 4) . For prohibitively high-risk inoperable patients, such a tradeoff is acceptable given the documented statistically-significant and clinically-important mortality benefit and functional improvement. For high surgical risk patients in whom mortality benefit has not been proven, the findings present a dilemma, given that the irreversible effects of stroke might be of greater potential clinical significance in terms of long-term disability, permanent dependency, and increased societal costs than the complications of sternotomy and bleeding. Although bleeding occurs acutely, is often overt, and has immediate clinical impact leading to increased length of stay and resource utilization, a “causal link” to adverse long-term clinical outcome remains unproven. Ultimately, the relative weights both patients and physicians assign to the utility associated with these periprocedural hazards is likely to impact individual case-based benefit/risk assessment and decision making. Cost considerations are also likely to materially impact the adoption of TAVR in treatment algorithms for AS.
      Figure thumbnail gr4
      Figure 4Benefit/risk balance in the PARTNER trial. Data are shown for every 1000 patients treated with TAVR instead of standard treatment in Cohort B (above) or standard AVR in Cohort A (below). The excesses listed are not mutually exclusive, because some patients had more than 1 event. Only data with statistically significant differences at 1 year of follow-up are shown except for deaths* (P = .44) and atrial fibrillation† (P = .07) in Cohort A. AR, Aortic valvular regurgitation; AVR, surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement.

      4.3.2.5 Medtronic CoreValve U.S. Pivotal Trial

      The U.S. pivotal trial with the Medtronic CoreValve self-expanding valve is currently enrolling patients at 40 sites (NCT # 01240902). Patients are allocated into either an Extreme Risk cohort, similar to Cohort B inoperable patients in the PARTNER trial or a High Risk cohort analogous to PARTNER Cohort A. There will be 487 patients enrolled in the extreme-risk group with an additional 100 patients with inadequate iliofemoral access placed in a nested registry of alternative access with either subclavian or direct aortic approaches. The High Risk cohort will enroll 790 patients in a 1:1 randomization between TAVR and surgical AVR.

      5. Integration of TAVR Into Clinical Practice

      5.1 Patient Evaluation and Management

      5.1.1 Multidisciplinary Team

      The creation of a multidisciplinary team that includes the patient in the decision process in choosing the most appropriate form of treatment for AS including AVR (ie, surgical or percutaneous) is essential. It is similar in concept to the “heart team” approach for CAD.
      • Serruys P.W.
      • Morice M.C.
      • Kappetein A.P.
      • et al.
      Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease.
      Factors such as sex, race, availability, experience, and institutional commitment to managing very high-risk patients, technical skills, local results, referral patterns, and patient preference all may have an impact on the decision-making process and should be taken into account by this multidisciplinary team. Ideally, such a team would be comprised of the patient’s primary cardiologist, cardiac surgeon, interventional cardiologist, echocardiographer, imaging specialists—CT or CMR, heart failure and valve disease specialist, cardiac anesthesiologist, nurse practitioner, and cardiac rehabilitation specialists. Such a strategy would result in input from multiple skill sets with the goal being the best possible course of therapy leading to the best possible clinical outcome for the specific patient.
      Localization of a heart team working together in a valve clinic will help optimize the functions of the valve team. Such a clinic should combine clinical cardiac care, advanced imaging capability, and surgical consultation to provide centralized assessment and treatment options for complex valve disorders. Patients referred to a valve clinic should be assessed by a cardiologist and a cardiovascular surgeon to discuss the options for surgical intervention if indicated. Prior diagnostic studies should be reviewed and additional diagnostic imaging (echocardiography, TEE, MDCT [multidetector computed tomography], CMR) performed as clinically indicated. Overall, a valve clinic should offer patients a personalized approach for the evaluation and treatment of complex valve disorders with the availability of a cardiologist and a cardiac surgeon specializing in valve disorders.

