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UNIVERSITY OF OULU P .O. Box 8000 F I -90014 UNIVERSITY OF OULU FINLAND
A C T A U N I V E R S I T A T I S O U L U E N S I S
Professor Esa Hohtola
University Lecturer Santeri Palviainen
Postdoctoral research fellow Sanna Taskila
Professor Olli Vuolteenaho
University Lecturer Veli-Matti Ulvinen
Director Sinikka Eskelinen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-1227-2 (Paperback)ISBN 978-952-62-1228-9 (PDF)ISSN 0355-3221 (Print)ISSN 1796-2234 (Online)
U N I V E R S I TAT I S O U L U E N S I S
MEDICA
ACTAD
D 1367
ACTA
Antonino S. R
ubino
OULU 2016
D 1367
Antonino S. Rubino
EFFICACY OF THE PERCEVAL SUTURELESS AORTIC VALVE BIOPROSTHESIS IN THE TREATMENT OF AORTIC VALVE STENOSIS
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;MEDICAL RESEARCH CENTER OULU;OULU UNIVERSITY HOSPITAL
A C T A U N I V E R S I T A T I S O U L U E N S I SD M e d i c a 1 3 6 7
ANTONINO S. RUBINO
EFFICACY OF THE PERCEVAL SUTURELESS AORTIC VALVE BIOPROSTHESIS IN THE TREATMENT OF AORTIC VALVE STENOSIS
Academic Dissertation to be presented with the assent ofthe Doctora l Train ing Committee of Health andBiosciences of the University of Oulu for public defence inAuditorium 1 of Oulu University Hospital, on 3 June2016, at 12 noon
UNIVERSITY OF OULU, OULU 2016
Copyright © 2016Acta Univ. Oul. D 1367, 2016
Supervised byProfessor Fausto BiancariProfessor Tatu Juvonen
Reviewed byDocent Juha NissinenDocent Otso Järvinen
ISBN 978-952-62-1227-2 (Paperback)ISBN 978-952-62-1228-9 (PDF)
ISSN 0355-3221 (Printed)ISSN 1796-2234 (Online)
Cover DesignRaimo Ahonen
JUVENES PRINTTAMPERE 2016
OpponentDocent Peter Raivio
Rubino, Antonino S., Efficacy of the Perceval sutureless aortic valve bioprosthesisin the treatment of aortic valve stenosis. University of Oulu Graduate School; University of Oulu, Faculty of Medicine; MedicalResearch Center Oulu; Oulu University HospitalActa Univ. Oul. D 1367, 2016University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
Aortic valve stenosis (AS) is one of the most diffuse valvular diseases in developed countries. ASis a progressive disease, which usually results in serious life-threatening adverse events. Defininga treatment strategy for AS is a focus of cardiovascular research, although the topic is stillcontroversial because of its related clinical and economical implications.
Surgical aortic valve replacement (AVR),which is regarded as the gold standard for thetreatment of severe symptomatic AS, affords excellent results, particularly in asymptomaticpatients with good functional status. AVR requires the institution of cardiopulmonary bypass andaortic cross-clamping, and the duration of these procedures is directly associated with increasingmorbidity and mortality, especially in patients with preoperative comorbidities.
Accordingly, techniques aimed at decreasing the duration of cardiopulmonary bypass andaortic cross-clamping have the potential to improve postoperative outcomes of AVR.
In the present study, we demonstrated that the Perceval sutureless bioprosthesis couldsignificantly reduce the duration of the surgical procedure. This was associated with improvedimmediate postoperative outcomes and long-term freedom from adverse events.
The use of a Perceval sutureless bioprosthesis can facilitate AVR through minimally invasiveapproaches and is associated with fewer transfusions of packed red cells compared to fullsternotomy approaches, even with traditional stented bioprostheses. It could be expected thatpatients at intermediate-high risk would benefit more from the combination of a fast surgicalprocedure, performed with reduced surgical invasiveness.
When compared to transcatheter aortic valve implantation (TAVI), the Perceval suturelessbioprosthesis was associated with increased incidence of device success as well as lessparavalvular leak, with similar immediate and 1-year outcomes.
Finally, AVR with the Perceval sutureless bioprosthesis provided excellent hemodynamics atrest and under high workload. The significant increase of effective orifice area under stresssuggests that the Perceval sutureless bioprosthesis is the valve of choice for patients with smallaortic annuli or when prosthesis-patient mismatch is anticipated.
Keywords: aortic stenosis, aortic valve replacement, cross-clamping time, sutureless
Rubino, Antonino S., Ompeleettoman biologisen Perceval-aorttaläppäproteesintehokkuus aorttaläpän ahtauman hoidossa. Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Medical ResearchCenter Oulu; Oulun yliopistollinen sairaalaActa Univ. Oul. D 1367, 2016Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Aorttaläpän ahtauma on yksi yleisimmistä läppävioista kehittyneissä maissa. Aorttaläpänahtauma on etenevä sairaus, joka yleensä johtaa vakaviin henkeä uhkaaviin haittatapahtumiin.Aorttaläpän ahtauman hoitotavasta keskustellaan kiivaasti sydän- ja verisuonitautien tutkimuk-sessa siihen liittyvien kliinisten ja taloudellisten vaikutusten vuoksi.
Aorttaläppäleikkausta, jossa aorttaläppä korvataan proteesilla, on aina pidetty vaikean oirei-sen aorttaläpän ahtauman hoidon kultaisena standardina, koska sen tulokset ovat erinomaisia,etenkin oireettomilla potilailla, joilla sydämen toiminta on hyvä. Leikkaus vaatii sydän-keuhko-koneen käyttöä ja aortan sulkemista, joiden kesto on suoraan yhteydessä kasvavaan sairastavuu-teen ja kuolleisuuteen erityisesti potilailla, joilla on muitakin sairauksia.
Niinpä tekniikat, jotka lyhentävät sydän-keuhkokoneen käyttöaikaa ja aortan sulkuaikaa, voi-vat mahdollisesti parantaa aorttaläppäleikkauksen tuloksia.
Tässä tutkimuksessa osoitettiin, että ompeleettoman biologisen Perceval-läppäproteesin käyt-tö vähensi merkittävästi leikkauksen kestoa. Tämä oli yhteydessä parantuneisiin lyhyen ja pit-kän aikavälin tuloksiin leikkauksen jälkeen.
Ompeleettoman biologisen Perceval-läppäproteesin käyttö voi helpottaa aorttaläppäleikkaus-ta, koska se voidaan asentaa vähemmän kajoavasta avauksesta, ja siihen liittyy vähemmän puna-solusiirtoja rintalastan kokoavaukseen verrattuna, myös silloin kun käytetään kokoavausta japerinteisiä stenttibioproteeseja. Voisi olla odotettavaa, että keskisuuren tai suuren riskin potilaathyötyisivät enemmän leikkauksesta, jossa yhdistyvät toimenpiteen nopeus ja vähäisempi kajoa-vuus.
Katetriteitse asennettuun biologiseen keinoläppään (TAVI) verrattuna ompeleeton biologinenPerceval-läppäproteesi oli yhteydessä parempaan laitteen toimimiseen ja pienempään paravalvu-laariseen vuotoon. Muut tulokset heti leikkauksen jälkeen ja yhden vuoden seurannassa olivatsamanlaisia.
Lopuksi voidaan todeta, että aorttaläppäleikkaukseen ompeleettomalla biologisella Perceval-läppäproteesilla liittyi erinomainen hemodynamiikka levossa ja korkean työkuorman aikana.Stressin aikaisen tehokkaan aorttaläpän aukon pinta-alan merkittävä kasvu osoittaa, että ompe-leeton biologinen Perceval-läppäproteesi on hyvä valinta potilaille, joilla on pieni aorttaläpänaukko tai kun on odotettavissa proteesin ja potilaan yhteensopimattomuutta.
Asiasanat: aortan sulkuaika, aorttaläppäleikkaus, aorttaläpän ahtauma, ompeleeton
To my beloved wife, my daughter and my son
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Acknowledgements
The present study was conducted at the Cardiac Surgery Unit, Azienda
Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele”, University of Catania,
Italy as well as Department of Cardiology and Cardiovascular Surgery, Centro
Clinico-Diagnostico “G.B. Morgagni” in Pedara (CT), Italy, during the years
2015-2016.
First of all, I had to express my full gratitude to my principal supervisor
Professor Fausto Biancari. Since we met for the first time during a congress in
Tampere, you recognized in me the attitude to research that you always have
prompted me to express at the best of my possibilities. You have supported me
during these last three years, helping me to achieve great goals, such as my first
AATS oral presentation. But, above all, I thank you for the opportunity to build a
strong friendship that lasts despite the great distances between Italy and Finland.
I want to thank my second supervisor Professor Tatu Juvonen for his
commitment in supervisoring me during my Doctoral program.
I sincerely thank my pre-examiners Docent Juha Nissinen and Docent Otso
Järvinen for academic revision of the manuscript of the thesis. The comments you
have expressed on my as thesis have helped me in impriving the quality of the
dissertation markedly. I also want to thank Ph.D. Deborah Kaska for careful
revision of the language and Eeva-Maja Kinnunen, MD PhD for revision of the
Finnish abstract.
I wish to thank the members of my follow-up group, Professor Pekka Rainio,
Professor Jouni Heikkinen and Professor Jarmo Lahtinen for your valuable and
encouraging feedback regarding the original articles as well as the progress of the
entire project.
I want to thank particularly Doctor Carmelo Mignosa, my Chief, mentor and
friend. You support me during my surgical training and always give me the
opportunity to have a particular exposure at several international meetings.
My special thanks go also to all the co-authors of the original articles for
collaboration. I believe that this experience have helped all of us to establish an
extensive cooperation between all our Institutions.
I am particularly grateful to Wanda Deste, Gianni Millan and the residents of
the School of Cardiology of the University of Catania for their support during all
the echocardiographic studies performed. A particular thank to Vincenzo Lavanco
and Vincenzo Caruso for their deep involvement in the project.
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My deepest gratitude and love goes to my parents, Angela e Guido. You have
always loved and encouraged me during all my life, at first as a child,
subsequently as a student and now as a father and husband. You are the examples
I want to give to my children.
Finally, my deepest and absolute love goes to my wife Lucia. I try with all
my efforts to give you a lovely life, but I cannot match what you have given me:
our children.
Catania, April 2016 Antonino S. Rubino
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Abbreviations
Ao aorta
AS aortic stenosis
AVA(i) aortic valve area (index)
AVR aortic valve replacement
CABG coronary artery bypass graft
CSA cross sectional area
DSE dobutamine stress echocardiography
DVI dimensionless velocity index
EOA(i) effective orifice area (index)
HR hazard ratio
LVEF left ventricular ejection fraction
LVOT left ventricular outflow tract
PPM prosthesis-patient mismatch
SV stroke volume
TAVI transcatheter aortic valve implantation
VTI velocity-time integral
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Original publications
This thesis is based on the following publications, which are referred throughout
the text by their Roman numerals:
I Rubino AS, Santarpino G, De Praetere H, Kasama K, Dalén M, Sartipy U, Lahtinen J, Heikkinen J, Deste W, Pollari F, Svenarud P, Meuris B, Fischlein T, Mignosa C & Biancari F (2014) Early and intermediate outcome after aortic valve replacement with a sutureless bioprosthesis: Results of a multicenter study. J Thorac Cardiovasc Surg 148:865–871.
II Dalén M, Biancari F, Rubino AS, Santarpino G, De Praetere H, Kasama K, Juvonen T, Deste W, Pollari F, Meuris B, Fischlein T, Mignosa C, Gatti G, Pappalardo A, Sartipy U & Svenarud P (2015) Mini-sternotomy versus full sternotomy aortic valve replacement with a sutureless bioprosthesis: a multicenter study. Ann Thorac Surg 99: 524–530.
III Dalén M, Biancari F, Rubino AS, Santarpino G, Glaser N, De Praetere H, Kasama K, Juvonen T, Deste W, Pollari F, Meuris B, Fischlein T, Mignosa C, Gatti G, Pappalardo A, Svenarud P &Sartipy U. (2016) Aortic valve replacement through full sternotomy with a stented bioprosthesis versus minimally invasive sternotomy with a sutureless bioprosthesis. Eur J Cardiothorac Surg 49: 220–227
IV D'Onofrio A, Salizzoni S, Rubino AS, Besola L, Filippini C, Alfieri O, Colombo A, Agrifoglio M, Fischlein T, Rapetto F, Tarantini G, Dalèn M, Gabbieri D, Meuris B, Savini C, Gatti G, Aiello ML, Biancari F, Livi U, Stefàno PL, Cassese M, Borrello B, Rinaldi M, Mignosa C & Gerosa G; Italian Transcatheter Balloon-Expandable Registry and the Sutureless Aortic Valve Implantation Research Groups. (In press) The rise of new technologies for aortic valve stenosis: A comparison of sutureless and transcatheter aortic valve implantation. J Thorac Cardiovasc Surg
V Biancari F, Barbanti M, Santarpino G, Deste W, Tamburino C, Gulino S, Immè S, Di Simone E, Todaro D, Pollari F, Fischlein T, Kasama K, Meuris B, Dalén M, Sartipy U, Svenarud P, Lahtinen J, Heikkinen J, Juvonen T, Gatti G, Pappalardo A, Mignosa C & Rubino AS (2015) Immediate outcome after sutureless versus transcatheter aortic valve replacement. Heart Vessels 31: 427–433.
VI Rubino AS, Biancari F, Caruso V, Lavanco V, Privitera F, Rinaldi I Sanfilippo M, Millan G, D’Urso LV, Castorina S & Mignosa C (2016) Hemodynamic assessment of the Perceval sutureless valve by dobutamine stress echocardiography. (Manuscript)
Contributions of the author of the thesis:
I Conception and design of the study, acquisition of data, drafting the article,
revising it critically for important intellectual content, final approval of the
final version of the manuscript to be submitted.
14
II Conception and design of the study, acquisition of data, revising the article
critically for important intellectual content, final approval of the final version
of the manuscript to be submitted.
III Conception and design of the study, acquisition of data, revising the article
critically for important intellectual content, final approval of the final version
of the manuscript to be submitted.
IV Conception and design of the study, acquisition of data, drafting the article,
revising it critically for important intellectual content, final approval of the
final version of the manuscript to be submitted.
V Conception and design of the study, acquisition of data, drafting the article,
revising it critically for important intellectual content, final approval of the
final version of the manuscript to be submitted.
VI Conception and design of the study, acquisition of data, drafting the article,
revising it critically for important intellectual content, final approval of the
final version of the manuscript to be submitted.
15
Contents
Abstract
Tiivistelmä
Acknowledgements 9 Abbreviations 11 Original publications 13 Contents 15 1 Introduction 19 2 Review of the literature 21
2.1 Epidemiology of aortic valve stenosis .................................................... 21 2.2 Etiopathogenesis and pathology of aortic valve stenosis ........................ 21 2.3 Diagnosis of aortic valve stenosis ........................................................... 22 2.4 Natural history of aortic valve stenosis ................................................... 26 2.5 Indications for treatment of aortic valve stenosis .................................... 26 2.6 Risk factors for associated morbidity and mortality after surgical
AVR ......................................................................................................... 33 2.6.1 Risk stratification and surgical scores .......................................... 33 2.6.2 Coronary artery disease ................................................................ 35 2.6.3 Left ventricular hypertrophy ......................................................... 36 2.6.4 Mitral valve disease ...................................................................... 36 2.6.5 Functional tricuspid regurgitation and pulmonary
hypertension ................................................................................. 38 2.6.6 Porcelain aorta .............................................................................. 38 2.6.7 Small aortic annulus and patient prosthesis mismatch ................. 39 2.6.8 Atrial fibrillation ........................................................................... 39 2.6.9 Advanced age ............................................................................... 40 2.6.10 Gender-related differences............................................................ 41 2.6.11 Low-flow/low-gradient aortic stenosis ......................................... 42 2.6.12 Aortic cross-clamping time .......................................................... 43 2.6.13 Redo operations ............................................................................ 44
2.7 The impact of minimally invasive approaches on outcomes after
AVR ......................................................................................................... 45 3 Aim of the research 47 4 Materials and methods 49
4.1 Study design and patient populations ...................................................... 49 4.2 Data collection and risk stratification ...................................................... 51
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4.3 Operative technique ................................................................................ 51 4.4 Endpoints of the study ............................................................................. 52 4.5 Statistical analysis ................................................................................... 53
5 Results 55 5.1 In-hospital and mid-term outcomes after AVR with Perceval
bioprosthesis (I) ....................................................................................... 55 5.1.1 Octogenarians ............................................................................... 59 5.1.2 Operative outcomes after full sternotomy vs minimally
invasive approach ......................................................................... 60 5.2 Stratification of in-hospital mortality according to quartiles of
EuroSCORE II (I) ................................................................................... 60 5.3 Implantation of Perceval bioprosthesis with minimally invasive
approaches (II) ........................................................................................ 61 5.4 Comparison of minimally invasive Perceval implantation to the
traditional approach with full sternotomy and stented valves (III) ......... 68 5.5 In-hospital outcomes and 1-year survival after AVR with the
Perceval sutureless bioprosthesis vs TAVI (IV) ...................................... 76 5.5.1 Perceval sutureless bioprosthesis vs all TAVI ............................... 78 5.5.2 Perceval sutureless bioprosthesis vs transapical TAVI ................. 78 5.5.3 Perceval sutureless bioprosthesis vs trans-femoral TAVI ............. 79
5.6 Immediate outcomes after AVR with the Perceval sutureless
bioprosthesisvs TAVI (V) ........................................................................ 80 5.7 Hemodynamic assessment of the Perceval sutureless
bioprosthesis with dobutamine stress echocardiography (VI) ................. 86 5.7.1 Variation of EOA in patients with baseline prosthesis-
patient mismatch ........................................................................... 88 5.7.2 Variation of EOA according to valve size ..................................... 88
6 Discussion 91 6.1 Impact of AVR with the Perceval sutureless bioprosthesis on in-
hospital and mid-term outcomes (I) ........................................................ 91 6.2 Usefulness of the Perceval sutureless bioprosthesis in minimally
invasive AVR (II) .................................................................................... 92 6.3 Advantages of minimally invasive AVR with the Perceval
sutureless bioprosthesis compared to traditional surgery (III) ................ 93 6.4 Different outcomes for different techniques (IV) .................................... 94
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6.5 Spreading light on the “gray-zone” between traditional AVR and
TAVI (V) ................................................................................................. 96 6.6 A stentless valve with a sutureless technology (VI) ................................ 97
7 Conclusions 99 8 Future perspectives 101 List of references 103 Original publications 117
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1 Introduction
The treatment strategy for aortic valve stenosis (AS) is a controversial topic in
cardiovascular research, because of the related clinical and economic implications.
It has been estimated that AS is one of the most common valvular diseases in
developed countries, second only to mitral valve disease, with an incidence that is
expected to double in the next 50 years [1].
AS stenosis is a progressive disease, which usually results in serious life-
threatening adverse events [2]. The chronic increased impedance to forward flow
is compensated initially by an increase of left ventricular wall thickness, but
invariably leads to various degrees of ventricular failure if the valve pathology is
misdiagnosed or left untreated.
Surgical aortic valve replacement (AVR) has always been regarded as the
gold standard treatment for severe symptomatic aortic stenosis, with excellent
results, especially in asymptomatic patients with good functional status [3,4].
However, the incidence of postoperative complications parallels the number of
other comorbidities that range from age to diabetes, from organ failure to
associated cardiac and non-cardiac pathologies, and include patient frailty.
AVR requires inevitably the institution of cardiopulmonary bypass and aortic
cross-clamping, the duration of which is directly associated with increasing
morbidity and mortality [5,6], especially in high risk patients.Therefore, new
technologies designed to reduce the adverse events associated with this procedure
have recently been developed.
The Perceval sutureless valve (Sorin Group, Saluggia, Italy) (Figure 1) is a
novel aortic valve bioprosthesis with a unique design that facilitates its surgical
implantation with reduced duration of the surgical procedure. There is increasing
evidence that AVR with a sutureless bioprostheses is associated with favorable
outcomes in intermediate risk patients [7,8]. Its use is particularly attractive in
minimally invasive surgery [9–11].
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Fig. 1. Perceval sutureless bioprosthesis is made of bovine pericardium, folded over a
nitinol stent.
Transcatheter aortic valve implantation (TAVI) provides excellent results in
patients at high or prohibitive surgical risk, and recently became a recommended
procedure for patients with absolute contraindications to surgery [12,13].
However, operative and follow-up results of TAVI in intermediate risk patients
are questionable, particularly because of the increased risk of incidence of
paravalvular leakage, which is a risk factor for adverse events.
This dissertation aims to clarify the effect of sutureless AVR on the
immediate operative morbidity and mortality, and to evaluate the durability of the
results at mid-term follow-up. In particular, the feasibility of a minimally invasive
implant will be investigated, also in comparison with traditional surgery
performed through full sternotomy and with the use of stented bioprostheses.
The potential benefits of sutureless AVR will be assessed in comparison to
TAVI, to ascertain which technique is preferred in intermediate risk patients with
severe AS.
Finally, the hemodynamic features of this valve will be examined under high
workload to ascertain if the indication to sutureless AVR could be extended also
to younger and physically active patients.
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2 Review of the literature
2.1 Epidemiology of aortic valve stenosis
AS is one of the most prevalent valvular disease in the developed countries
[15,16].
A recent systematic review showed that the pooled prevalence in the general
European population aged 55–74 years and >75 years is 2.9% (1.5–4.3%) and
13.6% 8.3–18.9%), respectively [15]. In particular, 21.6% (19.1–24.2%) of these
patients have severe AS and 71.1% (62.7–79.4%)are symptomatic. According to
these figures, it has been estimated that almost 9.2 million Europeans aged ≥55
years have AS, almost 2 million have severe AS, 1.2 million are eligible for
surgical aortic valve replacement (AVR) and 230.000 for transcatheter aortic
valve implantation (TAVI)being considered at high risk for surgery [15].
Osnabrugge et al.[16]reporteda pooled prevalence of AS of 12.4% (6.6–
18.2%) among elderly patients aged ≥75 years. Of them, 3.4% (1.1–5.7%) have
severe AS, with 75.6% being symptomatic. These data account for almost 1
million people in Europe and 540 000 in North America that suffer from severe
symptomatic AS.
With the ageing of the population, the prevalence of AS is expected to
increase. Iung & Vahanian recently reported that in France, the number of patients
aged ≥75 years with at least moderate AS is expected to double over the next 50
years [1].
Accordingly AS has a significant impact on public health management as it
requires an increasing burden of health care resources utilization.
2.2 Etiopathogenesis and pathology of aortic valve stenosis
Aortic valve degeneration is a progressive disease that begins with leaflet
thickening thateventually leadsto severe calcifications within the aortic cusps.
This process has been frequently considered a natural evolution of the valve
opening and closing cycles and often addressed as a senile degeneration of valve
tissues [16].
However, recent studieshave demonstrated that the degenerative processes
leading to severe aortic stenosis encompass biological pathways similar to
atherogenesis and osteogenesis [16–18].
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To better understand the etiopathogenesis of aortic valve degeneration, a
concise overview of the normal histology of the aortic valve is provided. The
aortic cusps are attached to the aortic wall in a semilunar fashion between the
three commissures. Vascular endothelial cells cover the valve on both the
ventricular and aortic sides. In between, there is a core of three layers of
interstitial cells in continuity with the supporting structures of the other valves,
but with differing extracellular matrix composition: the ventricularis (rich in
elastin), the spongiosa (rich in glycosaminoglycans) and the fibrosa (rich in
collagen).
The extracellular matrix is not directly involved in the degeneration process
of the aortic valve, as the role of the glycosaminoglycan layer is to facilitate the
rearrangements of the other two layers during the opening and closing cycles. On
the other hand, in vitro and in vivo studies have demonstrated that the interstitial
cells have the potential to promote osteogenesis and angiogenesis in response to
several stimuli, such as hypertension, elevated LDL concentrations, mechanical
stretch and stress on the leaflets or various inflammatory states associated with an
abnormal secretion of pro-inflammatory cytokines and growth factors. [16,17].
The remodeling process that eventually ends up in aortic stenosis can be
divided into two phases: an initiation phase with pathways similar to
atherogenesis (lipid deposition and inflammatory cascade activation), followed by
a propagation phase during which osteogenesis becomes prominent [18].
Briefly, endothelial injury is initiated by several stimuli (e.g. mechanical
stress, infections, systemic inflammation) with consequential lipid deposition and
oxidization in the interstitial layers. This promotes apoptosis with deposition of
microcalcifications. Endothelial injuries as well as increased mechanical stress in
the stiffer cusps initiate a pro-inflammatory cascade that is maintained in a self-
propagating loop. Accordingly, the interstitial cells initially produce a collagen
matrix (aortic sclerosis) and subsequently differentiate into osteoblast-like cells,
which are ultimately responsible for extensive calcium deposition over the
collagen scaffold. [17,18]
2.3 Diagnosis of aortic valve stenosis
Patients with suspected AS usually present with a heart murmur or abnormalities
in non-invasive tests. Regardless of the presentation, accurate history
investigation and physical examination should be performed in all patients with
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suspect or already diagnosed AS. In fact, patients often report an absence of
symptoms because they have progressively limited their daily activities, and this
should also be considered as a symptom.
A physical examination is important to assess the general condition as well as
to reveal other comorbidities.
Electrocardiography and chest X-ray are useful to investigate heart rhythm
and to give an estimate of pulmonary functional capacity. Accordingly,
electrocardiography may unveil underlying atrial fibrillation, as well as different
degrees of bundle branch block. X-ray can illuminate pulmonary congestion as
well as an enlarged cardiac silhouette.
However, transthoracic echocardiography represents the gold standard to
confirm clinical suspects and to assess the severity of the lesion [19].
Criteria and methods for the management of valvular pathology have been
defined in the most recent 2009 guidelines of the American Society of
Echocardiography/ European Association of Echocardiography [20].