      5.1.2 Patient Selection

      5.1.2.1 Inclusion/Exclusion Criteria

      TAVR is appropriate currently only for a highly select population and the valve team should systematically identify the characteristics that define that population with most benefit and acceptable risk. These identification criteria should be operationalized into practice and may evolve over time with this new technology as new data become available.
      The inclusion and exclusion criteria in extant randomized studies are generally appropriate for use in clinical practice (Table 9). These vary somewhat, but there are some criteria common to most studies. Some criteria can be precisely identified with objective measurements, but many require subjective estimates based on clinical judgment. These subjective assessments are at least as important as the objective determinations and necessarily create some variability in the process of patient selection. The criteria presented here are based on current technology and experience. As technology improves and experience is gained, it is likely that many of these criteria will change to expand TAVR to different populations that will be optimally treated with the next generation of devices. In addition, the arbitrary criteria such as qualifying aortic AVA measurement within 45 days within the procedure will be modified and made more flexible.
      Table 9Patient selection: Inclusion and exclusion criteria in clinical trials
      Inclusion criteria
      • 1.
        Patient has calcific aortic valve stenosis with echocardiographically derived criteria: mean gradient >40 mm Hg or jet velocity >4.0 m/s and an initial AVA of <0.8 cm2 or indexed EOA <0.5 cm2/m2. Qualifying AVA baseline measurement must be within 45 days of the date of the procedure.
      • 2.
        A cardiac interventionalist and 2 experienced cardiothoracic surgeons agree that medical factors either preclude operation or are high risk for surgical AVR, based on a conclusion that the probability of death or serious, irreversible morbidity exceeds the probability of meaningful improvement. The surgeons’ consult notes shall specify the medical or anatomic factors leading to that conclusion and include a printout of the calculation of the STS score to additionally identify the risks in the patient. At least 1 of the cardiac surgeon assessors must have physically evaluated the patient.
      • 3.
        Patient is deemed to be symptomatic from his/her aortic valve stenosis, as differentiated from symptoms related to comorbid conditions, and as demonstrated by NYHA functional class II or greater.
      Exclusion criteria (candidates will be excluded if any of the following conditions are present)
      • 1.
        Evidence of an acute myocardial infarction ≤1 month (30 days) before the intended treatment (defined as: Q-wave MI, or non–Q-wave MI with total CK elevation of CK-MB ≥ twice normal in the presence of MB elevation and/or troponin level elevation [WHO definition])
      • 2.
        Aortic valve is a congenital unicuspid or congenital bicuspid valve, or is noncalcified
      • 3.
        Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+)
      • 4.
        Hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation, or mechanical heart assistance within 30 days of screening evaluation
      • 5.
        Need for emergency surgery for any reason
      • 6.
        Hypertrophic cardiomyopathy with or without obstruction
      • 7.
        Severe left ventricular dysfunction with LVEF <20%
      • 8.
        Severe pulmonary hypertension and RV dysfunction
      • 9.
        Echocardiographic evidence of intracardiac mass, thrombus or vegetation
      • 10.
        A known contraindication or hypersensitivity to all anticoagulation regimens, or inability to be anticoagulated for the study procedure
      • 11.
        Native aortic annulus size <18 mm or >25 mm as measured by echocardiogram
        The boundaries of annulus size will continue to change in concert with changing device size.
      • 12.
        MRI confirmed CVA or TIA within 6 months (180 days) of the procedure
      • 13.
        Renal insufficiency (creatinine >3.0 mg/dL) and/or end-stage renal disease requiring chronic dialysis at the time of screening
      • 14.
        Estimated life expectancy <12 months (365 days) due to noncardiac comorbid conditions
      • 15.
        Severe incapacitating dementia
      • 16.
        Significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal luminal diameter 5 cm or greater; marked tortuosity (hyperacute bend), aortic arch atheroma (especially if thick [>5 mm], protruding or ulcerated) or narrowing (especially with calcification and surface irregularities) of the abdominal or thoracic aorta, severe “unfolding” and tortuosity of the thoracic aorta
      • 17.
        Severe mitral regurgitation
      AVA, Aortic valve area; AVR, aortic valve replacement; CK, creatine kinase; CVA, cerebrovascular accident; EOA, effective orifice area; LVEF, left ventricular ejection fraction; MB, MB isoenzyme; MI, myocardial infarction; MRI, magnetic resonance imaging; NYHA, New York Heart Association; RV, right ventricular; STS, Society of Thoracic Surgeons; TIA, transient ischemic attack; WHO, World Health Organization.
      The boundaries of annulus size will continue to change in concert with changing device size.