Peak aortic velocity
Peak aortic velocity is the most reliable predictor of poor outcome in patients with
AS [21]. It is measured with continuous wave Doppler from the best window
available (apical, suprasternal, right parasternal). The severity of AS is defined as
mild if the peak velocity is <2.9 m/sec, moderate if 3-3.9 m/sec and severe if >4.0
m/sec [13,20].
Transvalvular gradients
Peak and mean transvalvular gradients are measured with continuous wave
Doppler from the same windows and are a direct function of velocity. Peak
gradient is calculated as 4V2max according to the Bernoulli equation. Mean
gradients are calculated as the integral of the velocity trace during one systole. AS
is defined as mild if the mean gradient is <25 mmHg, moderate if 25-40 mmHg
and severe if >40 mmHg [13,20].
However, gradients are also linearly dependent on cardiac output (e.g. AS is
underestimated in case of hypovolemia, low output state, low ejection fraction)
and coexistent valvular diseases (increased gradients with associated aortic
regurgitation or decreased in case of associated mitral regurgitation).
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Aortic valve area
Aortic valve area is calculated according to the continuity equation
(SVLVOT=SVAo). Stroke volume can be expressed as the product of the cross-
sectional area and velocity-time integral (SV=CSAxVTI). Therefore, aortic valve
area (AVA) can be calculated as CSALVOT x VTILVOT / VTIAo [13,20].
LVOT diameter is measured in meso-systole from a long-axis view. VTILVOT
is measured with pulsed wave Doppler from a 5- or 3-chambers view, VTIAo is
measured with pulsed wave Doppler from the best view. This calculation is
dimension-dependent as also minimal variations of the LVOT diameter are
squared.
AS is considered mild if AVA is 1.5-2 cm2, moderate if 1.0-1.5 cm2 and
severe if <1.0 cm2. AVA calculation can be indexed to body surface area (AVA
index). In this case, the thresholds for AS classification are as follows: mild >0.85
cm2/m2, moderate 0.85-0.6 cm2/m2, severe <0.6 cm2/m2 [13,20].
Similarly, the functional area of an aortic valve prosthesis (effective orifice
area – EOA) can be calculated with the continuity equation as well. The EOA
indexed to the body surface area is of particular clinical relevance, as an EOAi
<0.85 cm2/m2 is diagnostic for prosthesis-patient mismatch (PPM), with EOAi
<0.65 cm2/m2 considered to be a severe PPM [22].
Velocity ratio or dimensionless velocity index (DVI)
Starting from the assumption that a normal aortic valve area is equal to that of the
corresponding LVOT in each individual, the ratio between the peak velocities (or
VTI) in LVOT to that across the aortic valve represents a simple method to assess
the severity of valve stenosis.
Therefore, AS is considered mild if DVI is 0.5-1, moderate if 0.25-0.5 and
severe if <0.25. Since DVI incorporates the effect of flow on velocity through the
valve and is much less dependent on valve size, this method can be particularly
useful for screening for valve dysfunction [13,20].
Left ventricular geometry
The increased transaortic impedance to blood flow is compensated by a reactive
concentric hypertrophy of the left ventricle. Interventricular septum, left
ventricular diameters and posterior wall thickness are usually recorded during
25
transthoracic echocardiography and give an estimate of the left ventricular mass.
Relative wall thickness is a derived parameter that is helpful to discern between
concentric remodeling, concentric hypertrophy and eccentric hypertrophy [23,24]
(Figure 2).
Fig. 2. Definition of different degrees of ventricular remodeling according to left
ventricular mass index, relative wall thickness and gender [modified from MDMath,
Canadian Society of Echocardiography - http://csecho.ca/mdmath/?tag=lvmlvmi]
Left ventricular function
Left ventricular systolic and diastolic function is a mandatory evaluation in the
echocardiographic work-up for AS.
In fact, all the estimates of aortic valve stenosis or prosthesis dysfunction are
directly correlated to the flow generated across the valve. Accordingly, the
severity of stenosis or prosthesis dysfunction can be underestimated in case of
reduced ejection fraction. This is the case of the so called low-flow low-gradient
AS. Typically, this is observed in the case of AVA<1 cm2, peak velocity <4 m/sec
or mean gradient <40 mmHg and a LVEF ≤50% [25].
Dobutamine stress echocardiography (DSE) is therefore recommended to
discriminate between a fixed aortic stenosis (significant increase in gradients and
velocities without increasing valve area under DSE) and a moderate stenosis
(slight increase in gradients and velocities with a significant increase of valve
area under DSE). DSE is an interesting investigational tool to assess prosthetic
valve function as an alternative to exercise echocardiography [26].
26
2.4 Natural history of aortic valve stenosis
AS is a progressive disease and requires prompt treatment once diagnosed.
Generally, only 10-15% of patients with aortic sclerosis develop a stenosis over a
period of 2 to 5 years. However, when even mild stenosis is diagnosed, the
progression to severe obstruction is unavoidable, with an expected increase of
transvalvular velocity from 0.1 to 0.3 m/sec/year and an increase of mean
gradient from 3 to 10 mmHg/year as well as a reduction rate of valve area by 0.1
cm2/year. [27]
Patients with severe stenosis, left on medical therapy alone, experience a poor
outcome, with worsening of symptoms and an expected survival of 50% at 2
years and 20% at 5 years [28]. The approximate time interval after the onset of
symptoms to death is 2 years for heart failure, 3 years for syncope and 5 years for
angina [2].
Therefore, prompt treatment is required at the time of diagnosis, especially
after symptom onset. In particular, symptomatic patients undergoing AVR
experience similar long-term outcomes compared to asymptomatic operated
patients. Conversely, the outcome at follow-up is poorer if asymptomatic patients
are left untreated, and even worse if symptomatic patients are left to the natural
history of their aortic valve pathology [3,4,21].
2.5 Indications for treatment of aortic valve stenosis
The goals of intervention in AS are to relieve symptoms, enhance exercise
capacity and quality of life, and prolong life expectancy. The desired effects of
relieving the barrage to the left ventricle are improvements in left ventricular
function and a regression of hypertrophy.
The Joint Task Force on the Management of Valvular Heart Disease of the
European Society of Cardiology (ESC) and the European Association for Cardio-
Thoracic Surgery (EACTS) published in 2012 the Guidelines on the management
of valvular heart disease [29].
The American College of Cardiology/American Heart Association Task Force
on Practice Guidelines has renewed in 2014 the indications for the management
of patients with valvular heart disease [13].
As far as the treatment of aortic valve stenosis is considered, both guidelines
are overlapping either in terms of diagnosis or indications. Accordingly, in the
present dissertation the more recent ACC/AHA guidelines will be discussed.
27
In this last edition of the guidelines, patients with AS have been divided into
four stages according to symptoms:
– Stage A – at risk: asymptomatic patients with known risk factors;
– Stage B – progressive: asymptomatic patients with mild-to-moderate severity
of disease with a progressive worsening of valve dysfunction;
– Stage C – asymptomatic severe: asymptomatic patients with diagnosis of
severe valve disease with normal ventricular function (C1) or ventricular
dysfunction (C2);
– Stage D – symptomatic severe: patients who developed symptoms directly
correlated to the valve disease: high-gradient AS (D1); low-flow low-gradient
AS (D2); low-gradient AS with normal EF or paradoxical low-flow AS (D3).
Patients in Stage A do not need follow-up evaluations unless new onset of
symptoms occurs. Conversely, patients in Stage D have a clear indication for the
treatment of AS. In between, patients in Stage B and C need routine follow-up
evaluations to assess the progression of the disease. In particular, patients in Stage
B should be scheduled every 3-5 years in case of mild disease or with a 1-2 year
interval in case of moderate stenosis; on the other hand, patients in Stage C need a
close follow-up of 6-12 months [13].
Irrespective of the stage, all other pre-existing risk factors should be
addressed with optimal medical therapy, particularly systemic hypertension [30].
Moderate physical exercise should be encouraged in any case, when feasible.
The decision to intervene should be weighted against the inherent risk of the
procedure (either surgical or transcatheter) and the natural history of the disease.
Several scoring systems (e.g. STS and EuroSCORE II) are able to predict
immediate mortality after surgery and therefore should be taken into account in
any counseling for surgical risk stratification [13]. However, the comprehensive
clinical and instrumental assessment of the patient’s clinical conditions is
mandatory to unveil underlying pathologies that would impair the immediate
result of the procedure (e.g. pulmonary or liver dysfunction, neurological
disorders, frailty). Moreover, surgery should be planned correctly during
preoperative work-up, to exclude any technical impediment, such as porcelain
aorta in case of AVR (Table 1).
28
Ta
ble
1. R
isk
as
se
ssm
en
t co
mb
inin
g S
TS
PR
OM
, F
rail
ty,
Ma
jor
org
an
co
mo
rbid
itie
s a
nd
pro
ced
ure
-sp
ec
ific
im
pe
dim
en
t (a
dap
ted
fro
m N
ish
imu
ra e
t al 2
01
4 [
13])
.
Para
mete
r to
be c
onsi
dere
d
Low
Ris
k
(Mu
st m
ee
t A
LL
crite
ria
)
Inte
rmedia
te R
isk
(An
y 1
crite
rio
n)
Hig
h R
isk
(An
y 1
crite
rio
n)
Pro
hib
itive
Ris
k
(An
y 1
crite
rio
n)
ST
S P
RO
M
<4
%
4%
-8%
>
8%
P
red
icte
d r
isk
of
de
ath
or
ma
jor
org
an
com
orb
iditi
es
>50
% a
t 1
yea
r
Fra
ilty1
N
one
1 in
dex
≥2 in
dic
es
Ma
jor
pre
op
era
tive
org
an
co
mp
rom
ise n
ot
to
be im
pro
ved p
ost
opera
tively
None
1 o
rgan s
yste
m
No m
ore
than 2
org
an
syst
em
s
≥3 o
rgan s
yste
ms
Pro
cedure
-speci
fic im
pedim
ent2
N
one
P
oss
ible
P
oss
ible
S
eve
re
1 F
railt
y ca
n b
e a
ssess
ed b
y K
atz
Act
iviti
es
of
Daily
Liv
ing a
nd in
dep
ende
nce
in a
mbu
latio
n,
as
well
as
oth
er
scoring s
yste
ms
2 F
or
exa
mple
tra
cheost
om
y pre
sent,
heavi
ly c
alc
ified a
scendin
g a
ort
a, ch
est
malfo
rmatio
n,
art
erial c
oro
nary
gra
ft a
dhere
nt to
po
sterior
chest
wall,
or
radia
tion
dam
age
29
Accordingly, a multidisciplinary Heart Valve Team should evaluate the
patient preoperatively when treatment is considered [13].
In accordance with all the criteria already discussed, AVR is recommended in
the case of severe AS in symptomatic patients with preserved LVEF or in the case
of asymptomatic patients with LVEF≤50%. When another kind of cardiac surgery
is performed, the threshold for surgical procedure is also reducedforasymptomatic
patients with severe AS. Complete guidelines on indications for AVR are shown
in Table 2.
30
Ta
ble
2. T
imin
g t
o i
nte
rve
nti
on
(a
dap
ted
fro
m N
ish
imu
ra e
t al 2
01
4 [
13
]).
Reco
mm
end
atio
ns
Cla
ss o
f R
eco
mm
endatio
n
Leve
l of E
vide
nce
AV
R is
reco
mm
en
ded f
or
sym
pto
matic
patie
nts
with
se
vere
hig
h-g
radie
nt
AS
who h
ave
sym
pto
ms
I B
by
his
tory
or
on e
xerc
ise test
ing (
sta
ge D
1)
AV
R is
re
com
me
nd
ed
fo
r a
sym
pto
ma
tic p
atie
nts
with
seve
re A
S (
sta
ge
C2)
an
d L
VE
F <
50
%
I B
AV
R is
indic
ate
d f
or
patie
nts
with
se
vere
AS
(st
age C
or
D)
when u
nd
erg
oin
g o
ther
card
iac
surg
ery
I
B
AV
R is
reaso
nable
for
asy
mpto
matic
patie
nts
with
very
seve
re A
S (
stage C
1, aort
ic v
elo
city
≥5
.0
IIa
B
m/s
and lo
w s
urg
ical r
isk)
AV
R is
reaso
nable
in a
sym
pto
matic
patie
nts
(st
age C
1)
with
seve
re A
S a
nd d
ecr
ease
d e
xerc
ise
IIa
B
tole
rance
or
an e
xerc
ise fall
in b
lood p
ress
ure
AV
R is
reaso
nable
in s
ympto
matic
pa
tients
with
low
-flo
w/lo
w-g
radie
nt
seve
re A
S w
ith r
educe
d
IIa
B
LV
EF
(st
age D
2)
with
a lo
w-d
ose
do
buta
min
e s
tress
stu
dy
that sh
ow
s an a
ort
ic v
elo
city
≥4.0
m/s
(o
r m
ea
n p
ress
ure
gra
die
nt ≥4
0 m
m H
g)
with
a v
alv
e a
rea ≤
1.0
cm
2 a
t any
dobuta
min
e d
ose
AV
R is
reaso
nable
in s
ympto
matic
pa
tients
who h
ave
low
-flo
w/lo
w-g
radie
nt se
vere
AS
(st
age D
3)
IIa
C
wh
o a
re n
orm
ote
nsi
ve a
nd
ha
ve a
n L
VE
F ≥
50%
if c
linic
al,
hem
odyn
am
ic,
and a
nato
mic
data
support
valv
e o
bst
ruct
ion a
s th
e m
ost
like
ly c
ause
of
sym
pto
ms
AV
R is
re
aso
na
ble
fo
r p
atie
nts
with
mo
de
rate
AS
(st
ag
e B
) (a
ort
ic v
elo
city
3.0
–3
.9 m
/s)
wh
o a
re
IIa
C
underg
oin
g o
ther
card
iac
surg
ery
AV
R m
ay
be c
onsi
dere
d for
asy
mpto
matic
patie
nts
with
seve
re A
S (
stage C
1)
and r
apid
dis
ease
IIb
C
pro
gre
ssio
n a
nd lo
w s
urg
ica
l ris
k
AV
R =
aort
ic v
alv
e r
epla
cem
ent, A
S =
aort
ic s
tenosi
s, L
VE
F =
left v
entr
icula
r eje
ctio
n fra
ctio
n
31
As far as the choice of the procedure is concerned, surgery is the gold
standard for patients at low or intermediate surgical risk. However, the guidelines
support and encourage the role of the Heart Team in decision-making about
patients with high or prohibitive surgical risk, as TAVI is now becoming a
standard practice in many centers. Finally, whatever the kind of procedure to be
performed, there is no indication for patients at prohibitive surgical risk when life
expectancy is lower than 12 months (Table 3).
32
Ta
ble
3. C
ho
ice
of
su
rgic
al
ao
rtic
va
lve r
ep
lac
em
en
t o
r TA
VI
(ad
ap
ted
fro
m N
ish
imu
ra e
t al 2
01
4 [
13])
.
Reco
mm
end
atio
ns
C
lass
of
Reco
mm
endatio
n
Leve
l of E
vide
nce
Surg
ical A
VR
is r
eco
mm
ended in
patie
nts
who m
eet an
indic
atio
n f
or
AV
R w
ith lo
w o
r in
term
edia
te
I A
surg
ica
l ris
k
For
patie
nts
in w
hom
TA
VI
or
hig
h-r
isk
surg
ica
l AV
R is
bein
g c
onsi
dere
d,
mem
bers
of
a H
ea
rt T
eam
I
C
should
co
llabora
te to p
rovi
de o
ptim
al p
atie
nt ca
re
TA
VI
is r
eco
mm
en
de
d in
pa
tien
ts w
ho
me
et
an
ind
ica
tion
fo
r A
VR
fo
r A
S w
ho
ha
ve a
pro
hib
itive
I
B
surg
ica
l ris
k a
nd
a p
red
icte
d p
ost
-TA
VI
surv
iva
l >1
2 m
on
ths
TA
VI
is a
re
aso
na
ble
alte
rna
tive
to
surg
ica
l AV
R in
patie
nts
who m
eet
an in
dic
atio
n f
or
AV
R w
ith
IIa
B
hig
h s
urg
ica
l ris
k
Perc
uta
neous
aort
ic b
allo
on d
ilatio
n m
ay
be c
onsi
dere
d a
s a b
ridge to s
urg
ical o
r tr
ansc
ath
ete
r IIb
C
AV
R in
seve
rely
sym
pto
matic
patie
nts
with
se
vere
AS
TA
VI
is n
ot
reco
mm
ended in
patie
nts
in w
hom
exi
stin
g c
om
orb
iditi
es
wou
ld p
recl
ude t
he e
xpect
ed
III: n
o b
enefit
B
be
ne
fit f
rom
co
rre
ctio
n o
f A
S
AV
R =
aort
ic v
alv
e r
epla
cem
ent, T
AV
I =
tra
nsc
ath
ete
r a
ort
ic v
alv
e im
pla
nta
tion, A
S =
aort
ic s
tenosi
s
33
2.6 Risk factors for associated morbidity and mortality after
surgical AVR
2.6.1 Risk stratification and surgical scores
A predictive score is a statistical algorithm that allows the individual risk of an
event to occur to be assessed before a specific intervention is performed.
Risk models are useful for counseling, decision-making and research
purposes.
Current guidelines recommend the use of risk scores as a useful tool in the
decision process on whether or not to intervene for patients with severe valvular
heart diseases [13].
The ideal risk score should have both good discrimination and calibration.
Discrimination is the ability to differentiate between high- and low-risk patients.
Calibration is the result of the comparison between observed and predicted
outcome.
The European System for Cardiac Operative Risk Evaluation (EuroSCORE II)
and the Society of Thoracic Surgeons (STS) Score are currently the most used
risk scores to predict operative mortality after adult cardiac surgery.
EuroSCORE II is the natural evolution of the Logistic EuroSCORE. It is
derived from a database including 22381 consecutive patients undergoing cardiac
surgery in 154 hospitals of 43 countries during a 12-week observation period
(from May to July 2010). A subsequent validation cohort of 5553 patients was
used for internal validation [31]. It is designed to predict operative mortality and
provide a single percentage independently for the kind of procedure itself. In the
internal validation study, EuroSCORE II provided good discrimination and
calibration [30]. However, an external validation study by Barili and coworkers
has recently demonstrated that EuroSCORE II has a good discrimination but lacks
calibration in high-risk patients [32].
The STS Score is a continuously updated score that is derived from the data
collected from several North American Institutions. The latest version available at
the time of the present thesis is version 2.81. It is designed to predict operative
mortality and morbidity. It provides three different risk models (isolated coronary
artery bypass grafting, valve surgery, valve surgery+coronary artery bypass
grafting) with internal discrimination between mitral valve repair and replacement,
for a total of 7 risk models [33].
34
Internal reports from the Society of Thoracic Surgeons recognized that, like
EuroSCORE II, the STS score had good discrimination but lacks calibration in
high-risk patients [34].
As far as the main postoperative outcome is concerned, both scores define
mortality as any death occurring within 30 days from the operation or even longer
if the patient is still hospitalized. Accordingly, comparative validation studies can
be performed to test the ability of both scores to predict operative mortality.
A recent meta-analysis by Biancari et al showed that both EuroSCORE II and
STS score are reliable risk models of operative mortality for patients with severe
AS. In particular, EuroSCORE II was the most accurate model in low-surgical
risk patients, who are ideal candidates for AVR. However, mortality is usually
overestimated in the surgical setting and underestimated for TAVI [35].
Accordingly, Kuwaki et al. found that EuroSCORE II had good calibration
for low-risk patients whereas it underestimated operative mortality in high-risk
patients. On the other hand, the STS score showed good calibration for high-risk
patients but overestimated mortality in low-risk patients [36]. Similarly, Wang et
al showed that STS had better calibration for patients with very-high-risk profiles
[37].
These results further suggest the need for an accurate risk/benefit balance
assessment during counseling for patients with severe aortic stenosis. For
example, when octogenarians are considered for treatment of AS, surgical risk is
increased due to the prevalence of several comorbidities. However, Tralhão et al
showed that both EuroSCORE II and STS score are well calibrated in this
particular cohort of patients [38].
Finally, as far as reoperative AVR is concerned, Holinski et al reported
extremely good discrimination and calibration for EuroSCORE II compared to
logistic EuroSCORE and STS score. Furthermore, they suggest a EuroSCORE II
risk of 10% as the threshold for procedures alternative to surgical reoperations,
such as valve-in-valve TAVI [39]. Conversely, Anselmi et al. provided evidence
that all three models overestimated the risk of operative mortality for reoperation
on the aortic valve [40].
Therefore, EuroSCORE II and STS score are reliable tools for risk
stratification of patients with severe AS. However, multicenter studies that
include a wider profile of patients with different comorbidities and risk profiles
would certainly improve the discrimination between patients who will better
benefit from surgery, transcatheter procedure or medical therapy alone.
35
2.6.2 Coronary artery disease
Concomitant coronary artery disease is a common finding among patients with
AS, affecting up to 57.7% of the population [41]. Generally, this subset of
patients has other severe comorbidities that significantly increase the operative
risk.
Shibayama et alreported an increased risk of mortality for untreated patients
with associated coronary disease and AS [41]. However, the benefits of
concomitant coronary revascularization are still controversial.
Recent guidelines recommend the combined treatment of both pathologies,
but clinical practice often differs from guideline indications. Accordingly, Di
Gioia et al.have recently demonstrated a significant improvement in long-term
survival when combined coronary artery bypass grafting (CABG) and AVR are
performed. However, when a combined procedure could not be performed,
percutaneous coronary intervention or AVR alone was associated with improved
survival compared to medical therapy alone [43].
Thalji et al reported the Mayo Clinic experience on 1308 consecutive patients
with significant coronary artery disease at the time of AVR between 2001 and
2010. Operative mortality was similar between the groups (AVR 3.0% vs
AVR+CABG 2.9%, p=0.90). However, 5- and 8-year survival was higher among
patients receiving CABG, with a favorable hazard ratio of 0.62 (95%CI 0.49-0.79,
p<0.001). These findings suggest that revascularization confers a survival
advantage in patients with coronary artery disease undergoing AVR [44].
These findings were confirmed also in studies of elderly populations, where
several authors reported improved survival at follow-up despite the increased risk
of immediate postoperative complications [45–47].
When the extension of coronary disease is considered, patients with left main
or three-vessel disease usually experience a significantly increased risk of
postoperative complications, with no difference in observed survival at 1-year
follow-up [48].
However, a recent meta-analysis including 176 studies with 683286 patients
demonstrated an increased mortality for concomitant CABG (5.5% vs 3.3%,
p<0.001 [49].
The impact of coronary artery disease on immediate and long-term outcome
of patients is also controversial among patients undergoing TAVI [50].
36
Accordingly, more studies addressing the impact of coronary disease on
patients with severe AS are needed to evaluate the best treatment options in this
high-risk subset of patients.
2.6.3 Left ventricular hypertrophy
Left ventricular mass hypertrophy is a compensatory mechanism in response to
chronic pressure overload induced by severe aortic stenosis. Initially, this
hypertrophy can counterbalance the increased wall stress secondary to the higher
afterload. Ultimately, it may progress to irreversible fibrosis with a significant
impairment of both systolic and diastolic function [51].
Left ventricular hypertrophy is an independent predictor of morbidity and
mortality at follow-up. Gerdts et al demonstrated an increase in hazard of 12% of
major cardiovascular events, 28% for ischemic cardiovascular events, 34% for
cardiovascular mortality and 23% for a composite endpoint of mortality and heart
failure in 1656 asymptomatic patients with mild-to-moderate AS [52].
Once irreversible myocardial damage is established, left ventricular mass
regression occurs less frequently and to a lesser extent after AVR. This finding
has a significant impact on immediate survival as well as freedom from
cardiovascular events at follow-up [53]. Furthermore, from a surgical point of
view, cardioplegic protection of hypertrophic ventricles has always been
challenging as increased ventricular mass may result in suboptimal myocardial
protection
Accordingly, more refined imaging methods (e.g. echocardiographic strain
analysis, cardiovascular magnetic resonance, computed tomography calcium
score, and even PET/CT) may help to identify patients at higher risk of
postoperative cardiovascular events and thus will refine the correct timing and
therapy for patients suffering from any degree of AS [54–56].
2.6.4 Mitral valve disease
Left ventricular remodeling occurring in aortic stenosis often leads to the
development of different degrees of functional mitral regurgitation [57]. Whether
mitral disease should be treated at the time of AVR is still debated and mainly
discerned on the basis of the degree of mitral regurgitation itself.
37
Schubert et al reported minimal or absent reduction of untreated mitral
regurgitation over a 5-year follow-up, with 17% of patients experiencing
regression of mitral regurgitation back to preoperative values or an increase in
mitral regurgitation grading. In this study, moderate mitral regurgitation did not
correlate with mortality at follow-up, but patients with mild mitral regurgitation
showed a slight trend towards improved survival. These results suggest a more
aggressive approach to moderate functional mitral regurgitation [58].
Similarly, Coutinho et al. showed that patients who had undergone
concomitant mitral valve surgery experienced a greater improvement in mitral
regurgitation grading at follow-up (treated 82.3% vs untreated 67.4%, p=0.011).
They demonstrated that preoperative atrial fibrillation and higher mitral
regurgitation grade at discharge were independent predictors of persistent mitral
regurgitation at follow-up. Of interest, persistent mitral regurgitation at discharge
has a significant impact on survival (HR 4.9, p=0.001). Accordingly, they suggest
that patients with preoperative atrial fibrillation receive treatment of concomitant
functional mitral regurgitation [59].
However, there is no striking evidence that suggests the need for treatment of
coexisting mitral regurgitation. A recent systematic review demonstrated that left
ventricular dysfunction, atrial fibrillation and left atrial enlargement were
associated with a progression of mitral regurgitation over time. However, the
authors did not find any evidence supporting the impact of residual mitral
regurgitation on late survival [60].
Accordingly, guidelines suggest that mitral valve repair for secondary
moderate mitral regurgitation can be considered as an option for patients
undergoing cardiac surgery for another reason, with a class of recommendation
IIB and a level of evidence C [13]. A case-by-case analysis is therefore
recommended to discern those patients who may benefit more from the increased
risks of double valve surgery (e.g. preoperative risk factors, expected survival,
extensive calcifications of the mitral annulus).