      5.1.2.2 Specific Patient Subsets

      5.1.2.2.1 Porcelain Aorta, Friable Aortic Atheroma, Radiation Heart Disease

      Occasionally, otherwise fairly healthy candidates for AVR will have local factors such as prior radiation therapy to their mediastinum and/or severe calcific changes within their ascending aorta (“porcelain aorta”) that add significant risk to a traditional open AVR. Rarely, transesophageal echocardiography will reveal advanced atherosclerosis with mobile and pedunculated atheromata that also increase risk for stroke or a major embolic event with traditional TAVR. Cases such as these are approached individually and the correct approach is at best an educated judgment on the part of the surgical team. TAVR offers an alternative for the treatment of AS when there is severe circumferential calcification (porcelain aorta) or heavy atherosclerotic disease burden in the ascending aorta.
      • Kempfert J.
      • Van Linden A.
      • Linke A.
      • et al.
      Transapical aortic valve implantation: therapy of choice for patients with aortic stenosis and porcelain aorta?.
      Patients with extensive atherothrombotic burden involving the ascending aorta should be approached very carefully irrespective of whether either a transapical or transfemoral procedure because of the potential for embolization.

      5.1.2.2.2 Very Elderly

      Advanced age has important implications, as typically these patients have several comorbid conditions (in addition to advanced age) that increase the risk of AVR or TAVR. Functional status and comprehensive assessment of comorbidities including CAD, history of transient ischemic attack or stroke, chronic kidney disease, and dementia should be performed. Finally, risk and benefit, including prognosis of existing conditions, should be thoroughly discussed with the patient and family as part of the initial meeting with the TAVR team and should include a review of postprocedural complications that may extend hospitalization. On the other hand, successful procedures result in improvement in dyspnea, a heightened energy level, and an overall improved quality of life. Life expectancy can be prolonged, since the mortality of medically-treated symptomatic severe AS carries a high mortality.
      As noted above, symptoms usually improve following valve replacement, but a caveat exists for elderly patients regarding dyspnea and the presence of LVH. LVH is seen in 54% of men and 81% of women with severe AS
      • Douglas P.S.
      • Otto C.M.
      • Mickel M.C.
      • et al.
      Gender differences in left ventricle geometry and function in patients undergoing balloon dilatation of the aortic valve for isolated aortic stenosis NHLBI Balloon Valvuloplasty Registry.
      • Carroll J.D.
      • Carroll E.P.
      • Feldman T.
      • et al.
      Sex-associated differences in left ventricular function in aortic stenosis of the elderly.
      • Aurigemma G.P.
      • Silver K.H.
      • McLaughlin M.
      • et al.
      Impact of chamber geometry and gender on left ventricular systolic function in patients > 60 years of age with aortic stenosis.
      • Legget M.E.
      • Kuusisto J.
      • Healy N.L.
      • et al.
      Gender differences in left ventricular function at rest and with exercise in asymptomatic aortic stenosis.
      whereas men more often have less LVH, some LV chamber enlargement, and some reduction in EF. Occasionally women will have such severe diastolic dysfunction that even when the afterload stress is relieved by TAVR, elevated LV filling pressures may result in persistent symptoms of shortness of breath. Since LVH may eventually regress following TAVR, shortness of breath may also eventually improve over several months following valve replacement. Men, who tend to have a greater degree of LV myocardial fibrosis and abnormal LV collagen network patterns,
      • Villari B.
      • Campbell S.E.
      • Schneider J.
      • et al.
      Sex-dependent differences in left ventricular function and structure in chronic pressure overload.
      may have more inherent reduced contractility, so that relieving afterload with TAVR may also not result in early or marked symptomatic improvement. When discussing TAVR with the very elderly, they should be made aware that symptomatic improvement may be delayed or minimal in some cases.

      5.1.2.2.3 Frailty and Futility Versus Utility

      As previously discussed, the concepts of frailty and futility will assume central importance in patient selection for TAVR by virtue of the extensive comorbidities present in this population. Frailty is an important and frequent condition in elderly patients and should be considered when dealing with invasive care in older adults.
      • Lunney J.R.
      • Lynn J.
      • Foley D.J.
      • et al.
      Patterns of functional decline at the end of life.
      Although it can have significant overlap with disability and comorbidity, it is a distinct syndrome and is characterized by a vicious cycle of decreasing muscle mass, energy expenditure, and malnutrition culminating in vulnerability to adverse events.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Cardiovascular Health Study Collaborative Research Group
      Frailty in older adults: evidence for a phenotype.
      In the PARTNER trial, frailty was present in as many as 23% of patients in Cohort B and 16% in Cohort A. Besides comorbidities, and frequently in combination with them, it is likely to play a role in the assessment of the individual’s candidacy for invasive care and therefore in withholding any intervention in nearly one half of high-risk patients with AS.
      • Himbert D.
      • Descoutures F.
      • Al-Attar N.
      • et al.
      Results of transfemoral or transapical aortic valve implantation following a uniform assessment in high-risk patients with aortic stenosis.
      It is important to consider that frailty may be a reversible physiological phenotype in some cases, and therefore it is premature to consider this a permanent characteristic of the individual patient. To the extent that AS may contribute to the declining health state, AVR or TAVR may reverse frailty. In this case, frailty may be a marker for treatment benefit. Conversely, if the individual is frail from multiple other organ system declines, frailty may be a marker of treatment risk.
      The impact of frailty on the clinical course and outcome of patients presenting with severe AS is beginning to be investigated but is difficult to assess because of its multidimensional phenotype and the lack of a clear and agreed-upon assessment. The definition of frailty used in recent studies ranges from the qualitative “eyeball test” to more quantitative scores such as the Fried Frailty Index.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Cardiovascular Health Study Collaborative Research Group
      Frailty in older adults: evidence for a phenotype.
      A simple test for defining frailty is a timed gait speed over 5 m. In a recent Canadian study,
      • Afilalo J.
      • Eisenberg M.J.
      • Morin J.F.
      • et al.
      Gait speed as an incremental predictor of mortality and major morbidity in elderly patients undergoing cardiac surgery.
      a time of >6 seconds as a measure of frailty was found to be an independent predictor of mortality compared with the STS risk algorithm alone. As such, it has recently been added to the STS database upgrade (Version 2.73, July 1, 2011) and will be uniformly collected in patients undergoing cardiac surgery.
      • Afilalo J.
      • Eisenberg M.J.
      • Morin J.F.
      • et al.
      Gait speed as an incremental predictor of mortality and major morbidity in elderly patients undergoing cardiac surgery.
      Future studies should aim at developing more reliable and reproducible ways of identifying frailty, as well as incorporating these assessments in development of risk and benefit prediction.
      Futility is also an important consideration for TAVR. There may be some patients in whom this procedure should not be performed because the clinical condition is too far advanced; in these patients, even a successful technical procedure is futile and does not improve health outcomes.
      Therapeutic futility may be determined based upon: (1) lack of medical efficacy, as judged by the patient’s physician; or (2) lack of a meaningful survival, as judged by the personal values of the patient.
      Consensus statement of the Society of Critical Care Medicine’s Ethics Committee regarding futile and other possibly inadvisable treatments.
      American Thoracic Society
      Withholding and withdrawing life-sustaining therapy This Official Statement of the American Thoracic Society was adopted by the ATS Board of Directors, March 1991.
      Although therapeutic futility may be invoked to justify denial, limitation, or withdrawal of care, the threshold for defining it is unclear, controversial, and often viewed differently by different stakeholders. In the PARTNER trial, the criterion for inoperability—used as a surrogate for futility with regards to surgical intervention—was an estimate of probability of death or serious, irreversible morbidity ≥50% by a cardiologist and 2 experienced cardiothoracic surgeons.
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      Despite successful correction of AS leading to an absolute 20% survival advantage, there was still 30% mortality in the TAVR treatment arm at 1 year, mainly due to noncardiac causes. The key to treatment in this group of “inoperable” patients is to define the “futility versus utility” treatment paradigm. Clearer definition of comorbid conditions that adversely affect survival despite successful valve implementation as well as quality of life and health economic assessment in those “inoperable” patients is crucial so that this therapy is appropriately used in patients likely to benefit (utility) compared with those unlikely to benefit despite successful therapy (futility). Although some might argue that it is inappropriate and misleading to say that treatment is futile simply because the probability that it will succeed is small, especially given the substantial uncertainty in our ability to prognosticate in individual patients and lack of validated tools that universally discriminate survivors from nonsurvivors of critical illness, it is nonetheless important to define meaningful cutoff points. This is particularly true when, in the course of a progressive illness, continued use of resources other than measures for comfort, is no longer reasonable, practical, or appropriate. Ultimately, these decisions must be guided by what our society considers to be the inherent value of human life and the resultant financial burden society is willing to bear for the provision of modern public health care.
      • McDermid R.C.
      • Bagshaw S.M.
      Prolonging life and delaying death: the role of physicians in the context of limited intensive care resources.