The case of concomitant mitral stenosis is different, however. Recently, a
significant decrease of rheumatic etiology leading to degenerative calcification
has been observed. Despite the etiology, there is reason to address both
pathologies in the case of severe double-valve disease. In a case of only moderate
mitral stenosis (mitral valve area 1.6-2.0 cm2), concomitant mitral valve
replacement can be considered in patients undergoing other cardiac surgery (IIB –
LOE C) [13].
38
2.6.5 Functional tricuspid regurgitation and pulmonary hypertension
Left and right ventricular interdependence also becomes evident in cases of
dilated left ventricles with displacement of septal right papillary muscle that
results in functional tricuspid regurgitation [61,62].
Several reports demonstrated that tricuspid regurgitation >2+ negatively
impacts long-term survival in patients undergoing AVR for aortic stenosis [63–65].
Therefore, associated tricuspid valve repair could be a useful adjunctive
procedure to improve long-term survival in this peculiar group of patients.
When severe pulmonary hypertension is considered, several studies
demonstrated that patients left untreated experienced significantly lower survival.
However, AVR should not be disregarded in this population, despite a predicted
increased in surgical risk [66,67]. On the other hand, a recent study by Zlotnick et
al reported a 6.9 fold incresed risk of in-hospital mortality when preoperative
pulmonary arterial pressure was estimated ≥60 mmHg. [68]. Accordingly, less
invasive procedures should be considered in this high-risk subset of patients.
2.6.6 Porcelain aorta
AVR in the case of a heavily calcified ascending aorta, a condition known as
porcelain aorta, is a technical challenge. Several methods have been described,
for example the use of deep hypothermic circulatory arrest [69].
In this setting, AVR with a sutureless bioprotheses can beconsidered avalid
bailout procedure, especially in the case of an unexpected finding of calcified root
[70]. Accordingly, a recent consensus of experts identified sutureless and rapid
deployment valves as the first choice in a case of porcelain aorta or in redo
surgery with calcified homograft or stentless valves. In these cases, the Perceval
sutureless prosthesis is particularly useful becausethe technique of implantation
requires only minimal manipulation of the aortic root [9].
However, circulatory arrest is associated with a 3-to-4-fold increased risk of
neurological events and operative mortality in octogenarians, compared to a
younger cohort [71].
Accordingly, patients with aortic stenosis at risk for diffuse aortic
calcifications should be accurately investigated preoperatively with a CT scan.
After careful evaluation by the Heart Team, such patients could possibly be better
treated with TAVI rather than conventional surgery [13].
39
2.6.7 Small aortic annulus and patient prosthesis mismatch
The performance of aortic bioprostheses in patients with small aortic root has
always been questioned, do to the potential risk of iatrogenic aortic stenosis. In
particular, an EOA indexed to the body surface area ≤0.85 cm2/m2 has been
considered suggestive of prosthesis-patient mismatch (PPM) [22]. This occures
more frequently in patients receiving stented bioprostheses.
Despite a long debate in cardiac surgery literature, there is not general
agreement on the impact of PPM on operative and long term mortality.
Accordingly, You et al described that early outcome and 10-year survival after
aortic valve replacement with stented bioprostheses was not affected by PPM [72].
Interestingly, Dayan et al suggested that PPM could be a surrogate marker of
comorbidities more than an indipendent risk factor for increased morbidity and
mortality [73]. Finally, Concistrè et al demonstrated that PPM does not affect
survival in older patients, thus suggesting that more aggressive strategies (such as
root enlargement or root replacement) are not justified in this high-risk cohort of
patients [74].
Among all bioprostheses available, stentless aortic valves are commonly
associated with larger EOA and with better ventricular remodeling at follow-up
[75,76].
However, the implantation of a stentless valve is usually time-comsuming,
thus exposing older patientsw with more comorbidities to an increased operative
risk. Accordingly, the combination of sutureless technologies with stentless
hemodynamic performances could be an intriguing solution for patients with
small aortic annuli [77–79].
2.6.8 Atrial fibrillation
Preoperative atrial fibrillation is not uncommon in patients with severe aortic
stenosis.The occurrenceis between 17.5% [80] and 25.8% [81], andits incidence
increases with age.
A recent subgroup analysis from the ROCKET-AF Trial demonstrated that
preoperative atrial fibrillation increases the risk of all-cause mortality (11.22
events per 100 patient-years) and morbidity (10.84 events per 100 patient-years)
in patients with severe aortic stenosis who were treated medically [82].
Similarly, Levy et al showed that preoperative atrial fibrillation was
associated with a HR2.31 of mortality even in patients undergoing AVR [80].
40
Accordingly, preoperative atrial fibrillation is a significant risk factor for
postoperative morbidity and mortality in the surgical setting and surgical ablation
should never be disregarded when feasible.
2.6.9 Advanced age
The significant improvements in medical and interventional therapy have led to
referral of anincreasing number of octogenarians for cardiac surgery. A recent
survey showed that 22.8% of patients >80 years had AS, with 5.8% being severe
[83].
Octogenarians represent a particularly high-risk subset of patients with aortic
stenosis because their functional status is frequently affected by several
comorbidities. However, AVR is still a valid option in the elderly [84-86].
Accordingly, Cappabianca et al reported an operative mortality of 4.5% among
264 octogenarians who underwent AVR. Independent predictors of operative
mortality were non-elective surgery (OR 5.7), cardiopulmonary bypass time (OR
1.02) and age (OR 1.36). Patients discharged from hospital experienced similar
survival compared to an age and gender matched population [87].
Shresta et al demonstrated that the use of the Perceval sutureless
bioprosthesis in patients aged ≥ 75 years and with small aortic annuli
significantly reduced the duration of cardiopulmonary bypass, with immediate
and mid-term outcomes comparable to conventional prostheses. This, in
combination with the more feasible implantation via minimally invasive
approaches, has the potential to improve postoperative outcomes in elderly
patients [78].
On the other hand, reoperations [88] and concomitant CABG [89] carries
significantly high mortality.
Accordingly, a recent meta-analysis showed a pooled proportion of
immediate postoperative mortality of 6.7 % for patients aged ≥ 80 years
undergoing isolated AVR [85] and of 9.7% for combined AVR and CABG [86].
Therefore, catheter-based interventional therapy could represent a valid
alternative to surgery in this peculiar subset of patients at high risk of operative
morbidity and mortality [90], but early and long term results are still controversial
in several all-comers registries [91,92].
41
Fig. 3. Early mortality increases with age in patients undergoing isolated AVR
(Biancari et al (2014) [48]).
Fig. 4. Early mortality increases with age in patients undergoing AVR and CABG
(Biancari et al (2014) [48]).
2.6.10 Gender-related differences
Despite similar clinical presentation, several studies showed difference between
males and females in terms of morphological aspects of the aortic valve as well as
remodeling behavior to increased afterload [93,94].
42
A multidisciplinary team from the Mayo Clinic demonstrated that the
deposition of calcium as well as aortic valve weight was lower in women, despite
similar gravity of AS [93].
Interestingly, Dobson et al. showed different patterns in ventricular
remodeling. In particular, women usually develop concentric hypertrophy and a
small ventricular cavity, whereas eccentric hypertrophy is more frequently
observed in men. These macroscopic findings correlate to peculiar histological
patterns. Accordingly, male heart develops a significantly greater increase of
fibrosis, with higher expression of collagen and metalloproteinase [94].
Results from the OBSERVANT registry showed that female gender was an
independent predictor of 30-day operative mortality (adjusted OR 2.34) after AVR
[95] and morbidity (transfusion, low-output state, acute renal failure and higher
trans-prosthetic gradients) [96].
Accordingly, a more tailored approach for the treatment of AS is warranted to
reduce complications and improve surgical and interventional outcomes.
2.6.11 Low-flow/low-gradient aortic stenosis
Low-flow low-gradient AS is a peculiar presentation of aortic stenosis and is
typical of patients with depressed left ventricular function or severe hypertrophy
and low stroke volume. Patients with low-flow low-gradient AS usually present
with more comorbidity, and all these conditions are well known risk factors of
poor immediate and long-term outcome [25].
Multicenter reports showed that AVR is associated with better survival
compared to medical therapy alone. Combined myocardial revascularization, low
preoperative mean gradient and absence of contractile reserve on DSE were
independently associated with increased operative mortality [97,98]. However,
these observations stem from surgical AVR performed between 1990 and 2005
(mortality 20% between 1990-1999, 10% between 2000 and 2005) and are not
similar to current practice, when novel surgical prostheses are available and TAVI
is a standard procedure in many centers.
Accordingly, Lopez-Marco et al reported similar in-hospital mortality
between patients with low-flow low-gradient AS compared to normal-flow high-
gradient counterparts (2% vs 1%, p=0.13). However, when 1- and 5-year survival
were analyzed, patients with low-flow low-gradient AS experienced higher
mortality, even when compared to paradoxical low-flow low-gradient patients
43
[99]. In particular, Tribouilloy et al demonstrated that the natural history of
patients with low-flow low-gradient AS and preserved ejection fraction is
comparable to that of mild-to-moderate AS patients and is not positively
influenced by AVR [100]. Accordingly, timing and indication for surgery in this
peculiar subset of patients is still questionable and further investigations are
needed to assess the correct management of patients with low-flow low-gradient
AS.
2.6.12 Aortic cross-clamping time
Prolonged cross-clamping time is a well-known risk factor for adverse event in
cardiac surgery. The extended duration of cardiopulmonary bypass and aortic
cross-clamping time – an indirect witness of the complexity of the surgical
procedure – expose the heart and all the other organs to the risk of severe
hypoxemia, which is responsible for postoperative organ failure[101–106].
Accordingly, Nissinen et al have demonstrated that a 30-minute increase of
aortic cross-clamping time (OR 1.24) and of cardiopulmonary bypass time
(OR1.47) are independently associated with an increased risk of 30-day mortality
and postoperative complications (stroke, de-novo dialysis, intra-aortic balloon
pump, ICU stay >4 days) [101].
In a multivariate analysis, Onorati et al showed that aortic cross-clamping
time >90 minutes and cardiopulmonary bypass time >180 minutes were
independently associated to postoperative mortality after CABG [102].
In a retrospective analysis of 3799 patients, Al-Sarraf et al showed a 2%
increase of operative mortality for an incremental increase of 1 minute of aortic
cross-clamping time. . In particular, the risk of mortality for low-risk patients
(EuroSCORE <6) with an aortic cross-clamping time of>90 minutes was
significantly higher (OR 3.1) than for those with an aortic cross-clamping time of
60-90 minutes (OR 1.6). This finding was confirmed in a high-risk cohort of
patients with EuroSCORE ≥6 (aortic cross-clamping 60-90 minutes OR 3.1;
aortic cross-clamping>90 minutes OR 4.7). Furthermore, cross-clamping
time >60 minutes was an independent predictor of low-output state, prolonged
ventilation, renal failure, transfusion and hospital stay [103].
As far as AVR is specifically concerned, Ranucci et al showed that aortic
cross-clamping time independently increases the risk of severe cardiovascular
morbidity by 1.4% per 1-minute increase. In a subgroup analysis, they found that
44
patients who may benefit most from reduced cross-clamping time were those with
reduced ventricular function (LVEF≤40%) and diabetes [104].
Similarly, Chalmers et al demonstrated a 2% increase of risk of operative
mortality per each minute increase of cardiopulmonary bypass in a cohort of 1863
primary isolated AVR [105].
Furthermore, Mistiaen and collaborators showed also that an aortic cross-
clamping time of >75 minutes was associated with an increased incidence of
postoperative renal dysfunction in a population of elderly patients undergoing
isolated AVR [106].
Therefore, novel sutureless bioprostheses, designed to shorten aortic cross-
clamping time, have the potential to reduce the risk of postoperative
complications. It can be expected that patients with more comorbidities (such as
older age, diabetes, left ventricular dysfunction, and preoperative renal
dysfunction) would benefit most from this technique.
2.6.13 Redo operations
Sternal re-entry is a common risk factor for postoperative morbidity and mortality.
However, patients undergoing redo surgical AVR can experience similar
immediate outcomes compared to first-time surgery [107–-111].
In a recent report from the Cleveland Clinic, 30-day mortality was 2.5% of
276 patients who had undergone redo AVR.This cohort of patients had frequent
comorbidities and needed combined procedures (CABG ± aortic surgery). High
STS score, higher grade of paravalvular regurgitation and higher pulmonary
arterial pressure were independent predictors of poor outcome at follow-up [107].
Data from the RECORD registry showed that redo AVR can be performed
with satisfactory operative mortality (5.1%). Preoperative severe left ventricular
dysfunction, intraoperative complications (major cardiovascular complications,
long cardiopulmonary bypass), length of stay and acute renal injury were
independent predictors of operative mortality [108]. These results were confirmed
whena subgroup of octogenarians undergoing redo AVR was considered [109].
Conversely, a similar analysis of 3380 patients from the STS database
showed that redo AVR was associated with higher in-hospital mortality compared
to primary AVR (4.6% vs 2.2%, p<0.001) and morbidity, although satisfactory
results are achievable (stroke 1.9% vs 1.4%, p=0.02; paravalvular leak ≥2+ 2.8%
45
vs 1.7%, p<0.001; permanent pacemaker implantation 11.0% vs 4.3%, p<0.001;
vascular complications 0.06% vs 0.01%, p=0.04) [110].
Furthermore, Pechlivanidis et al showed that redo AVR is a safe and effective
procedure (operative mortality 2.3%) without differences between patients aged
≥75 years and younger controls. Such results were better in elective cases, young
and healthier (NYHA I-II) patients, with other than endocarditis etiology. On the
other hand, endocarditis, poor functional class and non-elective procedures were
associated with poor immediate and long-term outcomes [111].
These results suggest that the transcatheter valve-in-valve procedure can be
considered in cases of biological prosthetic dysfunction, but age should not be
considered a contraindication for surgery per se [112].
2.7 The impact of minimally invasive approaches on outcomes
after AVR
A minimally invasive approach for AVR is increasingly used because of the
perceived reduced risk of morbidity and mortality [113,114]. However, minimally
invasive surgery is more technically demanding and often is associated with
longer cardiopulmonary and aortic cross-clamping time, which may lessen the
benefits of the reduced surgical invasiveness [113].
Single center experiences have demonstrated that minimally invasive AVR is
beneficial or even superior to conventional full sternotomy.
Shehada et al reported similar low mortality rate and survival at follow-up
between minimally invasive and conventional AVR, but minimally invasive
procedures were associated with a lower rate of postoperative complications [115].
Merk et al reported a significantly lower operative mortality (0.4% vs 2.3%,
p=0.013). Furthermore, minimally invasive AVR was an independent predictor of
long-term survival (HR 0.47), with a survival advantage at 5- and 8-year follow-
up [116]. These data are confirmed by a recent meta-analysis, which showed that
minimally invasive AVR is an independent predictor of lower operative mortality
[49].
Bakir et al reported a similar incidence of PPM between minimally invasive
AVR and a full sternotomy approach [117].
Furthermore, with the introduction of sutureless prostheses, AVR through
right anterior mini-thoracotomy gained widespread acceptance, and became
established as an excellent surgical approach in patients at high risk [118,119].
46
We suggest that the use of sutureless prostheses may further facilitate the
development of minimally invasive surgery programs in many centers, as these
prostheses are easily deployed with a reduced cross-clamping time.
47
3 Aim of the research
The aim of this study was to investigate the impact of the Perceval sutureless
bioprosthesis on the immediate and mid-term outcomes after AVRfor severe AS.
We aimed to assess the potential role of Perceval in combination with minimally
invasive approaches and in comparison with transcatheter procedures. The
specific aims numbered according to the original articles were:
I to investigate the in-hospital and mid-term outcomes after AVR with the
Perceval sutureless bioprosthesis, particularly in high risk patients.
II to investigate the feasibility and reliability of the implantation of the Perceval
sutureless bioprosthesis via minimally invasive approaches.
III to assess the potential advantages of usingthe Perceval sutureless
bioprosthesis implanted through a minimally invasive approach compared to
stented bioprosthesis implanted through full sternotomy.
IV to compare in-hospital outcomes in patients treated with the Perceval
sutureless bioprosthesis or TAVI for isolated AS.
V to compare the immediate outcome of patients undergoing TAVI versus AVR
with the Perceval sutureless bioprosthesis, irrespective of associated coronary
disease.
VI to assess the hemodynamics of the Perceval sutureless bioprosthesis with
dobutamine stress echocardiography.
48
49
4 Materials and methods
4.1 Study design and patient populations
The first five studies were retrospective analyses, while study VI is a prospective
echocardiographic evaluation of patients operated in a single center. The entire
series included consecutive patients in whom Perceval sutureless bioprosthesis
was implantedbetween 2007 and 2014at six European institutions (Cardiac
Surgery Unit, A.O.U. Policlinico-Vittorio Emanuele, University of Catania,
Catania, Italy; Department of Surgery, Oulu University Hospital, Oulu, Finland;
Department of Molecular Medicine and Surgery, Department of Cardiothoracic
Surgery and Anesthesiology, Karolinska Institutet, Karolinska University Hospital,
Stockholm, Sweden; Department of Cardiac Surgery, Klinikum Nürnberg,
Paracelsus Medical University, Nuremberg, Germany; Division of Cardiac
Surgery, Ospedali Riuniti, Trieste, Italy; Department of Cardiac Surgery,
University Hospital Gasthuisberg, Leuven, Belgium).
All studies included patients who have undergone an elective, urgent or
emergentAVR, with or without CABG. Patients undergoing procedures other than
associated CABG were excluded from this study, because the different underlying
pathologies might have had an impact either on the immediate or mid-term
outcomes.
Study I included 314 consecutive patients as described above. No additional
inclusion criteria were applied to this study population.
Study II included a consecutive series of 267 patients who underwent isolated
AVR with the Perceval sutureless bioprosthesis in the same observational timeline.
Patients undergoing concomitant procedures were excluded. The main endpoints
were early postoperative outcomes and 2-year survival. The purpose of this study
was to assess the potential advantages of mini-sternotomy over full sternotomy.
Propensity score matching was performed to adjust the effect of potential
confounders between the study groups.
Study III is an analysis of two consecutive series of patients who underwent
primary isolated non-emergent AVR. The data of 182 patients who underwent
AVR through mini-sternotomy with a Perceval sutureless bioprosthesis at the
above mentioned six European centers between 2007 and 2014 were compared
toa cohort of 383 patients receiving a stented, conventional aortic valve
bioprosthesis at the Karolinska University Hospital, Stockholm, Sweden, between
50
January 2005 and December 2010. Exclusion criteria were previous cardiac
surgery, active endocarditis or another concomitant cardiac procedure in addition
to AVR. In this study, we aimed to evaluate whether the use of the Perceval
sutureless bioprosthesis could overcome the potential disadvantages of minimally
invasive approaches (e.g. prolonged cardiopulmonary and cross-clamping time,
reduced visibility of the surgical field). A propensity score match analysis was
performed to adjust the effect of potential confounders between the study groups.
Study IV was planned to compare the hospital outcomes and 1-year survival
of patients undergoing AVR with the Perceval sutureless bioprosthesis with those
of patients treated with TAVI. Patients undergoing concomitant procedures were
excluded from the analysis. Data of 292 patients who underwent isolated AVR
with the Perceval sutureless bioprosthesis between 2010 and 2014 at the six
above-mentioned European centers were compared to those from 1885 patients
treated with TAVI from the Italian Transcatheter balloon Expandable Registry
(ITER) between 2007 and 2012. Propensity score matching was employed to
adjust for baseline differences of three different subgroups of patients (Perceval
vs. TAVI-general; Perceval vs. transfemoral TAVI; Perceval vs. transapical TAVI).
Study V was planned to compare the immediate results of AVR with a
Perceval sutureless bioprosthesis compared to a contemporary cohort of patients
treated with TAVI. The overall population consisted of patients from the above-
mentioned multicenter European registry of the Perceval sutureless bioprosthesis
and those who underwent TAVI in a high-volume institution. Since patients
differed significantly in preoperative comorbidities, a propensity score was
calculated to create two subgroups of patients with similar preoperative risk
profiles.
Study VI aimed to evaluate the performance of the Perceval sutureless
bioprosthesis implanted in patients in a single institution (Policlinico Vittorio
Emanuele, University of Catania, Catania, Italy) under increasing workload at the
mid-term follow-up. Only patients who underwent isolated AVR and with a
follow-up of at least 1 year were included in this analysis. Exclusion criteria were
residual mitral insufficiency, conduction disturbances, arrhythmias, or any known
contraindication to dobutamine stress. Accordingly, 32 patients were enrolled and
underwent dobutamine stress echocardiography (DSE).
51
4.2 Data collection and risk stratification
Each center involved in the study provided complete pre-, intra- and post-
operative data for all patients included in the studies. The databases were
implemented with additional data obtained by a retrospective analysis of patients’
records according to the design of the single sub-studies.
Data on freedom from adverse events at follow-up were retrieved by
reviewing the outpatient clinics records and/or by contacting the patient or her/his
cardiologist or general practitioner.
In studies I, II, IV and V operative risk was defined according to EuroSCORE
II. Preoperative risk factors defined according to EuroSCORE II definitions were
used to derive a non-parsimonious propensity score that was used to resample
pairs of propensity-matched groups for further analysis.
In study III, logistic EuroSCORE was used, because the more recently
available data from the Perceval cohort were compared to a retrospectively
collected database of patients operated before 2010 when EuroSCORE II was not
available.
In study VI, DSE was used to investigate the hemodynamics of the Perceval
sutureless bioprosthesis. A pharmacological test was preferred over a physical one
because this patient population included only very elderly patients who might be
unable to adequately perform an exercise protocol.
4.3 Operative technique
The operative technique was standardized throughout the study period in all the
centers involved in the study.
Full median sternotomy was achieved by midline incision from the
suprasternal notch to the xiphoid process.
The decision to perform minimally invasive surgery was left to the surgeon’s
preference. Briefly, right anterior mini-thoracotomy was performed with a 5-8 cm
incision at the second intercostal space if the aorta was placed rightward to the
sternum for at least 50% of its diameter at the level of the pulmonary artery
bifurcation; otherwise, a mini-sternotomy to the third or fourth intercostal space
was performed.
Central aortic cannulation was achieved in all cases. The right atrium was
cannulated in case of full sternotomy and mini-sternotomy approaches, whereas
52
the right common femoral vein was cannulated percutaneously in case of right
anterior mini-thoracotomy. A left ventricular vent was used during the procedure.
Once the aorta was clamped, cardioplegia was administered in the aortic root;
additional doses wereadministereddirectly into the coronary ostia in cases of
combined aortic insufficiency.
The implantation of this valve was considered feasible when the aortic
annulus size was between 19 mm and 27 mm and the ratio between the
sinotubular diameter and that of the aortic annulus was no more than 1.3.
The ascending aorta was incised transversally 1.5 cm above the sinotubular
junction. The aortic valve was removed and the annulus was completely
decalcified. Three 4/0 polypropylene guiding sutures were passed through the
aortic annulus at the nadir of each cusp. At the same time, an appropriate sized
prosthesis was collapsed in a side table and firmed into the manufacturer’s holder.
The three guiding sutures were passed through the three green eyelets arising
from the annular ring of the prosthesis, which was consequently seated on the
debrided annulus. The aortic valve was opened and the holder removed. The field
was rinsed with warm saline and the prosthesis dilated at 4 atm for 30 sec. After
closure of the aortotomy, transesophageal echocardiography was performed to
assess the correct implantation of the prosthesis and the presence of any valve
leak [120].
In case of incorrect position, the valve can be easily removed by twisting it in
a χ fashion, recollapsed and reimplanted [121].
4.4 Endpoints of the study
The main endpoints of studiesI-IVwere early and mid-term mortality.
Secondary endpoints were aortic cross-clamping time, cardiopulmonary
bypass time, conversion to full sternotomy (in case of planned minimally invasive
approaches), implantation success, device success, incidence of paravalvular
leaks, postoperative transfusion of packed red blood cells, bleeding (major or life
threatening), stroke, de novo dialysis, permanent pacemaker implantation, valve-
related mortality, reoperation for valve-related complications, prosthetic
endocarditis, intensive care unit and in-hospital stay.
Early mortality was defined as any postoperative death occurring within 30
days from surgery or even longer if the patient was still hospitalized.
53
Implantation success was defined as an implanted Perceval sutureless
bioprosthesis, which did not require its replacement during the same operation
with another Perceval sutureless bioprosthesis or conventional valve bioprosthesis.
The main outcome end-point of study V was in-hospital mortality. Secondary
end-points were device success, valvular regurgitation, stroke, bleeding, de novo
dialysis, permanent pacemaker implantation and reoperation for prosthesis valve
related complications.
The main end-pointsof study VIwere transvalvular gradients, EOA, DVI and
incidence of prosthesis-patient mismatch. A DVI<0.25 was diagnostic of severe
aortic stenosis. An EOAi ≤0.65 was considered suggestive of severe prosthesis-
patient mismatch, according to Pibarot and collegues [22].
4.5 Statistical analysis
Statistical analyses were performed with SPSS version 20.0 (IBM Corporation,
Armonk, New York, USA) (studies I and VI), SPSS version 22.0 (IBM SPSS Inc.,
Chicago, Ill) (study II, III and V), Stata version 13.1 (StataCorp LP, College
Station, TX) (studies II and III), SAS software package(SAS Institute, Cary, NC;
version 9.3) (study IV).
All tests were two-sided with the alpha level set at 0.05 for statistical
significance.No attempt to replace missing values was made in any of these
studies.
Continuous variables are reported as mean ± standard deviation or median
and interquartile range, nominal variables as counts and percentages.
Independent samples t-test, Mann-Whitney U-test, Chi-square test and Fisher
exact test were used for univariate analysis. No attempt to replace missing values
was made. Survival analysis was performed employing Kaplan-Meier’s method
and the log-rank test was used to compare differences between the study groups.