      5.1.3 Care Plan in Candidates for TAVR

      The health care team needs to be intimately involved in discussions on risk/benefits including detailed information on individualized risks for each patient and alignment of quality-of-life expectations. Failure to understand and comply with a plan of care may account for dissatisfaction with procedural outcomes and potential rehospitalizations.
      • Krumholz H.M.
      • Merrill A.R.
      • Schone E.M.
      • et al.
      Patterns of hospital performance in acute myocardial infarction and heart failure 30-day mortality and readmission.
      • Bernheim S.M.
      • Grady J.N.
      • Lin Z.
      • et al.
      National patterns of risk-standardized mortality and readmission for acute myocardial infarction and heart failure: update on publicly reported outcomes measures based on the 2010 release.
      One critical intervention to ensure effective care coordination and transition is that of comprehensive plan of care and educational material given to patient and/or caregivers prior to the planned procedures, and again during and after hospitalization. This process may encourage full participation of the patient and family about adherence to medication therapy and activity recommendations. Transitions of care and follow-up will be improved by discussion and written instructions reviewed with each patient including medications, timely follow-up with the various health care professionals involved with the patient’s ongoing care, and appropriate postprocedural activities. The ongoing care and coordination with the cardiovascular care team may decrease likelihood of readmission and improve overall adherence. Health care providers should pay close attention to psychosocial and socioeconomic issues that the patient and family face, including access to care, risk of depression, and health care disparities.
      • Bernheim S.M.
      • Spertus J.A.
      • Reid K.J.
      • et al.
      Socioeconomic disparities in outcomes after acute myocardial infarction.
      • Rahimi A.R.
      • Spertus J.A.
      • Reid K.J.
      • et al.
      Financial barriers to health care and outcomes after acute myocardial infarction.
      • Smolderen K.G.
      • Spertus J.A.
      • Reid K.J.
      • et al.
      The association of cognitive and somatic depressive symptoms with depression recognition and outcomes after myocardial infarction.

      5.1.4 Imaging Assessment

      Imaging plays an essential role in patient selection and procedural planning, performance, and follow-up.
      • Zamorano J.L.
      • Badano L.P.
      • Bruce C.
      • et al.
      EAE/ASE recommendations for the use of echocardiography in new transcatheter interventions for valvular heart disease.
      In each of these steps, optimal imaging can help to enhance successful outcome. There is variability in the specific imaging protocols preferred in individual institutions. This variability is the result of institutional and individual experience and equipment, as well as the specific patient characteristics to be considered.

      5.1.4.1 Echocardiography

      The following general recommendations can be made for echo assessment of patients being considered for TAVR. More detailed instructions can be found in a recent expert consensus statement from the American Society of Echocardiography and the European Society of Echocardiography.
      • Zamorano J.L.
      • Badano L.P.
      • Bruce C.
      • et al.
      EAE/ASE recommendations for the use of echocardiography in new transcatheter interventions for valvular heart disease.

      5.1.4.1.1 Annulus Size and Cusp and Root Anatomy

      Accurate assessment of annular size is critical. Underestimation of annular size could lead to selection and deployment of a valve which is too small, with risks of poor hemodynamics, paravalvular regurgitation, and valve migration and embolism. Overestimation of annular size and placement of a valve that is too large can lead to other adverse outcomes, including incomplete deployment (with both valvular and paravalvular regurgitation) or catastrophic annular rupture. In general, all TAVRs are designed to be deployed in annuli that are slightly smaller than the prosthesis size. This oversizing is required because the valves are sutureless and depend on radial force to prevent dislodgement. For the initial Sapien valves, the 23-mm valve was designed for 18-mm to 22-mm annuli, whereas the 26-mm prosthesis was designed for 21-mm to 25-mm annuli. The Sapien XT valve, with 23-mm, 26-mm, and 29-mm sizes, is designed for annuli from 18 mm to 27 mm. The CoreValve has 26-mm, 29-mm, and 31-mm prosthesis sizes (using a different sizing convention from the Sapien valve) designed for annuli from 20 mm to 23 mm for the 26-mm prosthesis, 24 mm to 27 mm for the 29-mm prosthesis, and 26 mm to 29 mm for the 31-mm annuli. Annular dimensions can be measured with either TTE or TEE.
      • Messika-Zeitoun D.
      • Serfaty J.M.
      • Brochet E.
      • et al.
      Multimodal assessment of the aortic annulus diameter: implications for transcatheter aortic valve implantation.
      With either modality, the annular anteroposterior diameter is measured from a long-axis view. Care must be taken to identify the true annulus, not overlying calcium. Measurements are made in systole at the hinge point of the leaflets into the LVOT with a trailing edge to leading edge convention. Because the annulus is often elliptical, optimal assessment should include measurement of the transverse (coronal) diameter, using the short-axis view, ideally with biplane TEE approach or CT, which allows simultaneous long- and short-axis interrogation of the annular plane.

      5.1.4.1.2 Aortic Root Disease and Ascending Aortic Dimensions

      Assessment of cusp and root anatomy is also critical. The PARTNER trial excluded all patients with bicuspid aortic valves for concern that such valves might distort the prosthesis, leading to paravalvular regurgitation. Thus, TAVR in any nontricuspid valve would be considered an off-label use, though successful treatment of bicuspid valves has been reported.
      • Delgado V.
      • Tops L.F.
      • Schuijf J.D.
      • et al.
      Successful deployment of a transcatheter aortic valve in bicuspid aortic stenosis: role of imaging with multislice computed tomography.
      It is often difficult to determine cusp anatomy in the densely calcified valves commonly treated by TAVR. In this setting, CT or review of old echocardiograms may allow better assessment of the underlying anatomy. Pathology reviews have demonstrated progressive increase with age in the proportion of trileaflet valves in severe AS patients, from 15% in those under 60 years to 60% over 70 years (72% for those over 80 years).
      • Roberts W.C.
      • Ko J.M.
      Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation.
      Of note, this study showed that even pathological examination cannot determine cusp anatomy in some heavily distorted valves.
      Several issues must be considered in assessing root anatomy and pathology. Care must be taken to assure that valve deployment will not compromise the coronary ostia, either from the device itself or from cusp calcification being shifted and displaced into the coronary. In general, CT scanning provides a more comprehensive assessment of the relationship of the coronary arteries to the annulus and valve leaflets, demonstrating an average annular–left coronary artery distance of 13.4 ± 3.2 mm and annular-right coronary artery distance of 13.6 ± 2.8 mm.
      • Akhtar M.
      • Tuzcu E.M.
      • Kapadia S.R.
      • et al.
      Aortic root morphology in patients undergoing percutaneous aortic valve replacement: evidence of aortic root remodeling.
      Nevertheless, echo, particularly TEE, can measure the distance from the aortic valve annulus to the right coronary ostium. Since the left coronary does not lie in a standard TEE or TTE imaging plane that intersects the annulus, measurement from 3D datasets may be a feasible approach for this.
      Accurate assessment of the aortic root and tubular portion is also important. The CoreValve Revalving System is designed with a supra-annular location of the porcine pericardial valve, located in the sinus of Valsalva. As a result, the CoreValve nitinol frame has a longer length than conventional surgical valves, ranging from 52 mm (for the 31-mm valve) to 55 mm (for the 26-mm valve) including its deployment hooks. It is recommended that the upper dimensions of the tubular aorta measured at 45 mm above the annulus be 40 mm for the 26-mm valve and 43 mm for the 29-mm and 31-mm CoreValve prostheses.
      Preprocedural assessment of AR in TAVR candidates should be governed by guidelines from the American Society of Echocardiography.
      • Zoghbi W.A.
      • Enriquez-Sarano M.
      • Foster E.
      • et al.
      Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography.
      This assessment is based on multiple parameters, including LV size, AR jet size and morphology, AR pressure half-time, and diastolic flow reversal in the aortic arch. Patients with >3+ AR were excluded from the PARTNER trial and should be considered relatively contraindicated for TAVR.