In Study I, the discriminatory ability of EuroSCORE II to predict operative
mortality was assessed with the area under the receiver operating characteristic
(ROC) curve. The accuracy of EuroSCORE II was assessed by the Brier score,
which is the average squared difference between the predicted probability and the
true occurrence of operative mortality. A Brier score should be as close to 0 as
possible, with 0.25 as an acceptable upper cutoff [122].
In study II, III, IV and V, a propensity score was calculated for each patient
by logistic regression in order to reduce selection bias.
54
In Study II, a propensity score matched cohort was constructed by nearest
neighbor matching without replacement, one mini-sternotomy patient to one full
sternotomy patient. We calculated standardized differences for variables to
investigate post-match balance. Standardized differences were calculated anda
value <10% was considered as a small and acceptable imbalance.
In Study III, a propensity score matched cohort was constructed as well by
nearest neighbor matching without replacement, one mini-sternotomy sutureless
bioprosthesis patient to one full sternotomy stented bioprosthesis patient.
Standardized differences were calculated and a value <10% was considered
as a small and acceptable imbalance.
In study IV, for propensity score matching each TAVI treated patient was
matched with a Perceval sutureless bioprosthesis patient with the closest
propensity score selected using a Greedy algorithm [124]. Goodness of matched
pairs was defined as those with the least absolute difference in matched
propensity score. Matching was calculated without replacement. The balance
between TAVI treated patients and matched SU-AVR treated patients was
assessed using Wilcoxon-Mann-Whitney testsand was reported for the same
number of patients from registries before and after matching with the propensity
score [124–-127]. To ascertain whether access type, trans-apical (TA-TAVI) and
trans-femoral TAVI (TF-TAVI), could confound the main findings we repeated all
analyses separately.
In study V, a propensity score was calculatedthat did not include coronary
artery disease in the regression model, because the details on this condition were
not complete in all centers. In order to identify a “gray zone” of indication for
either AVR with the Perceval sutureless bioprosthesis or TAVI, patients within the
25th and 75th percentiles of EuroSCORE II were further compared.
In Study VI, differences between measured parameters at rest and at maximal
exercise were assessed with paired sample t-test or Wilcoxon signed rank test
where appropriate. Differences in categorical variables were evaluated with the
McNemar test.
55
5 Results
5.1 In-hospital and mid-term outcomes after AVR with Perceval
bioprosthesis (I)
Study I included 314 patients who underwent AVR with the Perceval sutureless
bioprosthesis. Concomitant CABG was performed in 94 patients (29.9%). One
hundred and forty patients (44.6%) were operated through a minimal access
approach.
Baseline characteristics and operative details of these patients are
summarized in Table 4 and 5, respectively.
Table 4. Baseline characteristics of patients who underwent AVR with the Perceval
sutureless valve bioprosthesis.
Clinical variables No. (%)
Age (years) 77.9±5.0
Octogenarians 116 (36.9)
Females 189 (60.2)
Diabetes 94 (29.9)
Insulin-dependent diabetes 32 (10.2)
Creatinine clearance
> 85 ml/min 114 (36.3)
50-85 ml/min 126 (40.1)
<50 ml/min 73 (23.2)
on dialysis 1 (0.3)
New York Heart Association class
I 1 (0.3)
II 60 (19.1)
III 243 (77.4)
IV 10 (3.2)
Poor mobility 41 (13.1)
Chronic lung disease 56 (17.8)
Extracardiac arteriopathy 75 (23.9)
Left ventricular ejection fraction
>50% 271 (86.3)
31-50% 42 (13.4)
56
Clinical variables No. (%)
21-30% 1 (0.3)
Systolic pulmonary artery pressure
≤30 mmHg 143 (45.5)
31-55 mmHg 136 (43.3)
>55 mmHg 35 (11.1)
Indication for surgery
Stenosis 176 (56.1)
Regurgitation 1 (0.3)
Mixed pathology 137 (43.6)
Peak gradient (mmHg) 84.6±23.6
Mean gradient (mmHg) 51.9±18.3
AVA (cm2) 0.68±0.2
Active endocarditis 0 (0)
Critical preoperative state 1 (0.3)
Elective procedure 312 (99.4)
Previous cardiac surgery 24 (7.6)
Aortic valve surgery 9 (2.9)
Permanent pace-maker 9 (2.9)
EuroSCORE II (%) 9.0±7.6
Continuous variables are reported as mean ± standard deviation; dichotomous variables are reported as
counts and percentages in parentheses. AVA = aortic valve area. Definition criteria for preoperative
variables are according to EuroSCORE II.
57
Table 5. Operative data on patients who underwent AVR with the Perceval sutureless
bioprosthesis.
Operative data No. (%)
Access
Full sternotomy 174 (55.4)
Mini-sternotomy 131 (41.7)
Mini-thoracotomy 9 (2.9)
Concomitant coronary artery bypass surgery 94 (29.9)
N. of distal anastomoses 1.78±0.88
Prosthesis size
Small 37 (11.8)
Medium 135 (43.0)
Large 126 (40.1)
Extra large 16 (5.1)
Overall series
Aortic cross clamping time (min) 43±20
Aortic cross clamping time <30 min 79 (25.2)
Cardiopulmonary bypass time (min) 73±28
Cardiopulmonary bypass time <60 min 105 (33.4)
Isolated AVR
Aortic cross clamping time (min) 39±15
Aortic cross clamping time <30 min 64 (29.1)
Cardiopulmonary bypass time (min) 66±23
Cardiopulmonary bypass time <60 min 93 (42.3)
Combined procedure
Aortic cross clamping time (min) 52±26
Aortic cross clamping time <30 min 15 (16.0)
Cardiopulmonary bypass time (min) 88±32
Cardiopulmonary bypass time <60 min 12 (12.8)
Continuous variables are reported as mean ± standard deviation; dichotomous variables are reported as
counts and percentages in parentheses.
In-hospital mortality in the overall series was 3.2% (1.4% after isolated aortic
valve procedure and 7.4% after concomitant CABG, p=0.009). Other early
adverse events are summarized in Table 6.
58
Table 6. Postoperative data on patients who underwent AVR with the Perceval
sutureless bioprosthesis.
Postoperative outcomes No. (%)
Implantation success 313 (99.7)
Intraoperative paravalvular leak
None 274 (87.3)
Mild 38 (12.1)
Severe 2 (0.6)
Prosthesis dislodgment 1 (0.3)
Conversion to conventional AVR 2 (0.6)
Stroke 6 (1.9)
De novo dialysis 5 (1.6)
Pace-maker implantation 25 (8.0)
Reoperation for bleeding 8 (2.5)
Intensive care unit stay (days) 3.2±3.4
In-hospital stay (days) 13.4±6.5
In-hospital/30-day mortality 10 (3.2)
after isolated procedure 3 (1.4)
after combined procedure 7 (7.4)
Prosthesis-related early mortality 0 (0)
Continuous variables are reported as mean ± standard deviation; dichotomous variables are reported as
counts and percentages in parentheses. AVR = aortic valve replacement
Aortic cross-clamping time was a determinant of in-hospital mortality in the
overall series (area under the curve, 0.712, 95%CI 0.550-0.874, adjusted for
EuroSCORE II, p=0.005, OR 1.033, 95%CI 1.010-1.056) and in patients who
underwent concomitant CABG (area under the curve, 0.758, 95%CI 0.581-0.934,
adjusted for EuroSCORE II, p=0.027, OR 1.031, 95%CI 1.004-1.059), but not
among those who underwent an isolated procedure (area under the curve, 0.459,
95%CI 0.323-0.596, adjusted for EuroSCORE II, p=0.658, OR 1.033, 95%CI
0.901-1.068).
Freedom from mortality and adverse events at a median follow-up of 0.9
years (interquartile range, 0.08-3.02) are shown in Figure 5 and Table 7,
respectively.
59
Fig. 5. Kaplan-Meier estimate of intermediate survival after AVR with the Perceval
sutureless bioprosthesis.
Table 7. Freedom from adverse events at follow-up (including operative events)
Adverse events 1-year 2-year
Valve-related mortality 99.0% 98.0%
Stroke 98.1% 98.1%
Endocarditis 99.2% 99.2%
Reoperation 98.3% 98.3%
Peripheral thromboembolism 100% 100%
5.1.1 Octogenarians
Octogenarians had higher in-hospital mortality compared to younger patients (5.2%
vs. 2.0%, p=0.125), but the difference did not reach statistical significance.
Similar findings were observed in patients who underwent isolated AVR (2.7% vs.
0.7%, p=0.223) and those who underwent concomitant CABG (9.5% vs. 5.8%,
p=0.491).
60
5.1.2 Operative outcomes after full sternotomy vs minimally invasive approach
Full sternotomy was associated with significantly shorter aortic cross-clamping
time (35.6±16.3 vs. 41.1±14.3 min, p=0.003) and cardiopulmonary bypass
duration (58.2±21.7 vs. 71.0±22.2 min, p<0.0001) compared to minimally
invasive access.
Similar operative mortality rates were observed (1.3% vs. 1.4%; when
adjusted for age, creatinine clearance, left ventricular ejection fraction, pulmonary
disease, systolic pulmonary pressure and prior cardiac surgery: p=0.921, OR
0.886, 95%CI 0.064-12.346; when adjusted for EuroSCORE II: p=0.844, OR
1.284, 95%CI 0.107-15.376).
5.2 Stratification of in-hospital mortality according to quartiles of
EuroSCORE II (I)
The mean EuroSCORE II in the overall series was 9.0±7.6% (median 7.0%, range
1.08-60.0%). The area under the ROC curve for this risk scoring method was 0.65
(95%CI 0.48-0.81). The Brier score for EuroSCORE II was 0.038 indicating a
good precision in prediction probability. However, the Brier score rose markedly
with increasing quartiles of EuroSCORE II (0.014, 0.023, 0.043 and 0.073,
respectively).
In the present series, we observed a marked increase of the operative
mortality in the upper quartile of EuroSCORE II (Figure 6) and because of this,
the EuroSCORE II was dichotomized according to a cutoff value of 10%.
61
Fig. 6. Observed in-hospital mortality rates according to EuroSCORE II quartiles after
AVR with the Perceval sutureless bioprosthesis. The predicted mortality rates are
according to the mean EuroSCORE II in each quartile. O/E = observed/expected
mortality ratio in each EuroSCORE II quartile.
However, we could not demonstrate any differences in this subgroup analysis
(Table 8).
Table 8. Baseline characteristics of 32 patients included in the study, preoperative
echocardiographic details and size of implanted valves
Operative details EuroSCORE II <10% EuroSCORE II ≥10% p
Overall series 2.8% 4.0% 0.56
Isolated AVR 2.0% 0% 0.24
AVR+CABG 4.8% 12.9% 0.16
AVR: aortic valve replacement; CABG: coronary artery bypass graft
5.3 Implantation of Perceval bioprosthesis with minimally invasive
approaches (II)
In this study, 267 patients were included, 189 (70.8%) underwent AVR through
mini-sternotomy and 78 (29.2%) through full sternotomy.
Patients in the two groups had different baseline characteristics. Accordingly,
a propensity score was calculated and used to obtain 56 pairs with similar risk
profile (Table 9).
62
Ta
ble
9. B
as
eli
ne
ch
ara
cte
ris
tic
s o
f p
ati
en
ts w
ho
un
de
rwe
nt
su
ture
les
s A
VR
th
rou
gh
min
iste
rno
tom
y o
r fu
ll s
tern
oto
my.
Variable
s O
vera
ll co
hort
Pro
pensi
ty s
core
cohort
Min
i-st
ern
oto
my
189 p
atie
nts
Full
stern
oto
my
78 p
atie
nts
p
Min
i-st
ern
oto
my
56 p
atie
nts
Full
stern
oto
my
56 p
atie
nts
p
Sta
nd
ard
ize
d
diff
ere
nce
(%
)
Age (
years
) 77.4
±5.1
75.7
±5.5
0.0
16
76.0
±5.6
76.2
±5.0
0.8
40
3.7
Fe
ma
le g
en
de
r 1
16
(6
1)
55
(7
1)
0.1
64
45
(8
0)
42
(7
5)
0.5
33
1
3
Weig
ht (k
g)
74.7
±14.0
74.4
±15.2
0.8
74
73.6
±16.8
74.1
±14.3
0.8
80
3.0
Heig
ht (c
m)
164.2
±10.7
161.1
±7.6
0.0
18
160.6
±14.7
160.8
±7.4
0.9
50
1.1
Dia
be
tes
46
(2
4)
24
(3
1)
0.2
87
17
(3
0)
14
(2
5)
0.5
14
12
Insu
lin-d
ep
en
de
nt
dia
be
tes
12
(6
) 1
2 (
15
) 0
.03
2
8
(1
4)
6 (
11
) 0.5
66
11
Cre
atin
ine c
leara
nce
0.1
62
0.1
98
>8
5 (
ml/m
in)
76
(4
0)
21
(2
7)
12
(2
1)
19
(3
4)
28
50
-85
(m
l/min
) 7
2 (
38
) 3
4 (
44
)
2
5 (
45
) 2
2 (
39
)
11
<5
0 (
ml/m
in)
41
(2
2)
23
(3
0)
19
(3
4)
15
(2
7)
16
New
York
Heart
Ass
oci
atio
n c
lass
0.2
75
0.1
51
I 5
(2
.6)
1 (
1.3
)
2
(3
.6)
1 (
1.8
)
11
II
45
(2
4)
24
(3
1)
24
(4
3)
18
(3
2)
22
III
12
8 (
68
) 4
5 (
58
)
2
5 (
45
) 3
2 (
57
)
25
IV
11
(5
.8)
8 (
10
.3)
5 (
8.9
) 5
(8
.9)
0
Po
or
mo
bili
ty
26
(1
4)
4 (
5.1
) 0
.05
4
2
(3
.6)
3 (
5.3
) 0.6
57
8.6
CC
S c
lass
IV
2
(1
.1)
2 (
2.6
) 0
.58
3
2
(3
.6)
2 (
3.6
) 1.0
0
Co
ron
ary
art
ery
dis
ea
se
7 (
3.7
) 4
(5
.1)
0.7
36
6 (
11
) 2
(3
.6)
0.1
42
28
Chro
nic
pu
lmonary
dis
ease
20 (
11)
18 (
23)
0.0
12
15 (
27)
12 (
21)
0.4
93
12
Ext
raca
rdia
c a
rte
rio
pa
thy
28
(1
5)
19
(2
4)
0.0
77
10
(1
8)
10
(1
8)
1.0
0
Re
cen
t m
yoca
rdia
l in
farc
tion
2
(1
.1)
2 (
2.6
) 0
.58
3
2
(3
.6)
1 (
1.8
) 0.5
71
11
Left v
entr
icula
r eje
ctio
n fra
ctio
n
0.6
96
1.0
>5
0%
1
59
(8
4)
63
(8
1)
48
(8
6)
48
(8
6)
0
30
-50
%
29
(1
5)
14
(1
8)
7 (
13
) 7
(1
3)
0
63
Variable
s O
vera
ll co
hort
Pro
pensi
ty s
core
cohort
Min
i-st
ern
oto
my
189 p
atie
nts
Full
stern
oto
my
78 p
atie
nts
p
Min
i-st
ern
oto
my
56 p
atie
nts
Full
stern
oto
my
56 p
atie
nts
p
Sta
nd
ard
ize
d
diff
ere
nce
(%
)
<3
0%
1
(0
.5)
1 (
1.3
)
1
(1
.8)
1 (
1.8
)
0
Sys
tolic
pulm
onary
art
ery
pre
ssure
0.5
39
0.8
42
31
-55
(m
mH
g)
62
(3
3)
31
(4
0)
22
(3
9)
21
(3
8)
3.7
>5
5 (
mm
Hg
) 2
1 (
11
) 7
(9
.0)
3 (
5.4
) 5
(8
.9)
14
Critic
al p
reo
pera
tive s
tate
0
2 (
2.6
) 0.0
85
0
1 (
1.8
) -
1
9
Ele
ctiv
e p
roce
du
re
18
7 (
99
) 7
2 (
92
) 0
.01
0
5
4 (
96
) 5
4 (
96
) 1.0
0
Pre
vio
us
card
iac
surg
ery
7
(3
.7)
23
(3
0)
<0
.00
1
6
(1
1)
9 (
16
) 0.2
73
16
Pe
rma
ne
nt
pa
cem
ake
r 5
(2
.6)
2 (
2.6
) 1
.0
2
(3
.6)
2 (
3.6
) 1.0
0
Act
ive e
ndoca
rditi
s 0
0
-
0
0
-
-
Eu
roS
CO
RE
II
(%)
3.3
5±2
.86
4
.76
±4
.19
0
.04
4
3
.74
±3
.19
4
.00
±4
.17
0.6
62
7.2
Contin
uou
s va
riab
les
are
report
ed a
s m
ean ±
sta
ndard
devi
atio
n; d
ichoto
mous
variable
s are
report
ed a
s co
un
ts a
nd p
erc
enta
ge
s in
pare
nth
ese
s. D
efin
ition
crite
ria
fo
r p
reo
pe
rativ
e v
aria
ble
s a
re a
cco
rdin
g t
o E
uro
SC
OR
E II. A
VR
= a
ort
ic v
alv
e r
epla
cem
ent, C
AB
G =
coro
nary
art
ery
byp
ass
gra
ftin
g,
CC
S =
Cana
dia
n
Card
iova
scula
r S
oci
ety
.
64
Similar aortic cross-clamping time and cardiopulmonary bypass time were
observed, both in the unmatched and in the matched study populations.
Crystalloid cardioplegia was used more frequently in the mini-sternotomy group
(29% vs. 5.4%, p=0.007) (Table 10).
Similar major outcomes were observed. However, higher transvalvular
gradients were recorded among patients in the mini-sternotomy group (Table 11).
Similar results were observed at 2-year follow-up, both in the unmatched and
in the matched survival analysis (Figure 7 and 8).
65
Ta
ble
10
. O
pe
rati
ve
da
ta o
f p
ati
en
ts w
ho
un
de
rwe
nt
su
ture
les
s A
VR
th
rou
gh
min
iste
rno
tom
y o
r fu
ll s
tern
oto
my.
Variable
s O
vera
ll co
hort
Pro
pensi
ty s
core
cohort
Min
i-st
ern
oto
my
189 p
atie
nts
Full
stern
oto
my
78 p
atie
nts
p
Min
i-st
ern
oto
my
56 p
atie
nts
Full
stern
oto
my
56 p
atie
nts
p
Cry
sta
lloid
ca
rdio
ple
gia
3
1 (
16
) 4
(5
) 0
.01
9
1
6 (
29
) 3
(5
.4)
0.0
07
Hyp
oth
erm
ic c
ircu
lato
ry a
rre
st
0
2 (
2.6
) 0
.08
5
0
1
(1
.8)
-
Perc
eva
l bio
pro
sth
etic
valv
e s
ize
0.0
15
0.6
49
Sm
all
(21
mm
) 1
6 (
8.5
) 1
6 (
21
)
7
(1
2)
11
(2
0)
Me
diu
m (
23
mm
) 7
0 (
37
) 3
0 (
39
)
2
5 (
45
) 2
0 (
36
)
La
rge
(2
5 m
m)
82
(4
3)
29
(3
7)
22
(3
9)
22
(3
9)
Ext
ra la
rge
(2
7 m
m)
21
(1
1)
3 (
3.8
)
2
(3
.6)
3 (
5.4
)
Aort
ic c
ross
-cla
mp
tim
e (
min
) 41±18
43±36
0.5
27
44±23
44±18
0.9
31
Aort
ic c
ross
-cla
mp
tim
e <
30 m
in
45 (
24
) 1
7 (
22
) 0
.87
3
1
7 (
30
) 1
0 (
18
) 0.1
67
Card
iopulm
onary
byp
ass
tim
e (
min
) 70±23
70±24
0.9
79
69±23
74±28
0.3
63
Card
iopulm
onary
byp
ass
tim
e <
60
69 (
37)
31 (
40)
0.6
77
23 (
41)
18 (
32)
0.3
56
Contin
uou
s va
riab
les
are
report
ed a
s m
ean ±
sta
ndard
devi
atio
n; d
ichoto
mous
variable
s are
report
ed a
s co
un
ts a
nd p
erc
enta
ge
s in
pare
nth
ese
s.
66
Ta
ble
11
. P
eri
- a
nd
po
sto
pe
rati
ve
da
ta o
f p
ati
en
ts w
ho
un
de
rwe
nt
su
ture
les
s A
VR
th
rou
gh
min
iste
rno
tom
y o
r fu
ll s
tern
oto
my.
Variable
s O
vera
ll co
hort
Pro
pensi
ty s
core
cohort
Min
i-st
ern
oto
my
189 p
atie
nts
Full
stern
oto
my
78 p
atie
nts
p
Min
i-st
ern
oto
my
56 p
atie
nts
Full
stern
oto
my
56 p
atie
nts
p
Imp
lan
tatio
n s
ucc
ess
1
87
(9
9)
78
(1
00
) 1
.0
5
5 (
98
) 5
6 (
10
0)
-
Re
po
sitio
nin
g o
f p
rost
he
sis
5 (
3.0
) 1
(1
.7)
1.0
2 (
3.6
) 1
(1
.8)
-
Intr
ao
pe
rativ
e p
rost
he
sis
dis
lod
ge
me
nt
1 (
0.5
) 0
-
1
(1
.8)
0
-
Conve
rsio
n to im
pla
nta
tion o
f st
ente
d p
rost
hesi
s 1 (
0.5
) 0
-
0
0
-
Conve
rsio
n t
o f
ull
stern
oto
my
0
0
-
- -
-
Aort
ic v
alv
e P
eak
gra
die
nt (m
mH
g)
28.2
±10.9
25.0
±12.1
0.0
36
28.1
±10.6
23.3
±12.0
0.0
26
Aort
ic v
alv
e M
ean g
radie
nt (m
mH
g)
14.3
±5.9
13.1
±7.0
0.2
15
15.2
±6.1
11.7
±7.0
0.0
11
Para
valv
ula
r re
gurg
itatio
n
0.7
30
-
No
ne
1
84
(9
7)
77
(9
9)
53
(9
5)
56
(1
00
)
Mild
4
(2
.1)
1 (
1.3
)
2
(3
.6)
0
Mo
de
rate
or
seve
re
1 (
0.5
) 0
1
(1
.8)
0
Pack
ed r
ed b
lood c
ells
tra
nsf
usi
ons
(units
) 1.3
5±1.7
1
1.9
9±3.1
5
0.0
34
1.1
5±1.2
4
1.9
1±3.4
9
0.1
28
Str
oke
4
(2
.1)
2 (
2.6
) 1
.0
1
(1
.8)
1 (
1.8
) 1.0
De n
ovo
dia
lysi
s 2 (
1.1
) 4 (
5.1
) 0.0
62
0
2 (
3.6
) -
Pa
cem
ake
r im
pla
nta
tion
1
8 (
9.5
) 4
(5
.2)
0.3
29
6 (
11
) 2
(3
.6)
0.1
78
Re
op
era
tion
for
ea
rly
pa
rava
lvu
lar
reg
urg
itatio
n
1 (
0.5
) 0
-
1
(1
.8)
0
-
Re
op
era
tion
for
ma
jor
ble
ed
ing
8
(4
.2)
4 (
5.1
) 0
.75
1
1
. (1
.8)
3 (
5.4
) 0.3
41
Pro
sthesi
s endo
card
itis
0
0
-
0
0
-
Inte
nsi
ve c
are
unit
stay
(days
) 2.4
±2.3
3.3
±3.5
0.0
53
2.5
±2.8
3.3
±3.8
0.1
55
Hosp
ital s
tay
(days
) 12.2
±5.7
13.4
±10.0
0.3
41
12.5
±6.8
13.4
±10.9
0.5
69
In-h
osp
ital m
ort
alit
y 2
(1
.1)
2 (
2.6
) 0
.58
3
0
2
(3
.6)
-
30
-da
y m
ort
alit
y 1
(0
.5)
0
-
0
0
-
Pro
sth
esi
s-re
late
d e
arly
mo
rta
lity
0
0
-
0
0
-
Contin
uou
s va
riab
les
are
report
ed a
s m
ean ±
sta
ndard
devi
atio
n; d
ichoto
mous
variable
s are
report
ed a
s co
un
ts a
nd p
erc
enta
ge
s in
pare
nth
ese
s.
67
Fig. 7. Kaplan-Meier cumulative survival in the overall cohort (n=267, p=0.423).
Fig. 8. Kaplan-Meier cumulative survival in the propensity score matched cohort
(n=112, p=0.463).
68
5.4 Comparison of minimally invasive Perceval implantation to the
traditional approach with full sternotomy and stented valves (III)
In this study, we investigated the early outcomes and 2-year survival after AVR
performed in 182 patients through a mini-sternotomy with the Perceval sutureless
bioprosthesis compared to 383 patients with a full sternotomy and implantation of
a stented bioprosthesis.Propensity matching resulted in 171 pairs with similar
preoperative risk profiles (Table 12).
69
Ta
ble
12
. B
as
eli
ne
c
ha
rac
teri
sti
cs
fo
r p
ati
en
ts
wh
o
un
de
rwe
nt
ao
rtic
v
alv
e
rep
lac
em
en
t th
rou
gh
a
m
inis
tern
oto
my
w
ith
imp
lan
tati
on
of
a s
utu
rele
ss
bio
pro
sth
es
is o
r th
rou
gh
a f
ull
ste
rno
tom
y w
ith
a s
ten
ted
bio
pro
sth
es
is.