      5.1.4.1.3 Three-Dimensional Echocardiography

      Real-time 3D TEE is an important modality for preprocedural and intraprocedural assessment of TAVR patients.
      • Ng A.C.
      • Delgado V.
      • van der Kley F.
      • et al.
      Comparison of aortic root dimensions and geometries before and after transcatheter aortic valve implantation by 2- and 3-dimensional transesophageal echocardiography and multislice computed tomography.
      • Janosi R.A.
      • Kahlert P.
      • Plicht B.
      • et al.
      Measurement of the aortic annulus size by real-time three-dimensional transesophageal echocardiography.
      Similar to MDCT and CMR, it can help with precise assessment of the aortic root and annulus, potentially helping reduce the chance for prosthesis-sizing error in patients. However, multiple studies have demonstrated significant differences in dimensions of the aortic root and annulus measured by 2D TTE, 2D TEE, 3D TEE, and MDCT.
      • Ng A.C.
      • Delgado V.
      • van der Kley F.
      • et al.
      Comparison of aortic root dimensions and geometries before and after transcatheter aortic valve implantation by 2- and 3-dimensional transesophageal echocardiography and multislice computed tomography.
      • Janosi R.A.
      • Kahlert P.
      • Plicht B.
      • et al.
      Measurement of the aortic annulus size by real-time three-dimensional transesophageal echocardiography.
      Hence, it is imperative to realize that the imaging technique utilized might impact TAVR size selection and strategy. TEE, including real-time 3D TEE can help evaluate the extent of and precisely locate the jet of AR following prosthesis implantation.

      5.1.4.2 Tomographic Imaging

      5.1.4.2.1 Rationale for Tomographic Imaging

      Optimizing outcome relies heavily on image guidance for patient selection, preprocedural planning, and intraoperative decision making.
      • Schoenhagen P.
      • Tuzcu E.M.
      • Kapadia S.R.
      • et al.
      Three-dimensional imaging of the aortic valve and aortic root with computed tomography: new standards in an era of transcatheter valve repair/implantation.
      Correct positioning of the prosthesis relative to the annulus is critical. If valve deployment is too high, increased risk of paravalvular regurgitation, aortic injury, coronary occlusion, or embolization of the prosthesis can occur. If positioning is too low, mitral valve dysfunction, heart block, paravalvular regurgitation, or embolization into the left ventricular cavity can occur.
      • Al Ali A.M.
      • Altwegg L.
      • Horlick E.M.
      • et al.
      Prevention and management of transcatheter balloon-expandable aortic valve malposition.
      In addition, the relatively large delivery catheters currently required for valve insertion are associated with the risk of vascular complications, necessitating assessment of iliofemoral vasculature. This has led to the application of 3D imaging approaches for TAVR, including CT, CMR, 3D echocardiography, and C-arm CT
      • Messika-Zeitoun D.
      • Serfaty J.M.
      • Brochet E.
      • et al.
      Multimodal assessment of the aortic annulus diameter: implications for transcatheter aortic valve implantation.
      • Ng A.C.
      • Delgado V.
      • van der Kley F.
      • et al.
      Comparison of aortic root dimensions and geometries before and after transcatheter aortic valve implantation by 2- and 3-dimensional transesophageal echocardiography and multislice computed tomography.
      • Schwartz J.G.
      • Neubauer A.M.
      • Fagan T.E.
      • et al.
      Potential role of three-dimensional rotational angiography and C-arm CT for valvular repair and implantation.
      • Koos R.
      • Altiok E.
      • Mahnken A.H.
      • et al.
      Evaluation of aortic root for definition of prosthesis size by magnetic resonance imaging and cardiac computed tomography: implications for transcatheter aortic valve implantation.
      (Table 10).
      Table 10Potential approaches for imaging in TAVR
      Preprocedural assessment
      • 1.
        Assessment of aortic annular size and shape (CT, CMR, 2D and 3D echocardiography)
      • 2.
        Assessment of aortic valve for number of cusps, degree of calcification and valve area by planimetry (CT, CMR, 2D and 3D echocardiography)
      • 3.
        Measurement of the distance between annulus and coronary ostia (CT, CMR, 2D and 3D echocardiography)
      • 4.
        Planning for precise coaxial alignment of the stent-valve along the centerline of the aortic valve and aortic root (CT)
      • 5.
        Assessment of aortic dimensions (2D and 3D echocardiography, CT or CMR) and atherosclerosis (echocardiography, CT, or CMR)
      • 6.
        Assessment of dimensions and atherosclerosis of iliofemoral vessels (CT, MR, angiography)
      Postprocedural assessment
      • 1.
        Assessment of degree of aortic regurgitation (echocardiography or CMR)
      • 2.
        Assessment of cerebral embolization (cerebral MRI)
      2D, 2-dimensional; 3D, 3-dimensional; CMR, cardiac magnetic resonance; CT, computed tomography; MRI, magnetic resonance imaging; TAVR, transcatheter aortic valve replacement.