Va
ria
ble
s O
vera
ll co
hort
Pro
pensi
ty s
core
cohort
Min
i-st
ern
oto
my
sutu
rele
ss
189 p
atie
nts
Full
stern
oto
my
Ste
nte
d
383 p
atie
nts
p
Min
i-st
ern
oto
my
sutu
rele
ss
171 p
atie
nts
Full
stern
oto
my
Ste
nte
d
171 p
atie
nts
p
Sta
nd
ard
ize
d
diff
ere
nce
(%
)
Ag
e (
yea
rs)
77.5
±5.2
73.8
±8.2
<
0.0
01
77.3
± 5
.1
77.4
± 6
.1
0.9
23
-0
.9
Fem
ale
gender
11
2 (
62
) 1
72
(4
5)
<0
.00
1
1
02
(6
0)
10
8 (
63
) 0
.51
3
-7.2
Weig
ht (k
g)
74.5
±14
76.8
±16
0.0
88
74.8
±14
74.7
±15
0.9
45
0.7
Heig
ht (c
m)
164±11
160±40
0.0
58
165±11
159±36
0.0
72
21
Body
mass
inde
x (k
g/m
2)
27.3
±4.4
26.5
±4.5
0.0
58
27.3
±4.4
26.7
±4.7
0.2
68
11
Dia
bete
s m
elli
tus
43
(2
4)
55
(1
4)
0.0
09
38
(2
2)
31
(1
8)
0.3
09
10
Insu
lin-d
epe
ndent
21
(5
.5)
21
(5
.5)
0.8
46
10
(5
.9)
7 (
4.1
) 0.4
69
8.1
Cre
atin
ine c
leara
nce
<
0.0
01
0.8
23
>85 (
ml/m
in)
37
(2
0)
82
(2
2)
67
(4
0)
69
(3
9)
2.4
50
-85
(m
l/min
) 6
7 (
37
) 2
03
(5
4)
66
(3
9)
71
(4
2)
-6.0
<50 (
ml/m
in)
78
(4
3)
94
(2
5)
36
(2
1)
33
(1
9)
4.4
Coro
nary
art
ery
dis
ease
3
(1
.6)
22
(5
.7)
0.0
28
3 (
1.8
) 3
(1
.8)
1
0
Rece
nt m
yoca
rdia
l infa
rctio
n
2 (
1.1
) 1
1 (
2.9
) 0
.24
0
2
(1
.2)
3 (
1.8
) 0.6
57
-4
.9
Chro
nic
pu
lmonary
dis
ease
2
0 (
11
.0)
27
(7
.0)
0.1
41
15
(8
.8)
15
(8
.8)
1
0
Ext
raca
rdia
c a
rte
rio
pa
thy
25
(1
3.7
) 3
3 (
8.7
) 0
.07
5
2
2 (
13
) 2
0 (
12
) 0.7
15
3.6
Left v
entr
icula
r eje
ctio
n fra
ctio
n
0.0
64
0.8
84
>50%
1
52
(8
4)
29
7 (
79
)
1
43
(8
4)
14
2 (
83
)
1.6
30
-50
%
29
(1
6)
65
(1
7)
28
(1
6)
29
(1
7)
-1.6
<30%
1
(0
.5)
15
(4
.0)
0
0
-
-
Non-e
lect
ive p
roce
dure
2
(1
.1)
29
(7
.6)
0.0
02
2(1
.2)
3(1
.8)
0.6
57
-4
.9
Lo
gis
tic E
uro
SC
OR
E I
(%
) 7.7
±0.3
10.6
±0.6
<
0.0
01
9.8
±5.5
9.6
±6.9
0.7
01
3.6
Contin
uou
s va
riab
les
are
report
ed a
s m
ean ±
sta
ndard
devi
atio
n; d
ichoto
mous
variable
s are
report
ed a
s co
un
ts a
nd p
erc
enta
ge
s in
pare
nth
ese
s.
70
When operative details were considered, the use of the Perceval sutureless
prosthesis was associated with significantly shorter cross-clamping and
cardiopulmonary bypass times (Table 13).
71
Ta
ble
13
. A
ort
ic c
ros
s-c
lam
p a
nd
ca
rdio
pu
lmo
na
ry b
yp
as
s t
ime
fo
r p
ati
en
ts w
ho
un
de
rwe
nt
ao
rtic
va
lve r
ep
lace
me
nt
thro
ug
h a
min
iste
rno
tom
y w
ith
im
pla
nta
tio
n o
f a
su
ture
les
s b
iop
rosth
es
is o
r th
rou
gh
a f
ull s
tern
oto
my
wit
h a
ste
nte
d b
iop
rosth
esis
.
Variable
s O
vera
ll co
hort
Pro
pensi
ty s
core
cohort
Min
i-st
ern
oto
my
sutu
rele
ss
189 p
atie
nts
Full
stern
oto
my
Ste
nte
d
383 p
atie
nts
p
Min
i-st
ern
oto
my
sutu
rele
ss
171 p
atie
nts
Full
stern
oto
my
Ste
nte
d
171 p
atie
nts
p
Aort
ic c
ross
-cla
mp
tim
e (
min
) 41±17
65±15
<
0.0
01
40±15
65±15
<
0.0
01
Aort
ic c
ross
-cla
mp
tim
e <
30 m
in
45 (
25)
0
<0.0
01
43 (
25)
0
<0.0
01
Card
iopulm
onary
byp
ass
tim
e (
min
) 69±23
86±20
<
0.0
01
69±20
87±20
<
0.0
01
Card
iopulm
onary
byp
ass
tim
e <
60
69 (
38)
19 (
5.0
) <
0.0
01
65 (
38)
6 (
3.5
) <
0.0
01
Contin
uou
s va
riab
les
are
report
ed a
s m
ean ±
sta
ndard
devi
atio
n; d
ichoto
mous
variable
s are
report
ed a
s co
un
ts a
nd p
erc
enta
ge
s in
pare
nth
ese
s.
72
Operative mortality in the propensity-matched cohort was 1.8% in the mini-
sternotomy sutureless group and 2.3% in the full sternotomy stented group
(p=0.706).
Patients in the mini-sternotomy sutureless group required more frequent
implantation of permanent pacemaker (9.9 vs. 2.9%, p=0.016) but fewer
transfusions of packed red blood cells (1.4 vs. 2.4 units, p<0.001) (Table 14).
73
Ta
ble
14
. P
os
top
era
tiv
e d
ata
fo
r p
ati
en
ts w
ho
un
de
rwen
t ao
rtic
valv
e r
ep
lac
em
en
t th
rou
gh
a m
inis
tern
oto
my
wit
h i
mp
lan
tati
on
of
a s
utu
rele
ss
bio
pro
sth
es
is o
r th
rou
gh
a f
ull
ste
rno
tom
y w
ith
a s
ten
ted
bio
pro
sth
es
is.
Variable
s O
vera
ll co
hort
Pro
pensi
ty s
core
cohort
Min
i-st
ern
oto
my
sutu
rele
ss
189 p
atie
nts
Full
stern
oto
my
Ste
nte
d
383 p
atie
nts
p
Min
i-st
ern
oto
my
sutu
rele
ss
171 p
atie
nts
Full
stern
oto
my
Ste
nte
d
171 p
atie
nts
p
Para
valv
ula
r re
gurg
itatio
n
0.3
81
0.4
84
No
ne
1
78
(9
8)
37
0 (
97
)
1
67
(9
8)
16
5 (
96
)
Mild
4
(2
.2)
9 (
2.3
)
4
(2
.3)
4 (
2.3
)
Mo
de
rate
or
seve
re
0
4 (
1.0
)
0
2
(1
.2)
Pack
ed r
ed b
lood c
ells
tra
nsf
usi
ons
(units
) 1.4
±1.7
2.6
±4.5
<
0.0
01
1.4
±1.7
2.4
±2.7
<
0.0
01
Str
oke
4
(2
.2)
2 (
0.5
) 0
.08
8
4
(2
.3)
2 (
1.2
) 0.4
23
De
no
vo d
ialy
sis
2 (
1.1
) 1
0 (
2.6
) 0
.35
4
2
(1
.2)
3 (
1.8
) 0.6
57
Pa
cem
ake
r im
pla
nta
tion
1
7 (
9.3
) 7
(1
.8)
<0
.00
1
1
7 (
9.9
) 5
(2
.9)
0.0
16
Re
op
era
tion
for
ea
rly
pa
rava
lvu
lar
reg
urg
itatio
n
0
1 (
0.3
) 1
0
0
-
Re
op
era
tion
for
ma
jor
ble
ed
ing
8
(4
.4)
30
(7
.8)
0.1
52
7 (
4.1
) 1
1 (
6.4
) 0.3
23
Inte
nsi
ve c
are
unit
stay
(days
) 2.4
±2.3
1.6
±2.8
<
0.0
01
2.5
±2.3
1.9
±2.9
0.0
54
30
-da
y m
ort
alit
y 3
(1
.6)
8 (
2.1
) 1
3 (
1.8
) 4
(2
.3)
0.7
06
Contin
uou
s va
riab
les
are
report
ed a
s m
ean ±
sta
ndard
devi
atio
n; d
ichoto
mous
variable
s are
report
ed a
s co
un
ts a
nd p
erc
enta
ge
s in
pare
nth
ese
s.
74
Two-year survival was similar between the two groups in the unmatched
(mini-sternotomy 92.0% vs full sternotomy 92.4%, p=0.90) (Figure 9) and in the
matched analysis (mini-sternotomy91.0% vs full sternotomy 93.0%,
p=0.90)(Figure 10).
75
Fig. 9. Kaplan-Meier cumulative survival in the overall cohort (n=565, p=0.669). (FS =
full sternotomy; MS = ministernotomy).
Fig. 10. Kaplan-Meier cumulative survival in the propensity score matched cohort
(n=342, p=0.895). (FS = full sternotomy; MS = ministernotomy).
76
5.5 In-hospital outcomes and 1-year survival after AVR with the
Perceval sutureless bioprosthesis vs TAVI (IV)
TAVI is no longer an emerging technology for the treatment of severe
symptomatic aortic stenosis. Excellent results have been reported in inoperable or
high-risk patients. However, in study I we demonstrated that the observed
mortality was significantly lower than predicted when the Perceval sutureless
bioprosthesis was employed. Accordingly, the Perceval sutureless bioprosthesis
may further enhance surgical indications also for patients at high-risk. Therefore,
in this study we compared data of 292 patients receiving the Perceval sutureless
bioprosthesis from our multicenter European registry to those of 1885 patients
treated with the balloon expandable Sapien and Sapien XT bioprostheses
(Edwards Lifesciences, Irvine, CA, USA) from the Italian Transcatheter balloon
Expandable Registry – ITER.
In order to overcome significant differences in preoperative risk profiles,
three different propensity score matching procedures have been performed (Table
15).
Table 15. Postoperative data on patients who underwent AVR with the Perceval
sutureless bioprosthesis.
Variables Matching Sutureless TAVI p
Age Before matching a 76.8±5 81.7±6 <0.01
After individual matching b 77.4±5.4 77.7±7.9 0.08
After matching in TA c 78.3±5.3 78.5±8.7 0.18
After matching in TF d 77.7±5.0 77.7±7.0 0.57
Female gender Before matching a 188(64.4) 1139(60.4) 0.20
After individual matching b 138 (64.5) 139 (65.0) 0.92
After matching in TA c 69 (65.7) 69 (65.7) >0.99
After matching in TF d 139 (68.0) 131 (64.0) 0.41
Body Mass Index Before matching a 27.7±4.7 25.8±4.5 <0.01
After individual matching b 27.5±4.7 27.6±5.2 0.99
After matching in TA c 26.9±4.6 26.8±4.8 0.76
After matching in TF d 27.5±4.6 27.7±5.5 0.93
Diabetes Before matching a 77(26.4) 483(25.6) 0.79
After individual matching b 59 (27.6) 58 (27.1) 0.91
After matching in TA c 27 (25.7) 28 (26.7) 0.88
After matching in TF d 55 (26.7) 56 (27.2) 0.91
Extracardiac arteriopathy Before matching a 50(17.1) 657(34.9) <0.01
After individual matching b 46 (21.5) 48 (22.4) 0.82
After matching in TA c 33 (31.4) 37 (35.2) 0.56
77
Variables Matching Sutureless TAVI p
After matching in TF d 38 (18.5) 38 (18.5) >0.99
Chronic lung disease Before matching a 41(14.0) 462(24.5) <0.01
After individual matching b 39 (18.2) 36 (16.8) 0.70
After matching in TA c 20 (19.1) 20 (19.1) >0.99
After matching in TF d 36 (17.5) 38 (18.5) 0.80
Previous cardiac surgery Before matching a 29(9.9) 348(18.5) <0.01
After individual matching b 22 (10.3) 21 (9.8) 0.87
After matching in TA c 15 (14.3) 12 (11.4) 0.54
After matching in TF d 19 (9.2) 22 (10.7) 0.62
Renal impairment Before matching a <0.01
>85 ml/min 107 (36.6) 97 (5.2)
84-51 ml/min 111 (40.1) 618 (33.2)
≤50 ml/min 67 (23) 1090 (58.5)
dialysis 1 (0.3) 59 (3.2)
After individual matching b 0.97
>85 ml/min 46 (21.5) 42 (19.6)
84-51 ml/min 101 (47.2) 102(47.6)
≤50 ml/min 66 (30.8) 69 (32.2)
dialysis 1 (0.5) 1 (0.5)
After matching in TA c 0.66
>85 ml/min 10 (9.5) 12 (11.4)
84-51 ml/min 45 (42.9) 49 (46.7)
≤50 ml/min 66 (32.0) 44 (41.9)
dialysis 1 (0.5) 0
After matching in TF d 0.70
>85 ml/min 45 (21.8) 40 (19.4)
84-51 ml/min 94 (45.6) 104 (50.5)
≤50 ml/min 66 (32.0) 60 (29.1)
dialysis 1 (0.5) 2 (1.0)
Pulmonary hypertension Before matching a <0.01
No 246 (84.3) 742 (39.4)
31-55 mmHg 45 (15.4) 939 (49.8)
>55 mmHg 1 (0.3) 204 (10.8)
After individual matching b 0.60
No 168 (78.5) 170 (79.4)
31-55 mmHg 45 (21.0) 44 (20.6)
>55 mmHg 1 (0.5) 1 (0.5)
After matching in TA c 0.65
No 71 (67.6) 75 (71.4)
31-55 mmHg 33 (31.4) 28 (26.7)
>55 mmHg 1 (1.0) 2 (1.9)
After matching in TF d 0.57
78
Variables Matching Sutureless TAVI p
No 160 (77.7) 158 (76.7)
31-55 mmHg 45 (21.8) 48 (23.3)
>55 mmHg 1 (0.5) 0
Hystory of CAD Before matching a 12 (4.1) 767 (40.7) <0.01
After matching b 12 (5.6) 11 (5.1) 0.83
After matching in TA c 12 (11.4) 15 (14.3) 0.54
After matching in TF d 12 (5.8) 15 (7.3) 0.55
LVEF Before matching a 58.4±9.0 53.6±12.3 <0.01
After matching b 57.7±9.3 58.2±10.2 0.41
After matching in TA c 57.3±10.6 57.3±11.2 0.88
After matching in TF d 57.6±9.3 57.7±9.5 0.82
Only variables with less than 1% missing values were included in the analysis. Data are expressed in
numbers (percentage) or mean ± standard deviation. a There were 292 patients for the Sutureless treated group and 1885 patients for the TAVI treated group b There were 214 patients for the Sutureless treated group and 214 patients for the TAVI treated group
c There were 105 patients for the Sutureless treated group and 105 patients for the TAVI treated group d There were 206 patients for the Sutureless treated group and 206 patients for the TAVI treated group
Comparisons between groups are made using the Wilcoxon-Mann-Whitney test.
TAVI = Trans-catheter aortic valve implantation, TA = Trans-apical, TF = Trans-femoral, CAD = Coronary
artery disease, LVEF = left ventricular ejection fraction
5.5.1 Perceval sutureless bioprosthesis vs all TAVI
After matching all TAVI patients with patients who underwent AVR with the
Perceval sutureless bioprosthesis, we did not observe significant differences in
30-day and one-yearmortality, stroke, bleeding or myocardial infarction (Table
16).
TAVI patients had a significantly lower rate of device success (88.8% vs.
98.6%, p<0.01) and PM implantation (2.8% vs. 9.4%, p<0.01). Severe PVL (5.1%
vs. 0.5%) as well as any PVL (35.3 vs. 2.8 %; p<0.01) was higher in TAVI
patients. Transvalvular gradients were higher in the sutureless group, as well as
ICU and post-operative length of stay.
5.5.2 Perceval sutureless bioprosthesis vs transapical TAVI
Transapical TAVI and the Perceval sutureless bioprosthesishad similar 30-day and
one-yearmortality, device success, stroke, bleeding, PM implantation, myocardial
infarction and severe PVL.
79
The only significant difference was found in terms of mild PVL, which was
higher in transapical TAVI patients (36.1% vs. 2.9%, p<0.01), but not severe PVL
(1.0% vs. 1.0%, p=1.00). The Perceval study grouphad higher transvalvular
gradients and longer intensive care unit andin-hospital length of stay (Table 16).
5.5.3 Perceval sutureless bioprosthesis vs trans-femoral TAVI
Transfemoral TAVI patients had a lower rate of device success (85.9 vs. 98.1%,
p<0.01) when compared to AVR with the Perceval sutureless bioprosthesis.
Furthermore, in the transfemoral TAVI cohort we observed a higher incidence
of severe (6.3% vs. 0.5%, p=0.01) as well as any PVL (33.5 vs. 3.4 %; p<0.01).
There were no significant differences between groups in terms of 30-day and one-
yearmortality, stroke, bleeding, PM implantation and myocardial infarction.The
Perceval study group had higher transvalvular gradients and longer intensive care
unit and in-hospital length of stay (Table 16).
Table 16. Postoperative data on patients who underwent AVR with the Perceval
sutureless bioprosthesis.
Variables Matching Sutureless TAVI p
30-day mortality Before matching a 6 (2) 134 (7) <0.01
After individual matching b 5 (2.3) 8 (3.7) 0.401
After matching in TA c 3 (2.9) 4 (3.8) >0.99
After matching in TF d 5 (2.4) 9 (4.4) 0.28
1-year mortality Before matching a 13 (4.6) 7miss 242 (12.9)7miss <0.01
After individual matching b 12 (5.8) 6 miss 20 (9.4) 1 miss 0.16
After matching in TA c 8 (8.0) 5 miss 11 (10.5) 0.54
After matching in TF d 12 (6.0) 6 miss 15 (7.4) 2 miss 0.59
Device success Before matching a 288 (98.6) 1661 (88.1) <0.01
After individual matching b 211 (98.6) 190 (88.8) <0.01
After matching in TA c 103 (98.1) 99 (94.3) 0.28
After matching in TF d 202 (98.1) 177 (85.9) <0.01
Any stroke Before matching a 6 (2.1) 52 (2.8) 0.49
After individual matching b 4 (1.9) 4 (1.9) >0.99
After matching in TA c 2 (1.9) 1 (1.0) >0.99
After matching in TF d 2 (1.0) 3 (1.5) >0.99
Bleeding (life-threatening or
major)
Before matching a 44 (15.1) 381 (20.4) 0.03
After individual matching b 40 (18.7) 34 (16.1) 0.48
After matching in TA c 21 (20.0) 13 (13.0) 0.18
After matching in TF d 39 (19.0) 32 (15.0) 0.36
Permanent PM implantation Before matching a 26 (8.9) 116 (6.2) 0.08
80
Variables Matching Sutureless TAVI p
After individual matching b 20 (9.4) 6 (2.8) 0.01
After matching in TA c 10 (9.5) 4 (3.8) 0.10
After matching in TF d 19 (9.2) 12 (5.8) 0.19
Any myocardial infarction Before matching a 1 (0.3) 28 (1.5) 0.17
After individual matching b 1 (0.5) 2 (0.9) >0.99
After matching in TA c 1 (1.0) 2 (1.9) >0.99
After matching in TF d 1 (0.5) 1 (0.5) >0.99
Severe paravalvular leak Before matching a 1 (0.3) 98 (5.2) <0.01
After individual matching b 1 (0.5) 11 (5.1) 0.06
After matching in TA c 1 (1.0) 1 (1.0) >0.99
After matching in TF d 1 (0.5) 13 (6.3) <0.01
Any paravalvular leak Before matching a <0.01
No 268 (98.0) 1125 (62.7)
Mild 5 (1.7) 571 (31.8)
>Mild 1 (0.3) 98 (5.5)
After individual matching b <0.01
No 208 (97.2) 134 (64.7)
Mild 5 (2.3) 62 (30.0)
>Mild 1 (0.5) 11 (5.3)
After matching in TA c <0.01
No 101 (96.1) 66 (62.9)
Mild 3 (2.9) 38 (36.1)
>Mild 1 (1.0) 1 (1.0)
After matching in TF d <0.01
No 199 (96.6) 137(66.5)
Mild 5 (2.4) 56 (27.2)
>Mild 2 (1.0) 13 (6.3
Data are expressed in number (percentage) aThere were 292 patients for the SL treated group and 1885 patients for the TAVI treated group b There were 214 patients for the SL treated group and 214 patients for the TAVI treated group c There were 105 patients for the SL treated group and 105 patients for the TAVI treated group d There were 206 patients for the SL treated group and 206 patients for the TAVI treated group
Comparisons between groups are made using the Wilcoxon-Mann-Whitney test.
VARC = Valve academic research consortium, TAVI = Trans-catheter aortic valve implantation, TA =
Trans-apical, TF = Trans-femoral, PM = Pacemaker, miss = missing
5.6 Immediate outcomes after AVR with the Perceval sutureless
bioprosthesisvs TAVI (V)
We compared 379 patients who underwent AVR with the Perceval sutureless
bioprosthesiswith 394 patients treated with TAVI. Patients in both groups differed
81
in a number of baseline characteristics. In particular, 25.6% of patients in the
Perceval study group underwent concomitant CABG, whereas PCI was
performed only in 2.0% of TAVI patients (Table 17 and Figure 11). Unfortunately,
details on coronary disease and pattern were not available in the interventional
arm of the study, since current practice privileges TAVI alone in patients with
coronary artery disease, since the value of concomitant PCI is still controversial
[50]. Therefore, any coronary procedure in both groups was not considered for
the calculation of the propensity score.
Fig. 11. Distribution of patients to TAVI and sutureless aortic valve replacement (SU-
AVR) groups according to EuroSCORE II values.
82
Ta
ble
17
. B
as
eli
ne c
ha
rac
teri
sti
cs o
f p
ati
en
ts w
ho
un
de
rwe
nt
tran
sc
ath
ete
r (T
AV
I) v
ers
us
su
rgic
al
ao
rtic
valv
e r
ep
lac
em
en
t w
ith
Pe
rce
va
l s
utu
rele
ss
bio
pro
sth
es
is.
Variable
s O
vera
ll co
hort
25
th-7
5th p
erc
en
tile
of
ES
II
P
rop
en
sity
-ma
tch
ed
pa
irs
Su
ture
less
379 p
atie
nts
TA
VI
394 p
atie
nts
p
Sutu
rele
ss
180 p
atie
nts
TA
VI
180 p
atie
nts
p
Sutu
rele
ss
144 p
atie
nts
TA
VI
144 p
atie
nts
p
Age (
years
) 77.4
±5.4
80.8
±5.5
<
0.0
001
78.9
±5.3
81.5
±4.9
<
0.0
001
79.4
±5.4
79.0
±6.0
0.7
45
Fe
ma
les
23
6 (
62
.3)
22
9 (
58
.1)
0.2
39
11
3 (
62
.8)
13
5 (
64
.6)
0.7
10
88
(6
1.1
) 9
0 (
62
.5)
0.8
08
Insu
lin-d
ep
en
de
nt
dia
be
tes
37
(9
.8)
11
(2
.8)
<0
.00
01
1
6 (
8.9
) 5
(2
.4)
0.0
05
6 (
4.2
) 5
(3
.5)
0.7
59
Cre
atin
ine c
leara
nce
<
0.0
001
<
0.0
001
0.4
76
50
-85
ml/m
in
15
0 (
39
.6)
15
8 (
40
.1)
75
(4
1.7
) 9
1 (
43
.5)
67
(4
6.5
) 7
3 (
50
.7)
<5
0 m
l/min
8
5 (
22
.4)
20
3 (
51
.5)
44
(2
4.4
) 1
09
(5
2.2
)
4
6 (
31
.9)
48
(3
3.3
)
New
York
Heart
Ass
oci
atio
n c
lass
0.6
55
0.7
79
0.6
10
III
25
5 (
67
.3)
26
4 (
67
.0)
12
9 (
71
.7)
14
1 (
67
.5)
10
1 (
70
.1)
94
(6
5.3
)
IV
24
(6
.3)
30
(7
.6)
11
(6
.1)
12
(5
.7)
7 (
4.9
) 1
1 (
7.6
)
CC
S c
lass
IV
1
2 (
3.2
) 4
6 (
11
.7)
<
0.0
00
1
3 (
1.7
) 1
7 (
8.1
) 0
.00
5
6
(4
.2)
6 (
4.2
) 1
.00
0
Pu
lmo
na
ry d
ise
ase
6
3 (
16
.6)
13
6 (
34
.5)
<0
.00
01
3
5 (
19
.4)
67
(3
2.1
) 0
.00
5
3
8 (
26
.4)
35
(2
4.3
) 0
.68
4
Ext
raca
rdia
c a
rte
rio
pa
thy
83
(2
1.9
) 2
7 (
6.9
) <
0.0
00
1
43
(2
3.9
) 7
(3
.3)
<0
.00
01
1
2 (
8.3
) 1
3 (
9.0
) 0
.83
4
Re
cen
t m
yoca
rdia
l in
farc
tion
6
(1
.6)
68
(1
7.3
) <
0.0
00
1
3 (
1.7
) 2
4 (
11
.5)
<0
.00
01
5
(3
.5)
3 (
2.1
) 0
.72
3
Left v
entr
icula
r eje
ctio
n fra
ctio
n
<0.0
001
0.2
25
0.7
98
31
-50
%
57
(1
5.0
) 1
00
(2
5.4
)
2
8 (
15
.6)
41
(1
9.6
)
2
6 (
18
.1)
23
(1
6.0
)
21
-30
%
3 (
0.8
) 2
3 (
5.8
)
1
(0
.6)
5 (
2.4
)
3
(2
.1)
2 (
1.2
)
≤20
%
0
5 (
1.3
)
0
(0
) 1
(0
.5)
0 (
0)
0 (
0)
Sys
tolic
pulm
onary
art
erial p
ress
ure
<
0.0
001
<
0.0
001
0.9
83
31
-55
mm
Hg
1
40
(3
6.9
) 2
56
(6
5.0
)
7
3 (
40
.6)
14
8 (
70
.8)
75
(5
2.1
) 7
4 (
51
.4)
>5
5 m
mH
g
37
(9
.8)
51
(1
2.9
)
2
0 (
11
.1)
22
(1
0.5
)
1
7 (
11
.8)
18
(1
2.5
)
83
Variable
s O
vera
ll co
hort
25
th-7
5th p
erc
en
tile
of
ES
II
P
rop
en
sity
-ma
tch
ed
pa
irs
Su
ture
less
379 p
atie
nts
TA
VI
394 p
atie
nts
p
Sutu
rele
ss
180 p
atie
nts
TA
VI
180 p
atie
nts
p
Sutu
rele
ss
144 p
atie
nts
TA
VI
144 p
atie
nts
p
Critic
al p
reo
pe
rativ
e s
tate
3
(0
.8)
0
0.1
17
1 (
0.6
) 0
(0
) 0
.46
3
0
(0
) 0
(0
) -
Ele
ctiv
e p
roce
du
re
36
3 (
95
.8)
39
4 (
10
0)
<0
.00
01
1
76
(9
7.8
) 2
09
(1
00
) 0
.03
0
1
44
(1
00
) 1
44
(1
00
) -
Pre
vio
us
card
iac
surg
ery
3
3 (
8.7
) 6
0 (
15
.2)
0.0
05
13
(7
.2)
5 (
2.4
) 0
.02
9
1
2 (
8.3
) 1
5 (
10
.4)
0.5
44
Ao
rtic
va
lve
su
rge
ry
12
(3
.2)
9 (
2.3
) 0
.51
1
3
(1
.7)
0 (
0)
0.0
98
6 (
4.2
) 4
(2
.8)
0.5
20
Pe
rma
ne
nt
pa
ce-m
ake
r 1
0 (
2.6
) 3
5 (
8.9
) <
0.0
00
1
6 (
3.3
) 1
0 (
4.8
) 0
.47
2
7
(4
.9)
7 (
4.9
) 1
.00
0
Eu
roS
CO
RE
II
(%)
4.0
±3
.9
5.6
±4
.9
<0
.00
01
3
.4±1
.0
3.7
±1
.1
0.0
02
4.1
±3.2
3.6
±2.6
0.1
17
Contin
uou
s va
riab
les
are
report
ed a
s m
ean ±
sta
ndard
devi
atio
n; d
ichoto
mous
variable
s are
report
ed a
s co
un
ts a
nd p
erc
enta
ge
s in
pare
nth
ese
s; D
efin
ition
crite
ria f
or
pre
opera
tive v
ariab
les
are
acc
ord
ing
to
Eu
roS
CO
RE
II,
ES
= E
uro
SC
OR
E I
I.
84
In the unmatched population, we observed that TAVI was associated with an
increased risk of moderate-to-severe PVL and need for permanent pacemaker
implantation. Conversely, sutureless prostheses had a greater incidence of device
failure, because postprocedural echocardiography showed a mean gradient ≥20
mmHg in 16.1% of surgical patients (16.1% vs. 2.3%, p<0.0001). TAVI showed a
slight trend toward operative mortality, although it was not statistically significant
(2.6% after vs 5.3%, p=0.057) (Table 18).
Analyses including patients comprised between the 25th and 75th percentiles
of EuroSCORE II confirmed the previous findings, but we observed similar
trends for permanent pacemaker implantation (Table 18).
Propensity matching generated 144 pairs with similar preoperative risk
profiles. Operative mortality was significantly lower in the Perceval study group
(1.4% vs. 6.9%, p=0.035). TAVI was associated with a greater incidence of
vascular complication and the occurrence of PVL, whereas patients in the
Perceval study group had an increased risk of reoperation for major bleeding
(Table 18).
85
Ta
ble
18
. Im
med
iate
po
sto
pe
rati
ve
data
on
pati
en
ts w
ho
un
de
rwen
t tr
an
sc
ath
ete
r (T
AV
I) a
nd
su
rgic
al
ao
rtic
valv
e r
ep
lac
em
en
t
wit
h P
erc
ev
al
su
ture
les
s b
iop
ros
the
sis
.
Variable
s O
vera
ll co
hort
25
th-7
5th p
erc
en
tile
of
ES
II
P
rop
en
sity
-ma
tch
ed
pa
irs
Su
ture
less
379 p
atie
nts
TA
VI
394 p
atie
nts
p
Sutu
rele
ss
180 p
atie
nts
TA
VI
180 p
atie
nts
p
Sutu
rele
ss
144 p
atie
nts
TA
VI
144 p
atie
nts
p
Devi
ce s
ucc
ess
305 (
80.5
) 309 (
78.4
) 0.4
81
146 (
81.1
) 168 (
80.4
) 0
.85
6
1
15
(7
9.9
) 1
12
(7
7.8
) 0
.66
5
Valv
ula
r re
gurg
itatio
n
<0.0
001
<
0.0
001
<0.0
001
No
ne
3
70
(9
7.6
) 1
63
(4
1.9
)
1
74
(9
6.7
) 9
3 (
44
.7)
14
0 (
97
.2)
66
(4
6.5
)
Mild
8
(2
.1)
17
1 (
44
.0)
5 (
2.8
) 8
8 (
42
.3)
3 (
2.1
) 5
5 (
38
.7)
Mo
de
rate
- se
vere
1
(0
.3)
55
(1
4.1
)
1
(0
.6)
27
(1
3.0
)
1
(0
.7)
21
(1
4.8
)
Co
nve
rsio
n t
o c
on
ven
tion
al A
VR
2
(0
.5)
0 (
0)
0.2
40
1 (
0.6
) 0
(0
) 0
.46
3
0
(0
) 0
(0
) -
Str
oke
9
(2
.4)
5 (
1.3
) 0
.25
1
2
(1
.1)
2 (
1.0
) 1
.00
0
0
(0
) 3
(2
.1)
0.1
22
De
no
vo d
ialy
sis
11
(2
.9)
3 (
0.8
) 0
.03
1
5
(2
.8)
1 (
0.5
) 0
.10
0
3
(2
.1)
0 (
0)
0.2
47
Pa
ce-m
ake
r im
pla
nta
tion
3
7 (
9.8
) 6
8 (
17
.3)
0.0
03
20
(1
1.0
) 3
5 (
16
.8)
0.1
12
16
(1
1.2
) 2
2 (
15
.4)
0.2
96
Vasc
ula
r acc
ess
com
plic
atio
n
0 (
0)
45 (
11.4
) <
0.0
001
0 (
0)
28 (
13.4
) <
0.0
001
0 (
0)
15 (
10.4
) <
0.0
001
Re
op
era
tion
for
ma
jor
ble
ed
ing
1
4 (
3.7
) 0
(0
) <
0.0
00
1
9 (
5.0
) 0
(0
) 0
.00
1
6
(4
.2)
0 (
0)
0.0
13
In-h
osp
ital m
ort
alit
y 1
0 (
2.6
) 2
1 (
5.3
) 0
.05
7
2
(1
.1)
8 (
3.8
) 0
.11
5
2
(1
.4)
10
(6
.9)
0.0
35
Contin
uou
s va
riab
les
are
report
ed a
s m
ean ±
sta
ndard
devi
atio
n; d
ichoto
mous
variable
s are
report
ed a
s co
un
ts a
nd p
erc
enta
ge
s in
pa
ren
the
ses.
ES
=
Eu
roS
CO
RE
II.
86
5.7 Hemodynamic assessment of the Perceval sutureless
bioprosthesis with dobutamine stress echocardiography (VI)
Baseline characteristics and detail of size of the prosthesis are shown in Table 19.
Table 19. Baseline characteristics, preoperative echocardiographic details and size of
implanted valves.
Variables n=32
Age at surgery (years) 74.6±5.6
Gender (F) 18 (56.3%)
Height (m) 160.7±8.1
Weight (Kg) 70.1±13.3
Body surface area (m2) 1.76±0.18
Body mass index (Kg/m2) 27.2±5.2
eGFR classes
>85 ml/min/m2 3 (9.4%)
50-85 ml/min/m2 21 (65.6%)
<50 ml/min/m2 8 (25%)
Extracardiac arteriopathy 4 (12.5%)
Poor mobility 1 (3.1%)
Redo 2 (6.3%)
Chronic lung disease 5 (15.6%)
IDDM 6 (18.8%)
NYHA III-IV 24 (75%)
LVEF 57.3±8.1%
LVEF classes
>50% 25 (78.1%)
30-50% 7 (21.9%)
PAPs (mmHg) 31.9±7.9
PAPs classes
<30 mmHg 15 (46.9%)
31-55 mmHg 17 (53.1%)
EuroSCORE II 4.16±3.47%
Annulus (mm) 22.2±1.8
Sinuses of Valsalva (mm) 30.0±2.9
Sino-tubular junction (mm) 26.6±2.3
Aortic root height (mm) 17.7±2.6
Peak gradient (mmHg) 81.0±24.1
Mean gradient (mmHg) 48.6±18.0
AVA (cm2) 0.7±0.2
AVAi (cm2/m2) 0.38±0.15
Full sternotomy 18 (52.2%)
87
Variables n=32
J mini-sternotomy 14 (43.8%)
Size
S 10 (31.3%)
M 9 (28.1%)
L 8 (25%)
XL 5 (15.6%)
AVA(i) = aortic valve area (index)
Gradients and valve area at discharge significantly improved compared to
preoperative values, and remained stable after a median follow-up of 19.5 months
(IQR 15.3-27.3) (Table 20). However, 8 patients (25%) showed severe PPM.
Table 20. Variation of transvalvular gradients and valve areas from preoperative
values to follow-up.
Variables Preoperative Discharge Follow-up
Peak gradient 81.0±24.1 22.9±9.4*** 24.0±7.6NS
Mean gradient 48.6±18.0 12.6±5.5*** 12.6±4.2 NS
AVA 0.7±0.2 1.5±0.2*** 1.5±0.5 NS
AVAi 0.38±0.15 0.85±0.14*** 0.84±0.26 NS
AVA(i) = aortic valve area (index). *** = p<0.001 vs preoperative, NS = p not significant vs discharge
All patients completed the DSE test without complications. We have observed a
significant increase of transvalvular gradients, EOA, EOAi and DVI.
Mean percentage increase of EOAi was 40.3±28.0% (Table 21).
Table 21. Hemodynamic assessments during dobutamine stress echocardiography.
Variables Rest Exercise p
Heart rate 71.0±10.5 119.0±11.0 <0.001
Stroke volume (ml) 69.1±14.2 90.1±17.1 <0.001
LVEF (%) 57.6±7.4 62.8±7.5 <0.001
Peak gradient 24.0±7.6 38.7±13.6 <0.001
Mean gradient 12.6±4.2 19.8±8.3 <0.001
EOA 1.5±0.5 2.1±0.7 <0.001
EOAi 0.84±0.26 1.17±0.37 <0.001
DVI 0.47±0.13 0.66±0.20 <0.001
Severe PPM 8 (25%) 1 (3.1%) <0.001
LVEF = left ventricular ejection fraction, EOA(i) = effective orifice area (index), DVI = dimensionless
velocity index, PPM = prosthesis-patient mismatch.
88
5.7.1 Variation of EOA in patients with baseline prosthesis-patient mismatch
When the subgroup of 8 patients with baseline PPM was analyzed, we observed
similar improvement in EOA and EOAi with concordant increase in DVI. Only
one patient had a significant PPM at peak dobutamine stress (Table 22).
Table 22. Hemodynamic assessments during dobutamine stress echocardiography in
patients with prosthesis-patient mismatch (n=8).
Variables Rest Exercise p
Peak gradient 25.0±8.8 40.0±16.5 0.005
Mean gradient 13.0±4.5 22.3±10.2 0.004
EOA 1.0±0.1 1.4±0.4 0.005
EOAi 0.58±0.05 0.79±0.14 0.003
DVI 0.39±0.04 0.53±0.11 0.003
EOA(i) = effective orifice area (index), DVI = dimensionless velocity index.
5.7.2 Variation of EOA according to valve size
S size valves showed the highest percentage increase in EOA, but such a
difference did not reach statistical significance (S 46.0±27.5% vs M 45.4±34.5%
vs L 32.7±26.4% vs XL 32.1±20.5%; p=0.66 at Kruskal-Wallis test). However,
the observed trends were confirmed also in a single subgroup of patients,
according to the valve size (Table 23).
Table 23. Hemodynamic assessments during dobutamine stress echocardiography
according to valve size.
Valve size Variables Rest Exercise p
S Peak gradient 28.6±6.7 46.9±15.5 0.002
Mean gradient 15.2±3.5 24.2±9.3 0.002
EOA 1.4±0.5 2.0±0.8 0.001
EOAi 0.83±0.32 1.19±0.45 0.001
DVI 0.48±0.19 0.69±0.19 0.001
M Peak gradient 25.0±5.6 36.9±9.6 0.001
Mean gradient 12.9±3.0 18.1±4.9 0.005
EOA 1.5±0.3 2.1±0.5 0.006
EOAi 0.84±0.16 1.21±0.30 0.006
DVI 0.47±0.06 0.68±0.18 0.006
89
Valve size Variables Rest Exercise p
L Peak gradient 19.8±8.0 29.4±11.9 0.001
Mean gradient 9.9±3.9 14.8±7.4 0.011
EOA 1.5±0.5 2.0±0.9 0.021
EOAi 0.86±0.30 1.13±0.42 0.016
DVI 0.47±0.12 0.62±0.20 0.014
XL Peak gradient 20.0±7.7 40.6±10.1 0.002
Mean gradient 11.0±5.3 22.2±8.9 0.008
EOA 1.6±0.5 2.1±0.5 0.021
EOAi 0.85±0.29 1.10±0.28 0.021
DVI 0.47±0.13 0.62±0.11 0.017
EOA(i) = effective orifice area (index), DV = dimensionless velocity index.
90
91
6 Discussion
6.1 Impact of AVR with the Perceval sutureless bioprosthesis on
in-hospital and mid-term outcomes (I)
In study I, we have evaluated the use of the Perceval sutureless bioprosthesis in a
cohort of patients undergoing AVR±CABG at five European institutions. The
baseline characteristics of this cohort are typical of medium-high operative risk
patients, in fact 36.9% were octogenarians, 80.6% were symptomatic (NYHA III-
IV), 29.9% underwent concomitant CABG. These data accounted for a
EuroSCORE II of 9.0±7.6%.
Operative mortality was low (3.2%), especially in those patients undergoing
isolated AVR (1.4%). These data are extremely encouraging for the diffusion of a
sutureless bioprosthesis in the clinical practice. In fact, our data demonstrate a
significantly lower mortality compared to that reported in a recent meta-analysis,
which showed an overall mortality of 4.3% (3.3% after isolated AVR, 5.5% after
combined CABG) [49].
It is noteworthy that EuroSCORE II overpredicted operative mortality,
especially in those patients in the higher quartile of EuroSCORE II (≥4%) and
among patients undergoing isolated AVR (mean EuroSCORE II 8.7±7.9%).
The observed short cross-clamping and cardiopulmonary bypass time may
have a beneficial impact on operative mortality. In particular, aortic cross-
clamping time was an independent predictor of operative mortality in the overall
series as well as in patients undergoing CABG. This association was not observed
in patients who had undergone isolated AVR. These data confirm the findings of
Ranucci et al., who showed an increasing risk of morbidity of 1.4% per 1-minute
increase of aortic cross-clamping time [104] and those of Chalmers et al, who
demonstrated a 2% increase of risk of operative mortality per each minute
increase of cardiopulmonary bypass in a cohort of 1863 primary isolated AVR
[105].
Interestingly, the observed mortality of 7.4% in those patients undergoing
concomitant CABG suggest that changes in addition to reduction of cross-
clamping time may be required to reduce mortality in high-risk patients.
Accordingly, less invasive procedures, such as hybrid PCI or TAVI, could be
valuable alternative options.In fact, a recent meta-analysis showed a pooled rate
of 6.3% operative mortality in TAVI patients with or without concomitant PCI
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[128]. Similarly, isolated AVR is not a risk factor for operative mortality in
patients referred primarily for severe aortic stenosis, with an incidental diagnosis
of concomitant coronary artery disease [43].
Interestingly, a clinical benefit is observed among octogenarians, especially
those undergoing isolated AVR (mortality 2.7%). It could be speculated that the
extremely low incidence of paravalvular leakage – secondary to a complete
decalcification of the aortic annulus – in association with a reduced cross-
clamping time may translate into a clinical benefit in this subgroup of patients
[78,87].
The observed high-incidence of pacemaker implantation (9.9%) is certainly a
striking result. A recent study has demonstrated that preoperative right bundle
branch block is an independent predictorof permanent pacemaker implantation
after sutureless AVR [129].However, details on preoperative rhythm disturbances
are missing in study I and therefore such analysis hasnot been performed.
Survival analysis and freedom from adverse events at follow-up further
suggest that the beneficial effects of sutureless AVR are not only limited to the
immediate postoperative period, but may be durable over time.
The retrospective design of study I, as well as for studies II, III and IV, is
certainly a limitation. Moreover, patients included in this series were operated
mainly on an elective basis and have a preserved ejection fraction. Accordingly,
this study lacks patients who may best benefit from sutureless AVR, such as those
operated on an urgent/emergent basis or with reduced left ventricular function.
Furthermore, the lack of a control group, such as patients undergoing AVR with
conventional prostheses or TAVI, prevents the acquisition of more conclusive
results on the benefits associated with the use of this sutureless valve.
6.2 Usefulness of the Perceval sutureless bioprosthesis in
minimally invasive AVR (II)
Study II confirmed that AVR with the Perceval sutureless bioprosthesis is a safe
and effective procedure that could be performed either through full sternotomy or
mini-sternotomy.
Several studies have demonstrated that minimally invasive AVR is associated
with a lower incidence of operative mortality, perioperative complications and
shorter length of stay [115, 130–132]. However, minimally invasive surgery is
technically more demanding and therefore could be associated with prolonged
93
cross-clamping and cardiopulmonary bypass time, thus minimizing the potential
beneficial effects of minimal invasive approaches [131].
Accordingly, in study II we hypothesized that minimally invasive AVR with
implantation of the Perceval sutureless bioprosthesis could combine the benefits
of the two techniques without prolonging operative time.
To avoid any potential selection bias, a propensity-matched analysis has been
performed.
The only observed differences in the matched cohort were slightly higher
transvalvular gradients in the mini-sternotomy group, despite similar prosthetic
sizes or patients’ antropometrics. However, such gradients never reached clinical
significance, but the underlying reason for these small differences in
postoperative aortic valve gradients is still unknown.
6.3 Advantages of minimally invasive AVR with the Perceval
sutureless bioprosthesis compared to traditional surgery (III)
In Study III, we compared minimally invasive implantation of the sutureless
Perceval bioprosthesis through mini-sternotomy with conventional implantation
of the Carpentier-Edwards Perimount stented bioprosthesis through a full
sternotomy.
To avoid any selection bias, a propensity score based matching was
performed, resulting in two cohorts of patients with similar risk profile.
This study showed that sutureless AVR through a mini-sternotomyis as safe
and reproducible as conventional AVR with stented prosthesis implanted through
full sternotomy. Operative mortality and 2-year survival were comparable
between the two groups.
The association between sutureless bioprostheses and short procedural times
has been reported previously [120], even in minimally invasive procedures [118,
133–-135].
Interestingly, in this study we have confirmed that sutureless AVR with the
Perceval sutureless bioprosthesis allows a significantly reducedcross-clamping
and cardiopulmonary bypass times, compared to a traditional approach requiring
full sternotomy and stented valves [120, 135–-136].
Mini-sternotomy AVR was associated with less transfusion of packed red
blood cells, either in the overall or in the matched cohort. This finding confirmed
94
those of previous studies, which reported that patients undergoing minimally
invasive procedures or sutureless AVR received fewer transfusions [132,137,138].
Finally, the higher incidence of implantation of a permanent pacemaker in
patients undergoing sutureless AVR is noteworthy. Other studies confirm the
association between the use of the Perceval sutureless bioprosthesis and an
increased rate of permanent pacemaker implantation [120,129,139,140].
The higher incidence of permanent pacemaker implantation might be
influenced by multiple different preoperative factors (age, combined surgical
procedures, preoperative conduction disturbances, extensive calcifications of the
aortic root) [129,139]. Technical details are certainly important determinants of
permanent pacemaker implantation. Interestingly, Bonneau et al demonstrated
that the incidence of complete atrio-ventricular block is more frequent if the gap
between the remaining aortic annulus and the lower portion of the skirt of the
Perceval sutureless bioprosthesis is 5-7 mm [Personal communication].
Accordingly, aggressive oversizing seemed to be associated with higher
permanent pacemaker implantation. A difference between the nominal valve size
and the LVOT ≤5 mm seems to be protective[Personal communication].
Furthermore, Perceval registry reflects the high variability of permanent
pacemaker implantation among countries and even among centers in the same
country. Therefore, although the implant technique was standardized among
participating centers, several uninvestigated variables may have been responsible
for the increased incidence of complete atrio-ventricular block in this registry.
6.4 Different outcomes for different techniques (IV)
This study merged data from two completely different populations of patients,
with patients receiving TAVI having a higher preoperative risk profile (logistic
EuroSCORE 21.2±13.6% vs. 9.5±6.0%). Accordingly, logistic regression analysis
was used to calculate three different propensity scores that allowed selection of
three pairs of subpopulations with similar baseline characteristics. In particular,
logistic EuroSCORE in the three pairs was almost 10% in both subgroups,
therefore this study ascertained differences among patients in the so-called ”grey-
zone” between surgery and interventional procedures [140,141].
The main findings of this study are that TAVI and sutureless AVR have
similar outcomes in terms of 30-day mortality, 1-year mortality, stroke, bleeding
and myocardial infarction. While the Perceval sutureless bioprosthesis showed a
95
higher incidence of device success, TAVI had a trend towards a lower rate of
permanent pacemaker implantation. Furthermore, TAVI provided lower trans-
aortic gradients and shorter in-hospital and ICU stay.
Despite similar short-term outcomes, either 30-day or 1-year, the major
incidence of paravalvular leakage should not be disregarded in an analysis on
intermediate risk patients. Accordingly, several reports confirmed that
paravalvular leakage negatively impact long-term survival after TAVI [142,143].
Therefore, a word of caution should be raised when asserting that TAVI is an
alternative to conventional or sutureless AVR in the intermediate risk population.
However, different technical approaches (transapical better than transfemoral) or
a promising new TAVI device (e.g. SAPIEN 3) may significantly increase the rate
of device success, thus improving the results of patients undergoing TAVI at
intermediate risk.
A higher incidence of permanent pacemaker implantation could only be
demonstrated when sutureless patients were compared to the overall cohort of
TAVI procedures. On the other hand, the even higher rate of pacemaker
implantation did not reached statistical significance after matching separately
transfemoral and transapical approaches. A possible explanation for this result can
be found in the different characteristics of the two valves. The Perceval sutureless
bioprosthesis is a self-expanding prosthesis that leads to a continuous
compression on the atrioventricular conduction system. On the other hand,
SAPIEN and SAPIEN-XT are balloon-expandable devices with a low profile that
potentially does not interfere with the conduction tissue. However, the high
incidence of pacemaker implantation in the TAVI population is correct and has
been described with other self-expanding devices [144].
The Perceval cohort showed higher transvalvular gradients at discharge
compared to TAVI. However, these hemodynamics were confirmed in previous
studies [120,133] but the clinical impact of these details is questionable. Indeed
the two populations differed in several variables that may have influenced
Doppler echocardiographic assessment, such as hemodilution-related
postoperative anemia.
The different length of hospital stay observed in this study may stem from
either the inherent less invasiveness of transcatheter procedures or even from
different institutional policiesof the implanting centers. Accordingly, no definitive
conclusions could be made on this topic.
96
However, all these details could help the Heart Team to tailor the most
appropriate procedure for each patient.
6.5 Spreading light on the “gray-zone” between traditional AVR
and TAVI (V)
This study was designed to assess potential differences in immediate outcomes
after TAVI or sutureless AVR in a population of all comers with severe
symptomatic aortic stenosis.
The results described in Study V suggest that sutureless AVR is associated
with more favorable immediate outcomes compared to TAVI.
In particular, operative survival was higher after surgery, with an observed
trend in the overall population but a clinical significance after matching.
Although TAVI enlarged the therapeutic horizon to patients with high or
prohibitive surgical risk, the novel sutureless prosthesis maintained a favorable
gap supporting surgery compared to interventional procedures. However, this
study showed that a significant number of patients with preoperative low risk
profiles according to EuroSCORE II received TAVI. However, this study lacked
details that may have justified the use of less invasive procedures in patients at
low surgical risk (e.g. neurological dysfunction, liver comorbidities, porcelain
aorta).
However, other major investigated outcomes were similar between groups
(stroke, de novo dialysis, conversion to conventional AVR). It is interesting to
note that the main observed differences were coherent with the different technical
procedures.
Accordingly, surgery was associated with a greater increase of postoperative
bleeding requiring reoperation, whereas vascular access complications were more
frequently observed in TAVI patients. Similarly, different etiologies were
responsible for the observed freedom from immediate device success (PVL in the
TAVI cohort, higher gradients in the Perceval cohort). This study further confirms
that the two techniques are completely different, either from a procedural or
outcome point of view. This has been already highlighted by other institutional
reports as well as in our previous Study IV [145–147].However, future
improvement in valve profile as well as in technical devices that will ensure a
more precise positioning will probably improve the operative results in both
techniques.
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6.6 A stentless valve with a sutureless technology (VI)
The aim of study VI was to stimulate sutureless valve function in conditions of
increased cardiac output.
Because of the increasing use of the Perceval sutureless bioprosthesis, the
assessment of its hemodynamic performance under high workload conditions
assumes a clinical importance.
Accordingly, exercise echocardiography or DSE are useful tools for the
hemodynamic evaluation of aortic valve prosthesis and may unveil a prosthetic
valve dysfunction that usually remains asymptomatic at rest [148,149].
Where valve performance at rest is concerned, we have observed similar
results compared to other recently published studies, both in terms of peak and
mean gradients or EOA [150,151] and when compared to a propensity-matched
cohort of patients undergoing TAVI [152].
Increased transvalvular gradients are general findings of aortic prostheses
investigated under stress as a result of increased heart rate and stroke volumes.
Accordingly, Khoo et al. [153] observed that stentless valves perform similarly to
mildly stenosed native aortic valves under stress, whereas stented and mechanical
prostheses resembled the performances of mild-to-moderate stenosis. Similarly,
Repossini et al. [154] described an increase in mean transvalvular gradients
during exercise in patients who had undergone AVR with the Freedom SOLO
bioprosthesis.
On the other hand, despite increased gradients, we observed a significant
increase in EOA, EOAi and DVI under stress. Similarly, the same report of
Repossini et al. [154] demonstrated an increase in EOA from 1.74±0.33 cm2 to
1.80±0.36 cm2 at exercise stress echocardiography. When these last results are
compared to the findings of our study, we observed a significantly greater
increase of EOA at DSE, reaching 2.1±0.7 cm2 at peak stress. This finding is of
particular importance, considering that the stentless Freedom SOLO and the
Perceval sutureless bioprosthesis have similar valve profile. Accodingly, Perceval
sutureless bioprosthesis can actually be considered a stentless valve with a
sutureless technology [78]. Subgroup analysis for each valve size confirmed these
results.
We could speculate that the nitinol struts, over which the pericardium is fixed,
do not interfere with valve function but rather might facilitate the opening and
closing mechanism of the leaflets according to the physiological expansion of the
aortic root during the cardiac cycle.
98
This is of particular interest, especially in those patients with small aortic
annuli, who are at greater risk for PPM. It is noteworthy that EOAi under stress
increased over 0.65cm2/m2, generally considered diagnostic for severe PPM [22].
Accordingly, Villa et al. have recently demonstrated the satisfactory performance
of the S size Perceval valve, either at discharge or early follow-up [155].
The small sample size is certainly one major limitation of Study V. However,
the single-center design of the study guarantees uniformity of the surgical
technique and of echocardiographic evaluations.
One of the major strengths of this analysis is the strict inclusion criteria used
for the enrollment of these patients. In particular, the exclusion of patients with
mitral valve regurgitation prevented any bias of Doppler quantifications.
Furthermore, in an attempt to better validate our hypothesis, we selected
patients with the longest follow-up available, in order to assess the performance
of this prosthesis long after surgery. Finally, each patient served as her/his own
control, thus limiting selection biases.
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7 Conclusions
In the present study, the immediate and mid-term outcomes after AVR with the
Perceval sutureless prosthesis have been investigated.This study showed that
AVR with the Perceval valve is safe and effective, and allows a significant
reduction of aortic cross-clamping and cardiopulmonary bypass time. Its simple
technique of implantation may providemost of its benefits in minimally invasive
surgery, especially in patients at medium-high operative risk. Furthermore, great
adaptability to increased stroke volumes have been demonstrated.
The conclusions related to the specific questions are:
I The results of this multicenter retrospective study showed that the use of the
Perceval sutureless bioprosthesis is associated with excellent early
postoperative outcomes. The benefits of a short period of myocardial
ischemia seem pronounced in patients undergoing isolated AVR and in those
with high EuroSCORE II. Octogenarians and low-risk patients requiring
concomitant CABG may particularly benefit from this prosthesis. However,
further studies are needed to better assess the value of alternative procedures
such as TAVI or hybrid PCI in the high-risk subset of patients with severe AS
requiring concomitant procedures.
II AVR with the Perceval sutureless bioprosthesis implanted through a mini-
sternotomy is a safe and reproducible procedure. Aortic cross-clamping or
cardiopulmonary bypass times were similar to those observed during
procedures performedwith full sternotomy. Early postoperative outcomes and
2-year survival were similar between patients undergoing mini-sternotomy
and full sternotomy.
III AVR through a mini-sternotomy with implantation of the Perceval sutureless
bioprosthesis was a safe and reproducible procedure with 30-day mortality
and 2-year survival comparable to a full sternotomy with a stented
bioprosthesis. Mini-sternotomy sutureless AVR was associated with shorter
aortic cross-clamp and cardiopulmonary bypass times and reduced
transfusion of red blood cells, but a higher risk for postoperative permanent
pacemaker implantation compared to AVR through a full sternotomy with a
stented bioprosthesis.
IV Sutureless AVR and TAVI are both reasonable therapeutic strategies in
patients with severe symptomatic aortic valve stenosis. After matching, we
did not observe differences in 30-day and 1-year mortality as well as major
100
postoperative complications. AVR with the Perceval sutureless bioprosthesis
is associated with better device success and lower incidence of PVL as
compared to TAVI, even if this advantage is less evident in transapical TAVI.
On the other hand AVR with the Perceval sutureless bioprosthesis seems to
provide higher trans-aortic gradients, longer post-operative length of stay and
a trend towards higher pacemaker implantation rate. Due to the multiple
therapeutic options now available, every patient may now receive the most
appropriate treatment tailored according to her/his baseline and procedure-
related risks.
V AVR with the Perceval sutureless bioprosthesis is associated with excellent
operative survival and a low incidence of postoperative PVL. This study
suggests that the use of sutureless prostheses can improve the results of
surgery in patients at intermediate risk.
VI AVR with the Perceval sutureless bioprosthesis provides excellent
hemodynamics at rest and under DSE. The significant increase of EOAi
under DSE suggests that the Perceval sutureless bioprosthesisis the valve of
choice for patients with small aortic annuli or when PPM is anticipated.
Furthermore, Perceval could be also the solution for those patients with
calcified aortic root, in which any attempt to enlarge the annulus may
endanger the outcome of these patients.
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8 Future perspectives
The findings of this preliminary experience with the Perceval sutureless
bioprosthesis indicate that this valve could be considered a valid alternative to
conventional aortic valve bioprostheses, particularly in patients with unfavorable
anatomic conditions. Based on these results, a prospective randomized study, the
Perceval Sutureless Implant vs Standard Aortic Valve Replacement (PERSIST-
AVR) Trial (ClinicalTrials.gov NCT02673697), have been planned in order to
compare the efficacy and durability of this sutureless bioprosthesis with
conventional, stented bioprostheses. Similarly, we are planning a prospective,
multicenter registry in order to further compare the Perceval sutureless
bioprosthesis with TAVI.
102
103
List of references
1. Iung B & Vahanian A (2012) Degenerative calcific aortic stenosis: a natural history. Heart 98: iv7–iv13.
2. Ross J Jr & Braunwald E (1968) Aortic stenosis. Circulation 38: 61–67. 3. Brown ML, Pellikka PA, Schaff HV, Scott CG, Mullany CJ, Sundt TM, Dearani JA,
Daly RC & Orszulak TA (2008) The benefits of early valve replacement in asymptomatic patients with severe aortic stenosis. J Thorac Cardiovasc Surg 135: 308–315.
4. Di Eusanio M, Fortuna D, De Palma R, Dell'Amore A, Lamarra M, Contini GA, Gherli T, Gabbieri D, Ghidoni I, Cristell D, Zussa C, Pigini F, Pugliese P, Pacini D & Di Bartolomeo R (2011) Aortic valve replacement: results and predictors of mortality from a contemporary series of 2256 patients. J Thorac Cardiovasc Surg 141: 940 – 947.
5. Ranucci M, Frigiola A, Menicanti L, Castelvecchio S, de Vincentiis C & Pistuddi V (2012) Aortic cross-clamp time, new prostheses, and outcome in aortic valve replacement. J Heart Valve Dis 21: 732–739.
6. Al-Sarraf N, Thalib L, Hughes A, Houlihan M, Tolan M, Young V & McGovern E (2011) Cross-clamp time is an independent predictor of mortality and morbidity in low- and high-risk cardiac patients. Int J Surg 9: 104–109.
7. Meuris B, Flameng WJ, Laborde F, Folliguet TA, Haverich A & Shrestha M (2015) Five-year results of the pilot trial of a sutureless valve. J Thorac Cardiovasc Surg 150: 84–84.
8. Shrestha M, Fischlein T, Meuris B, Flameng W, Carrel T, Madonna F, Misfeld M, Folliguet T, Haverich A & Laborde F (2016) European multicentre experience with the sutureless Perceval valve: clinical and haemodynamic outcomes up to 5 years in over 700 patients. Eur J Cardiothorac Surg 49: 234–241.
9. Gersak B, Fischlein T, Folliguet TA, Meuris B, Teoh KH, Moten SC, Solinas M, Miceli A, Oberwalder PJ, Rambaldini M, Bhatnagar G, Borger MA, Bouchard D, Bouchot O, Clark SC, Dapunt OE, Ferrarini M, Laufer G, Mignosa C, Millner R, Noirhomme P, Pfeiffer S, Ruyra-Baliarda X, Shrestha M, Suri RM, Troise G, Diegeler A, Laborde F, Laskar M, Najm HK & Glauber M (2016) Sutureless, rapid deployment valves and stented bioprosthesis in aortic valve replacement: recommendations of an International Expert Consensus Panel. Eur J Cardiothorac Surg 49: 709–718.
10. Miceli A, Santarpino G, Pfeiffer S, Murzi M, Gilmanov D, Concistré G, Quaini E, Solinas M, Fischlein T & Glauber M (2014). Minimally invasive aortic valve replacement with Perceval S sutureless valve: early outcomes and one-year survival from two European centers. J Thorac Cardiovasc Surg 148: 2838–2843.
11. Gilmanov D, Miceli A, Ferrarini M, Farneti P, Murzi M, Solinas M & Glauber M (2014) Aortic valve replacement through right anterior minithoracotomy: can sutureless technology improve clinical outcomes? Ann Thorac Surg 98: 1585–1592.
104
12. Makkar RR, Jilaihawi H, Mack M, Chakravarty T, Cohen DJ, Cheng W, Fontana GP, Bavaria JE, Thourani VH, Herrmann HC, Pichard A, Kapadia S, Babaliaros V, Whisenant BK, Kodali SK, Williams M, Trento A, Smith CR, Teirstein PS, Cohen MG, Xu K, Tuzcu EM, Webb JG & Leon MB (2014) Stratification of outcomes after transcatheter aortic valve replacement according to surgical inoperability for technical versus clinical reasons. J Am Coll Cardiol 63: 901–911.
13. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O'Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM 3rd & Thomas JD; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. (2014) 2014 AHA/ACC guideline 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. J Am Coll Cardiol 63: e57–e185.
14. De Sciscio P, Brubert J, De Sciscio M, Serrani M, Stasiak J & Moggridge GD (2015) Prevalence, Treatment Eligibility and Postoperative Survival for Europeans with Aortic Stenosis (abstract). Journal of Cardiothoracic Surgery 10(Suppl 1): A162.
15. Osnabrugge RL, Mylotte D, Head SJ, Van Mieghem NM, Nkomo VT, LeReun CM, Bogers AJ, Piazza N & Kappetein AP (2013) Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. J Am Coll Cardiol 62: 1002–1012.
16. Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, Simmons CA, Masters KS, Mathieu P, O'Brien KD, Schoen FJ, Towler DA, Yoganathan AP & Otto CM (2011) Calcific aortic valve disease: not simply a degenerative process: A review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: Calcific aortic valve disease-2011 update. Circulation 124: 1783–1791.
17. Pasipoularides A (In press) Calcific Aortic Valve Disease: Part 1-Molecular Pathogenetic Aspects, Hemodynamics, and Adaptive Feedbacks. J Cardiovasc Transl Res.
18. Pawade TA, Newby DE & Dweck MR (2015) Calcification in Aortic Stenosis: The Skeleton Key. J Am Coll Cardiol 66: 561–577.
19. Capoulade R & Pibarot P (2015) Assessment of Aortic Valve Disease: Role of Imaging Modalities. Curr Treat Options Cardiovasc Med 17: 49.
20. Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, Iung B, Otto CM, Pellikka PA & Quiñones M; American Society of Echocardiography; European Association of Echocardiography (2009) Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr 22: 1–23.
21. Rosenhek R, Zilberszac R, Schemper M, Czerny M, Mundigler G, Graf S, Bergler-Klein J, Grimm M, Gabriel H & Maurer G (2010) Natural history of very severe aortic stenosis. Circulation 121: 151–156.
22. Pibarot P & Dumesnil JG (2006) Prosthesis-patient mismatch: definition, clinical impact, and prevention. Heart 92: 1022–1029.
105
23. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W & Voigt JU (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 28: 1–39.
24. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I & Reichek N (1986) Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 57: 450–458.
25. Orwat S, Kaleschke G, Kerckhoff G, Radke R & Baumgartner H (2013) Low flow, low gradient severe aortic stenosis: diagnosis, treatment and prognosis. EuroIntervention 9 Suppl: S38–S42.
26. Garbi M, Chambers J, Vannan MA & Lancellotti P (2015) Valve Stress Echocardiography: A Practical Guide for Referral, Procedure, Reporting, and Clinical Implementation of Results From the HAVEC Group. JACC Cardiovasc Imaging 8: 724–736.
27. Otto CM & Prendergast B (2014) Aortic-valve stenosis - from patients at risk to severe valve obstruction. N Engl J Med 371: 744–756.
28. Lester SJ, Heilbron B, Gin K, Dodek A & Jue J (1998) The natural history and rate of progression of aortic stenosis. Chest 113: 1109–1114.
29. Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS), Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schäfers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M (2012) Guidelines on the management of valvular heart disease. Eur Heart J 33:2451–2496.
30. Gosavi S, Channa R & Mukherjee D (2015) Systemic Hypertension in Patients with Aortic Stenosis: Clinical Implications and Principles of Pharmacological Therapy. Cardiovasc Hematol Agents Med Chem 13: 50–53.
31. Nashef SA, Roques F, Sharples LD, Nilsson J, Smith C, Goldstone AR & Lockowandt U (2012) EuroSCORE II. Eur J Cardiothorac Surg 41: 734–744.
32. Barili F, Pacini D, Capo A, Rasovic O, Grossi C, Alamanni F, Di Bartolomeo R & Parolari A (2013) Does EuroSCORE II perform better than its original versions? A multicentre validation study. Eur Heart J 34: 22–29.
33. STS Adult Cardiac Surgery Database Version 2.81 (2016) URI: http://http://riskcalc.sts.org/. Cited 2016/03/03.
34. Shih T, Paone G, Theurer PF, McDonald D, Shahian DM & Prager RL (2015) The Society of Thoracic Surgeons Adult Cardiac Surgery Database Version 2.73: More Is Better. Ann Thorac Surg 100: 516–521.
106
35. Biancari F, Juvonen T, Onorati F, Faggian G, Heikkinen J, Airaksinen J & Mariscalco G (2014) Meta-analysis on the performance of the EuroSCORE II and the Society of Thoracic Surgeons Scores in patients undergoing aortic valve replacement. J Cardiothorac Vasc Anesth 28: 1533–1539.
36. Kuwaki K, Inaba H, Yamamoto T, Dohi S, Matsumura T, Morita T & Amano A (2015) Performance of the EuroSCORE II and the Society of Thoracic Surgeons Score in patients undergoing aortic valve replacement for aortic stenosis. J Cardiovasc Surg (Torino) 56: 455–462.
37. Wang TK, Choi DH, Stewart R, Gamble G, Haydock D & Ruygrok P (2015) Comparison of four contemporary risk models at predicting mortality after aortic valve replacement. J Thorac Cardiovasc Surg 149: 443–448.
38. Tralhão A, Teles RC, Almeida MS, Madeira S, Santos MB, Andrade MJ, Mendes M & Neves JP (2015) Aortic valve replacement for severe aortic stenosis in octogenarians: patient outcomes and comparison of operative risk scores. Rev Port Cardiol 34: 439–446.
39. Holinski S, Jessen S, Neumann K & Konertz W (2015) Predictive Power and Implication of EuroSCORE, EuroSCORE II and STS Score for Isolated Repeated Aortic Valve Replacement. Ann Thorac Cardiovasc Surg 21: 242–246.
40. Anselmi A, Ruggieri VG, Harmouche M, Mascle S, Auffret V, Le Breton H, Beneux X& Verhoye JP (2015) Is the EuroSCORE II best suited for reoperative risk estimation in patients with structural deterioration of aortic bioprostheses? Med Hypotheses 84: 470–473.
41. Emren ZY, Emren SV, Kılıçaslan B, Solmaz H, Susam İ, Sayın A, Abud B, Aydın M & Bayturan Ö (2014) Evaluation of the prevalence of coronary artery disease in patients with valvular heart disease. J Cardiothorac Surg 9: 153.
42. Shibayama K, Daimon M, Watanabe H, Kawata T, Miyazaki S, Morimoto-Ichikawa R, Maruyama M, Chiang SJ, Miyauchi K & Daida H (2016) Significance of Coronary Artery Disease and Left Ventricular Afterload in Unoperated Asymptomatic Aortic Stenosis. Circ J 80: 519–525.
43. Di Gioia G, Pellicano M, Toth GG, Casselman F, Adjedj J, Van Praet F, Stockman B, Degrieck I, Trimarco B, Wijns W, De Bruyne B & Barbato E (In press) Clinical Outcome of Patients with Aortic Stenosis and Coronary Artery Disease Not Treated According to Current Recommendations. J Cardiovasc Transl Res.
44. Thalji NM, Suri RM, Daly RC, Greason KL, Dearani JA, Stulak JM, Joyce LD, Burkhart HM, Pochettino A, Li Z, Frye RL & Schaff HV (2015) The prognostic impact of concomitant coronary artery bypass grafting during aortic valve surgery: implications for revascularization in the transcatheter era. J Thorac Cardiovasc Surg 149: 451–460.
45. Fukui T, Bando K, Tanaka S, Uchimuro T, Tabata M &Takanashi S (2014) Early and mid-term outcomes of combined aortic valve replacement and coronary artery bypass grafting in elderly patients. Eur J Cardiothorac Surg 45: 335–340.
107
46. Litmathe J, Boeken U, Feindt P & Gams E (2003) Concomitant CABG-procedures in elderly patients undergoing aortic valve replacement. An additional risk factor? Z Kardiol 92: 947–952.
47. Sasaki Y, Hirai H, Hosono M, Bito Y, Nakahira A, Suehiro Y, Kaku D, Okada Y & Suehiro S (2013) Adding coronary artery bypass grafting to aortic valve replacement increases operative mortality for elderly (70 years and older) patients with aortic stenosis. Gen Thorac Cardiovasc Surg 61: 626–631.
48. Li Z, Anderson I, Amsterdam EA, Young JN, Parker J & Armstrong EJ (2013) Effect of coronary artery disease extent on contemporary outcomes of combined aortic valve replacement and coronary artery bypass graft surgery. Ann Thorac Surg 96: 2075 – 2082.
49. Biancari F, Martin M, Bordin G, Vettore E, Vinco G, Anttila V, Airaksinen J & Vasques F (2014) Basic data from 176 studies on the immediate outcome after aortic valve replacement with or without coronary artery bypass surgery. J Cardiothorac Vasc Anesth 28: 1251–1256.
50. Danson E, Hansen P, Sen S, Davies J, Meredith I & Bhindi R (In press) Assessment, treatment, and prognostic implications of CAD in patients undergoing TAVI. Nat Rev Cardiol.
51. Elmariah S (2015) Patterns of left ventricular remodeling in aortic stenosis: therapeutic implications. Curr Treat Options Cardiovasc Med 17: 391.
52. Gerdts E, Rossebø AB, Pedersen TR, Cioffi G, Lønnebakken MT, Cramariuc D, Rogge BP & Devereux RB (2015) Relation of Left Ventricular Mass to Prognosis in Initially Asymptomatic Mild to Moderate Aortic Valve Stenosis. Circ Cardiovasc Imaging 8: e003644.
53. Une D, Mesana L, Chan V, Maklin M, Chan R, Masters RG, Mesana TG & Ruel M (2015) Clinical Impact of Changes in Left Ventricular Function After Aortic Valve Replacement: Analysis From 3112 Patients. Circulation 132: 741–747.
54. Călin A, Roşca M, Beladan CC, Enache R, Mateescu AD, Ginghină C & Popescu BA (2015). The left ventricle in aortic stenosis - imaging assessment and clinical implications. Cardiovasc Ultrasound 13: 22.
55. Chin CW, Pawade TA, Newby DE & Dweck MR (2015) Risk Stratification in Patients With Aortic Stenosis Using Novel Imaging Approaches. Circ Cardiovasc Imaging 8: e003421.
56. Une D, Mesana L, Chan V, Maklin M, Chan R, Masters RG, Mesana TG & Ruel M (2015) Clinical Impact of Changes in Left Ventricular Function After Aortic Valve Replacement: Analysis From 3112 Patients. Circulation 132: 741–747.
57. Rossi A, Dandale R, Nistri S, Faggiano P, Cicoira M, Benfari G, Onorati F, Santini F, Messika-Zeitoun D, Enriquez-Sarano M & Vassanelli C (2014) Functional mitral regurgitation in patients with aortic stenosis: prevalence, clinical correlates and pathophysiological determinants: a quantitative prospective study. Eur Heart J Cardiovasc Imaging 15: 631–636.
108
58. Schubert SA, Yarboro LT, Madala S, Ayunipudi K, Kron IL, Kern JA, Ailawadi G, Stukenborg GJ & Ghanta RK (In press) Natural history of coexistent mitral regurgitation after aortic valve replacement. J Thorac Cardiovasc Surg.
59. Coutinho GF, Correia PM, Pancas R & Antunes MJ (2013) Management of moderate secondary mitral regurgitation at the time of aortic valve surgery. Eur J Cardiothorac Surg 44: 32–40.
60. Alghamdi AA, Elmistekawy EM, Singh SK & Latter DA (2010) Is concomitant surgery for moderate functional mitral regurgitation indicated during aortic valve replacement for aortic stenosis? A systematic review and evidence-based recommendations. J Card Surg 25: 182–187.
61. Spinner EM, Sundareswaran K, Dasi LP, Thourani VH, Oshinski J & Yoganathan AP (2011) Altered right ventricular papillary muscle position and orientation in patients with a dilated left ventricle. J Thorac Cardiovasc Surg 141: 744–749.
62. Santamore WP & Dell'Italia LJ (1998) Ventricular interdependence: significant left ventricular contributions to right ventricular systolic function. Prog Cardiovasc Dis 40: 289–308.
63. Mascherbauer J, Kammerlander AA, Marzluf BA, Graf A, Kocher A & Bonderman D. (2015) Prognostic Impact of Tricuspid Regurgitation in Patients Undergoing Aortic Valve Surgery for Aortic Stenosis. PLoS One 10: e0136024.
64. Taramasso M, Maisano F, De Bonis M, Pozzoli A, Schiavi D, Benussi S, Grimaldi A, La Canna G & Alfieri O. (2016) Prognostic Impact and Late Evolution of Untreated Moderate (2/4+) Functional Tricuspid Regurgitation in Patients Undergoing Aortic Valve Replacement. J Card Surg 31: 9–14.
65. Jeong DS, Sung K, Kim WS, Lee YT, Yang JH, Jun TG & Park PW (2014) Fate of functional tricuspid regurgitation in aortic stenosis after aortic valve replacement. J Thorac Cardiovasc Surg 148: 1328–1333.
66. Cam A, Goel SS, Agarwal S, Menon V, Svensson LG, Tuzcu EM & Kapadia SR (2011) Prognostic implications of pulmonary hypertension in patients with severe aortic stenosis. J Thorac Cardiovasc Surg 142: 800–808.
67. Malouf JF, Enriquez-Sarano M, Pellikka PA, Oh JK, Bailey KR, Chandrasekaran K, Mullany CJ & Tajik AJ (2002) Severe pulmonary hypertension in patients with severe aortic valve stenosis: clinical profile and prognostic implications. J Am Coll Cardiol 40: 789–795.
68. Zlotnick DM, Ouellette ML, Malenka DJ, DeSimone JP, Leavitt BJ, Helm RE, Olmstead EM, Costa SP, DiScipio AW, Likosky DS, Schmoker JD, Quinn RD, Sisto D, Klemperer JD, Sardella GL, Baribeau YR, Frumiento C, Brown JR, O'Rourke DJ; Northern New England Cardiovascular Disease Study Group (2013) Effect of preoperative pulmonary hypertension on outcomes in patients with severe aortic stenosis following surgical aortic valve replacement. Am J Cardiol 112: 1635–1640.
69. Idrees J, Roselli EE, Raza S, Krishnaswamy A, Mick S, Kapadia S, Pettersson GB, Tuzcu M & Svensson LG (2015) Aborted sternotomy due to unexpected porcelain aorta: does transcatheter aortic valve replacement offer an alternative choice? J Thorac Cardiovasc Surg 149: 131–134.
109
70. Gatti G, Benussi B, Camerini F & Pappalardo A (2014) Aortic valve replacement within an unexpected porcelain aorta: the sutureless valve option. Interact Cardiovasc Thorac Surg 18: 396–398.
71. Kaneko T, Neely RC, Shekar P, Javed Q, Asghar A, McGurk S, Gosev I, Byrne JG, Cohn LH & Aranki SF (2015) The safety of deep hypothermic circulatory arrest in aortic valve replacement with unclampable aorta in non-octogenarians. Interact Cardiovasc Thorac Surg 20: 79–84.
72. You JH, Jeong DS, Sung K, Kim WS, Carriere KC, Lee YT, Park PW. (In press) Aortic Valve Replacement With Carpentier-Edwards: Hemodynamic Outcomes for the 19-mm Valve. Ann Thorac Surg.
73. Dayan V, Soca G, Stanham R, Lorenzo A, Ferreiro A (2015) Is patient-prosthesis mismatch a predictor of survival or a surrogate marker of co-morbidities in cardiac surgery? Int J Cardiol 190: 389–392
74. Concistrè G, Dell'aquila A, Pansini S, Corsini B, Costigliolo T, Piccardo A, Gallo A, Passerone G, Regesta T (2013) Aortic valve replacement with smaller prostheses in elderly patients: does patient prosthetic mismatch affect outcomes? J Card Surg 28: 341–347
75. Grubitzsch H, Wang S, Matschke K, Glauber M, Heimansohn D, Tan E, Francois K, Thalmann M (2015) Clinical and haemodynamic outcomes in 804 patients receiving the Freedom SOLO stentless aortic valve: results from an international prospective multicentre study. Eur J Cardiothorac Surg 47: e97–e104
76. Murashita T, Okada Y, Kanemitsu H, Fukunaga N, Konishi Y, Nakamura K, Koyama T (2015) Efficacy of Stentless Aortic Bioprosthesis Implantation for Aortic Stenosis with Small Aortic Annulus. Thorac Cardiovasc Surg 63: 446–451
77. Villa E, Messina A, Laborde F, Shrestha M, Troise G, Zannis K, Haverich A, Elfarra M & Folliguet T (2015) Challenge for perceval: aortic valve replacement with small sutureless valves-a multicenter study. Ann Thorac Surg 99: 1248–1254.
78. Shrestha M, Maeding I, Höffler K, Koigeldiyev N, Marsch G, Siemeni T, Fleissner F & Haverich A (2013) Aortic valve replacement in geriatric patients with small aortic roots: are sutureless valves the future? Interact Cardiovasc Thorac Surg 17: 778–782
79. Shalabi A, Spiegelstein D, Sternik L, Feinberg MS, Kogan A, Levin S, Orlov B, Nachum E, Lipey A, Raanani E (In press) Sutureless Versus Stented Valve in Aortic Valve Replacement in Patients With Small Annulus. Ann Thorac Surg
80. Levy F, Rusinaru D, Maréchaux S, Charles V, Peltier M & Tribouilloy C 82015) Determinants and prognosis of atrial fibrillation in patients with aortic stenosis. Am J Cardiol 116: 1541–1546.
81. Chopard R, Teiger E, Meneveau N, Chocron S, Gilard M, Laskar M, Eltchaninoff H, Iung B, Leprince P, Chevreul K, Prat A, Lievre M, Leguerrier A, Donzeau-Gouge P, Fajadet J, Mouillet G & Schiele F; FRANCE-2 Investigators (2015) Baseline Characteristics and Prognostic Implications of Pre-Existing and New-Onset Atrial Fibrillation After Transcatheter Aortic Valve Implantation: Results From the FRANCE-2 Registry. JACC Cardiovasc Interv 8: 1346–1355.
110
82. Breithardt G, Baumgartner H, Berkowitz SD, Hellkamp AS, Piccini JP, Lokhnygina Y, Halperin JL, Singer DE, Hankey GJ, Hacke W, Becker RC, Nessel CC, Mahaffey KW, Califf RM, Fox KA & Patel MR; ROCKET AF Steering Committee & Investigators. (In press) Native valve disease in patients with non-valvular atrial fibrillation on warfarin or rivaroxaban. Heart.
83. Rezzoug N, Vaes B, de Meester C, Degryse J, Van Pottelbergh G, Mathei C, Adriaensen W, Pasquet A & Vanoverschelde JL (2016) The clinical impact of valvular heart disease in a population-based cohort of subjects aged 80 and older. BMC Cardiovasc Disord 16: 7.
84. Di Eusanio M, Fortuna D, De Palma R, Dell'Amore A, Lamarra M, Contini GA, Gherli T, Gabbieri D, Ghidoni I, Cristell D, Zussa C, Pigini F, Pugliese P, Pacini D & Di Bartolomeo R (2011) Aortic valve replacement: results and predictors of mortality from a contemporary series of 2256 patients. J Thorac Cardiovasc Surg 141: 940–947.
85. Vasques F, Messori A, Lucenteforte E & Biancari F (2012) Immediate and late outcome of patients aged 80 years and older undergoing isolated aortic valve replacement: a systematic review and meta-analysis of 48 studies. Am Heart J 163: 477–485.
86. Vasques F, Lucenteforte E, Paone R, Mugelli A & Biancari F (2012) Outcome of patients aged ≥80 years undergoing combined aortic valve replacement and coronary artery bypass grafting: a systematic review and meta-analysis of 40 studies. Am Heart 164: 410–418.
87. Cappabianca G, Ferrarese S, Musazzi A, Terrieri F, Corazzari C, Matteucci M & Beghi C (In press) Predictive factors of long-term survival in the octogenarian undergoing surgical aortic valve replacement: 12-year single-centre follow-up. Heart Vessels.
88. Deschka H, Machner M, Welp H, Dell'Aquila AM, Erler S & Wimmer-Greinecker G (In press) Cardiac reoperations in octogenarians: Do they really benefit? Geriatr Gerontol Int.
89. Lopez-Marco A, Tymko R & Von Oppell U (2015) Valve Replacement for Moderate Aortic Stenosis in Octogenarians Undergoing Revascularization. J Heart Valve Dis 24: 405–411.
90. Reardon MJ, Adams DH, Kleiman NS, Yakubov SJ, Coselli JS, Deeb GM, Gleason TG, Lee JS, Hermiller JB Jr, Chetcuti S, Heiser J, Merhi W, Zorn GL 3rd, Tadros P, Robinson N, Petrossian G, Hughes GC, Harrison JK, Maini B, Mumtaz M, Conte JV, Resar JR, Aharonian V, Pfeffer T, Oh JK, Qiao H, Popma JJ (2015) 2-year outcomes in patients undergoing surgical or self-expanding transcatheter aortic valve replacement. J Am Coll Cardiol 66: 113–121.
91. Thyregod HG, Steinbrüchel DA, Ihlemann N, Nissen H, Kjeldsen BJ, Petursson P, Chang Y, Franzen OW, Engstrøm T, Clemmensen P, Hansen PB, Andersen LW, Olsen PS, Søndergaard L (2015) Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1-year results from the all-comers NOTION randomized trial. J Am Coll Cardiol 65: 2184–2194.
111
92. Fraccaro C, Tarantini G, Rosato S, Tellaroli P, D'Errigo P, Tamburino C, Onorati F, Ranucci M, Barbanti M, Grossi C, Santoro G, Santini F, Covello RD, Fusco D, Seccareccia F; OBSERVANT Research Group (2016) Early and Midterm Outcome of Propensity-Matched Intermediate-Risk Patients Aged ≥ 80 Years With Aortic Stenosis Undergoing Surgical or Transcatheter Aortic Valve Replacement (from the Italian Multicenter OBSERVANT Study). Am J Cardiol 117: 1494–1501.
93. Thaden JJ, Nkomo VT, Suri RM, Maleszewski JJ, Soderberg DJ, Clavel MA, Pislaru SV, Malouf JF, Foley TA, Oh JK, Miller JD, Edwards WD & Enriquez-Sarano M (2016) Sex-related differences in calcific aortic stenosis: correlating clinical and echocardiographic characteristics and computed tomography aortic valve calcium score to excised aortic valve weight. Eur Heart J 37: 693–639.
94. Dobson LE, Fairbairn TA, Plein S & Greenwood JP (2015) Sex Differences in Aortic Stenosis and Outcome Following Surgical and Transcatheter Aortic Valve Replacement. J Womens Health (Larchmt) 24: 986–995.
95. Onorati F, D'Errigo P, Barbanti M, Rosato S, Covello RD, Maraschini A, Ranucci M, Santoro G, Tamburino C, Grossi C, Santini F, Menicanti L & Seccareccia F; OBSERVANT Research Group (2014) Different impact of sex on baseline characteristics and major periprocedural outcomes of transcatheter and surgical aortic valve interventions: Results of the multicenter Italian OBSERVANT Registry. J Thorac Cardiovasc Surg 147: 1529–1539.
96. Onorati F, D'Errigo P, Barbanti M, Rosato S, Covello DR, Maraschini A, Ranucci M, Grossi C, Santoro G, Tamburino C, Santini F & Seccareccia F; OBSERVANT Research Group (2013) Results differ between transaortic and open surgical aortic valve replacement in women. Ann Thorac Surg 96: 1336–1342.
97. Levy F, Laurent M, Monin JL, Maillet JM, Pasquet A, Le Tourneau T, Petit-Eisenmann H, Gori M, Jobic Y, Bauer F, Chauvel C, Leguerrier A & Tribouilloy C (2008) Aortic valve replacement for low-flow/low-gradient aortic stenosis operative risk stratification and long-term outcome: a European multicenter study. J Am Coll Cardiol 51: 1466–1472.
98. Tribouilloy C, Lévy F, Rusinaru D, Guéret P, Petit-Eisenmann H, Baleynaud S, Jobic Y, Adams C, Lelong B, Pasquet A, Chauvel C, Metz D, Quéré JP & Monin JL (2009) Outcome after aortic valve replacement for low-flow/low-gradient aortic stenosis without contractile reserve on dobutamine stress echocardiography. J Am Coll Cardiol 53: 1865–1873.
99. Lopez-Marco A, Miller H, Youhana A, Ashraf S, Zaidi A, Bhatti F, Ionescu A, Kumar P (In press) Low-flow low-gradient aortic stenosis: surgical outcomes and mid-term results after isolated aortic valve replacement. Eur J Cardiothorac Surg.
100. Tribouilloy C, Rusinaru D, Maréchaux S, Castel AL, Debry N, Maizel J, Mentaverri R, Kamel S, Slama M & Lévy F (2015) Low-gradient, low-flow severe aortic stenosis with preserved left ventricular ejection fraction: characteristics, outcome, and implications for surgery. J Am Coll Cardiol 65: 55–66.
112
101. Nissinen J, Biancari F, Wistbacka JO, Peltola T, Loponen P, Tarkiainen P, Virkkilä M & Tarkka M (2009) Safe time limits of aortic cross-clamping and cardiopulmonary bypass in adult cardiac surgery. Perfusion 24: 297–305.
102. Onorati F, De Feo M, Mastroroberto P, Cristodoro L, Pezzo F, Renzulli A & Cotrufo M (2005) Determinants and prognosis of myocardial damage after coronary artery bypass grafting. Ann Thorac Surg 79: 837–845.
103. Al-Sarraf N, Thalib L, Hughes A, Houlihan M, Tolan M, Young V & McGovern E (2011) Cross-clamp time is an independent predictor of mortality and morbidity in low- and high-risk cardiac patients. Int J Surg 9: 104–109.
104. Ranucci M, Frigiola A, Menicanti L, Castelvecchio S, de Vincentiis C & Pistuddi V (2012) Aortic cross-clamp time, new prostheses, and outcome in aortic valve replacement. J Heart Valve Dis 21: 732–739.
105. Chalmers J, Pullan M, Mediratta N & Poullis M (2014) A need for speed? Bypass time and outcomes after isolated aortic valve replacement surgery. Interact Cardiovasc Thorac Surg 19: 21–26.
106. Mistiaen W, Van Cauwelaert P, Muylaert P & De Worm E (2009) A thousand pericardial valves in aortic position: risk factors for postoperative acute renal function impairment in elderly. J Cardiovasc Surg (Torino) 50: 233–237.
107. Naji P, Griffin BP, Sabik JF, Kusunose K, Asfahan F, Popovic ZB, Rodriguez LL, Lytle BW, Grimm RA, Svensson LG & Desai MY (2015) Characteristics and Outcomes of Patients With Severe Bioprosthetic Aortic Valve Stenosis Undergoing Redo Surgical Aortic Valve Replacement. Circulation 132: 1953–1960.
108. Onorati F, Biancari F, De Feo M, Mariscalco G, Messina A, Santarpino G, Santini F, Beghi C, Nappi G, Troise G, Fischlein T, Passerone G, Heikkinen J & Faggian G (2015) Mid-term results of aortic valve surgery in redo scenarios in the current practice: results from the multicentre European RECORD (REdo Cardiac Operation Research Database) initiative. Eur J Cardiothorac Surg 47: 269–280.
109. Onorati F, Biancari F, De Feo M, Mariscalco G, Messina A, Santarpino G, Santini F, Beghi C, Nappi G, Troise G, Fischlein T, Passerone G, Heikkinen J & Faggian G. Outcome of redo surgical aortic valve replacement in patients 80 years and older: results from the Multicenter RECORD Initiative. Ann Thorac Surg 97: 537–543.
110. Kaneko T, Vassileva CM, Englum B, Kim S, Yammine M, Brennan M, Suri RM, Thourani VH, Jacobs JP & Aranki S (2015) Contemporary Outcomes of Repeat Aortic Valve Replacement: A Benchmark for Transcatheter Valve-in-Valve Procedures. Ann Thorac Surg 100: 1298–1304.
111. Pechlivanidis K, Onorati F, Petrilli G, Santini F, Milano A, Torre S, Calzaferri D, Mazzucco A & Faggian G (2014) In which patients is transcatheter aortic valve replacement potentially better indicated than surgery for redo aortic valve disease? Long-term results of a 10-year surgical experience. J Thorac Cardiovasc Surg 148: 500–508.
113
112. Erlebach M, Wottke M, Deutsch MA, Krane M, Piazza N, Lange R, Bleiziffer S (2915) Redo aortic valve surgery versus transcatheter valve-in-valve implantation for failing surgical bioprosthetic valves: consecutive patients in a single-center setting. J Thorac Dis 7: 1494–1500.
113. Salenger R, Gammie JS & Collins JA (2016) Minimally Invasive Aortic Valve Replacement. J Card Surg 31: 38–50.
114. Hassan M, Miao Y, Maraey A, Lincoln J, Brown S, Windsor J & Ricci M (2015) Minimally Invasive Aortic Valve Replacement: Cost-Benefit Analysis of Ministernotomy Versus Minithoracotomy Approach. J Heart Valve Dis 24: 531–539.
115. Shehada SE, Öztürk Ö, Wottke M & Lange R (2016) Propensity score analysis of outcomes following minimal access versus conventional aortic valve replacement†. Eur J Cardiothorac Surg 49: 464–470.
116. Merk DR, Lehmann S, Holzhey DM, Dohmen P, Candolfi P, Misfeld M, Mohr FW, & Borger MA (2015) Minimal invasive aortic valve replacement surgery is associated with improved survival: a propensity-matched comparison. Eur J Cardiothorac Surg. 47: 11–17.
117. Bakir I, Casselman FP, Onan B, Van Praet F, Vermeulen Y & Degrieck I (2014) Does a minimally invasive approach increase the incidence of patient-prosthesis mismatch in aortic valve replacement? J Heart Valve Dis 23: 161–167.
118. Glauber M, Gilmanov D, Farneti PA, Kallushi E, Miceli A, Chiaramonti F, Murzi M& Solinas M (2015) Right anterior minithoracotomy for aortic valve replacement: 10-year experience of a single center. J Thorac Cardiovasc Surg 150: 548–556.
119. Krishna RK, Santana O, Mihos CG, Pineda AM, Weiss UK & Lamelas J (2014) Minimally invasive aortic valve replacement in octogenarians performed via a right anterior thoracotomy approach. J Heart Valve Dis 23: 671–674.
120. Rubino AS, Santarpino G, De Praetere H, Kasama K, Dalén M, Sartipy U, Lahtinen J, Heikkinen J, Deste W, Pollari F, Svenarud P, Meuris B, Fischlein T, Mignosa C & Biancari F (2014) Early and intermediate outcome after aortic valve replacement with a sutureless bioprosthesis: Results of a multicenter study. J Thorac Cardiovasc Surg 148: 865–871.
121. Santarpino G, Pfeiffer S, Concistrè G & Fischlein T (2012) A supra-annular malposition of the Perceval S sutureless aortic valve: the 'χ-movement' removal technique and subsequent reimplantation. Interact Cardiovasc Thorac Surg 15: 280–281.
122. Brier KL, Tornow JJ, Ries AJ, Weber MP & Downs JR (1999) Forecasting patient outcomes in the management of hyperlipidemia. Arch Intern Med 159: 569–575.
123. Parsons LS, Ovation Research Group, Seattle, WA (2001) Reducing Bias in a Propensity Score Matched-Pair Sample Using Greedy Matching Techniques. SAS SUGI; Paper 214–226.
124. D’Agostino RB (1998) Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 17: 2265–2281.
125. Rosenbaum PR (1989) Optimal matching for observational studies. J Am Stat Ass 84: 1024–1032.
114
126. Rosenbaum PR & Ruben D (1985) The bias due to incomplete matching. Biometrics 41: 103–116.
127. Rosenbaum PR & Ruben D (1983) The central role of propensity score in observational studies for causal effects. Biometrika 70: 41–55.
128. Messori A, Trippoli S & Biancari F (2013) Early and intermediate survival after transcatheter aortic valve implantation: systematic review and meta-analysis of 14 studies. BMJ Open 3.
129. Vogt F, Pfeiffer S, Dell'Aquila AM, Fischlein T & Santarpino G (2016) Sutureless aortic valve replacement with Perceval bioprosthesis: are there predicting factors for postoperative pacemaker implantation? Interact Cardiovasc Thorac Surg 22: 253–258.
130. Murtuza B, Pepper JR, Stanbridge RD, Jones C, Rao C, Darzi A & Athanasiou T (2008) Minimal access aortic valve replacement: is it worth it? The Annals of thoracic surgery 85: 1121–1131.
131. Brown ML, McKellar SH, Sundt TM & Schaff HV (2009) Ministernotomy versus conventional sternotomy for aortic valve replacement: a systematic review and meta-analysis. J Thorac Cardiovasc Surg 137: 670–679.
132. Gilmanov D, Bevilacqua S, Murzi M, Cerillo AG, Gasbarri T, Kallushi E, Miceli A & Glauber M (2013) Minimally invasive and conventional aortic valve replacement: a propensity score analysis. Ann Thorac Surg 96: 837–843.
133. Dalén M, Biancari F, Rubino AS, Santarpino G, De Praetere H, Kasama K, Juvonen T, Deste W, Pollari F, Meuris B, Fischlein T, Mignosa C, Gatti G, Pappalardo A, Sartipy U & Svenarud P (2015) Mini-sternotomy versus full sternotomy aortic valve replacement with a sutureless bioprosthesis: a multicenter study. Ann Thorac Surg 99: 524–530.
134. Glauber M & Miceli A (2016) Minimally invasive aortic valve replacement with sutureless valve is the appropriate treatment option for high-risk patients and the “real alternative” to transcatheter aortic valve implantation. J Thorac Cardiovasc Surg 151: 610–613.
135. Fischlein T, Pfeiffer S, Pollari F, Sirch J, Vogt F & Santarpino G (2015) Sutureless Valve Implantation via Mini J-Sternotomy: A Single Center Experience with 2 Years Mean Follow-up. Thorac Cardiovasc Surg 63: 467–471.
136. Forcillo J, Bouchard D, Nguyen A, Perrault L, Cartier R, Pellerin M, Demers P, Stevens LM & Carrier M (In press) Perioperative outcomes with sutureless versus stented biological aortic valves in elderly persons. J Thorac Cardiovasc Surg.
137. Santarpino G, Pfeiffer S, Concistre G, Grossmann I, Hinzmann M & Fischlein T (2013) The Perceval S aortic valve has the potential of shortening surgical time: does it also result in improved outcome? Ann Thorac Surg 96: 77–81.
138. Pollari F, Santarpino G, Dell'Aquila AM, Gazdag L, Alnahas H, Vogt F, Pfeiffer S & Fischlein T (2014) Better short-term outcome by using sutureless valves: a propensity-matched score analysis. Ann Thorac Surg 98: 611–616.
139. van Boxtel AG, Houthuizen P, Hamad MA, Sjatskig J, Tan E, Prinzen FW & van Straten AH (2014) Postoperative conduction disorders after implantation of the self-expandable sutureless Perceval S bioprosthesis. J Heart Valve Dis 23: 319–324.
115
140. Muneretto C, Bisleri G, Moggi A, Di Bacco L, Tespili M, Repossini A & Rambaldini M (2015) Treating the patients in the ‘grey-zone’ with aortic valve disease: a comparison among conventional surgery, sutureless valves and transcatheter aortic valve replacement. Interact Cardiovasc Thorac Surg 20: 90–95.
141. D'Onofrio A, Messina A, Lorusso R, Alfieri OR, Fusari M, Rubino P, Rinaldi M, Di Bartolomeo R, Glauber M, Troise G & Gerosa G (2012) Sutureless aortic valve replacement as an alternative treatment for patients belonging to the "gray zone" between transcatheter aortic valve implantation and conventional surgery: a propensity-matched, multicenter analysis. J Thorac Cardiovasc Surg 144: 1010–1016.
142. Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, Fontana GP, Dewey TM, Thourani VH, Pichard AD, Fischbein M, Szeto WY, Lim S, Greason KL, Teirstein PS, Malaisrie SC, Douglas PS, Hahn RT, Whisenant B, Zajarias A, Wang D, Akin JJ, Anderson WN & Leon MB; PARTNER Trial Investigators (2012) Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 366: 1686–1695.
143. Athappan G, Patvardhan E, Tuzcu EM, Svensson LG, Lemos PA, Fraccaro C, Tarantini G, Sinning JM, Nickenig G, Capodanno D, Tamburino C, Latib A, Colombo A & Kapadia SR (2013) Incidence, predictors, and outcomes of aortic regurgitation after transcatheter aortic valve replacement: meta-analysis and systematic review of literature. J Am Coll Cardiol 61: 1585–1595.
144. Moretti C, D'Ascenzo F, Mennuni M, Taha S, Brambilla N, Nijhoff F, Fraccaro C, Barbanti M, Tamburino C, Tarantini G, Rossi ML, Presbitero P, Napodanno M, Stella P, Bedogni F, Omedè P, Conrotto F, Montefusco A, Giordana F, Biondi Zoccai G, Agostoni P, D'Amico M, Rinaldi M, Marra S & Gaita F (2015) Meta-analysis of comparison between self-expandable and balloon-expandable valves for patients having transcatheter aortic valve implantation. Am J Cardiol 115: 1720–1725.
145. D'Onofrio A, Salizzoni S, Rubino AS, Besola L, Filippini C, Alfieri O, Colombo A, Agrifoglio M, Fischlein T, Rapetto F, Tarantini G, Dalèn M, Gabbieri D, Meuris B, Savini C, Gatti G, Aiello ML, Biancari F, Livi U, Stefàno PL, Cassese M, Borrello B, Rinaldi M, Mignosa C & Gerosa G; Italian Transcatheter Balloon-Expandable Registry and the Sutureless Aortic Valve Implantation Research Groups. (In press) The rise of new technologies for aortic valve stenosis: A comparison of sutureless and transcatheter aortic valve implantation. J Thorac Cardiovasc Surg
146. Thyregod HG, Steinbrüchel DA, Ihlemann N, Nissen H, Kjeldsen BJ, Petursson P, Chang Y, Franzen OW, Engstrøm T, Clemmensen P, Hansen PB, Andersen LW, Olsen PS & Søndergaard L (2015) Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Valve Stenosis: 1-Year Results From the All-Comers NOTION Randomized Clinical Trial. J Am Coll Cardiol 65: 2184–2194.
147. D'Onofrio A, Rizzoli G, Messina A, Alfieri O, Lorusso R, Salizzoni S, Glauber M, Di Bartolomeo R, Besola L, Rinaldi M, Troise G & Gerosa G (2013) Conventional surgery, sutureless valves, and transapical aortic valve replacement: what is the best option for patients with aortic valve stenosis? A multicenter, propensity-matched analysis. J Thorac Cardiovasc Surg 146: 1065–1670.
116
148. Kadir I, Walsh C, Wilde P, Bryan AJ & Angelini GD [2002] Comparison of exercise and dobutamine echocardiography in the haemodynamic assessment of small size mechanical aortic valve prostheses. Eur J Cardiothorac Surg 21: 692–697.
149. Garbi M, Chambers J, Vannan MA & Lancellotti P (2015) Valve Stress Echocardiography: A Practical Guide for Referral, Procedure, Reporting, and Clinical Implementation of Results From the HAVEC Group. JACC Cardiovasc Imaging 8: 724–736.
150. Laborde F, Fischlein T, Hakim-Meibodi K, Misfeld M, Carrel T, Zembala M, Madonna F, Meuris B, Haverich A & Shrestha M; Cavalier Trial Investigators (2016) Clinical and haemodynamic outcomes in 658 patients receiving the Perceval sutureless aortic valve: early results from a prospective European multicentre study (the Cavalier Trial). Eur J Cardiothorac Surg 49: 978–986.
151. Meuris B, Flameng WJ, Laborde F, Folliguet TA, Haverich A & Shrestha M (2015) Five-year results of the pilot trial of a sutureless valve. J Thorac Cardiovasc Surg 150: 84–88.
152. Miceli A, Gilmanov D, Murzi M, Marchi F, Ferrarini M, Cerillo AG, Quaini E, Solinas M, Berti S & Glauber M (2016) Minimally invasive aortic valve replacement with a sutureless valve through a right anterior mini-thoracotomy versus transcatheter aortic valve implantation in high-risk patients. Eur J Cardiothorac Surg 49: 960–965.
153. Khoo JP, Davies JE, Ang KL, Galiñanes M & Chin DT (2013) Differences in performance of five types of aortic valve prostheses: haemodynamic assessment by dobutamine stress echocardiography. Heart 99: 41–47.
154. Repossini A, Rambaldini M, Lucchetti V, Da Col U, Cesari F, Mignosa C, Picano E & Glauber M (2012) Early clinical and haemodynamic results after aortic valve replacement with the Freedom SOLO bioprosthesis (experience of Italian multicenter study). Eur J Cardiothorac Surg 41: 1104–1110.
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Original publications
I Rubino AS, Santarpino G, De Praetere H, Kasama K, Dalén M, Sartipy U, Lahtinen J, Heikkinen J, Deste W, Pollari F, Svenarud P, Meuris B, Fischlein T, Mignosa C, Biancari F (2014) Early and intermediate outcome after aortic valve replacement with a sutureless bioprosthesis: Results of a multicenter study. J Thorac Cardiovasc Surg 148: 865–871.
II Dalén M, Biancari F, Rubino AS, Santarpino G, De Praetere H, Kasama K, Juvonen T, Deste W, Pollari F, Meuris B, Fischlein T, Mignosa C, Gatti G, Pappalardo A, Sartipy U, Svenarud P (2015) Mini-sternotomy versus full sternotomy aortic valve replacement with a sutureless bioprosthesis: a multicenter study. Ann Thorac Surg