      5.1.4.2.2 Multidetector Computed Tomography

      MDCT provides comprehensive assessment of the aortic root, atherosclerotic burden, and course of the thoracoabdominal aorta and its iliofemoral branches (Figure 5) . MDCT in the context of TAVR eligibility assessment has become routine in many large-volume centers.
      • Schoenhagen P.
      • Numburi U.
      • Halliburton S.S.
      • et al.
      Three-dimensional imaging in the context of minimally invasive and transcatheter cardiovascular interventions using multi-detector computed tomography: from pre-operative planning to intra-operative guidance.
      Figure thumbnail gr5
      Figure 5Reconstructed multidetector computed tomographic images of the abdominal aorta and its pelvic branches demonstrating tortuosity and extensive calcific atherosclerosis. The extent and degree of peripheral arterial disease is essential in determining the feasibility and safety of transfemoral approaches. In some patients with extensive disease, alternative approaches such as direct aortic, subclavian, or transapical procedures should be considered.
      MDCT systems with at least 64 detectors and a spatial resolution of 0.5 mm to 0.6 mm are recommended. The specific scan protocols used for assessment vary but generally include imaging of the aortic root and the thoracoabdominal aorta and its iliofemoral branches. ECG-synchronized imaging of the aortic root is important to avoid image quality degradation due to motion artifacts, and image reconstruction is performed at the desired phase of the cardiac cycle (eg, a systolic 30% to 40% phase for valve area and annular assessment). Using the retrospectively ECG-gated helical acquisition, CT data can be acquired throughout the entire cardiac cycle, enabling 4D image reconstructions for evaluation of valvular function, albeit at the expense of a higher radiation dose.
      • Chenot F.
      • Montant P.
      • Goffinet C.
      • et al.
      Evaluation of anatomic valve opening and leaflet morphology in aortic valve bioprosthesis by using multidetector CT: comparison with transthoracic echocardiography.
      Alternatively, prospectively ECG-triggered axial CT data acquisition requires much less radiation; however, images are acquired during a prespecified phase of the cardiac cycle and reconstruction in other phases or 4D cine loops may not be reconstructible.
      • Earls J.P.
      • Berman E.L.
      • Urban B.A.
      • et al.
      Prospectively gated transverse coronary CT angiography versus retrospectively gated helical technique: improved image quality and reduced radiation dose.
      However, protocols with newer generation scanners allow prospective acquisition at a lower radiation dose with subsequent display of cine loops.
      • Feuchtner G.
      • Goetti R.
      • Plass A.
      • et al.
      Dual-step prospective ECG-triggered 128-slice dual-source CT for evaluation of coronary arteries and cardiac function without heart rate control: a technical note.
      Although radiation exposure is important to consider with any CT acquisition, it is less a concern in the elderly patients currently considered for TAVR.
      Because a standard bolus of 80 mL to 120 mL of low-osmolar iodinated contrast is necessary, the benefits versus risks of iodinated contrast need to be carefully weighed.
      • Bagur R.
      • Webb J.G.
      • Nietlispach F.
      • et al.
      Acute kidney injury following transcatheter aortic valve implantation: predictive factors, prognostic value, and comparison with surgical aortic valve replacement.
      An alternative approach involves a pelvic scan after intra-arterial contrast injection into the infrarenal abdominal aorta (catheter left in place after cardiac catheterization) using a very low dose (15 mL) of contrast.
      • Joshi S.B.
      • Mendoza D.D.
      • Steinberg D.H.
      • et al.
      Ultra-low-dose intra-arterial contrast injection for iliofemoral computed tomographic angiography.
      If contrast administration is not feasible, a noncontrast scan, although not optimal, still allows the assessment of overall vessel size, calcification, and tortuosity.
      As previously mentioned, analysis and measurement of the annulus size and shape are crucial for procedural success. Typical annulus measurements, obtained using 2D TTE or TEE provide a single diameter measurement, assuming a circular annular orifice.
      • Moss R.R.
      • Ivens E.
      • Pasupati S.
      • et al.
      Role of echocardiography in percutaneous aortic valve implantation.
      In contrast, 3D CT systolic reconstruction of the annulus orthogonal to the center-axis of the LVOT allows for the assessment of minimal and maximal diameter, circumference, and area measurements.
      • Messika-Zeitoun D.
      • Serfaty J.M.
      • Brochet E.
      • et al.
      Multimodal assessment of the aortic annulus diameter: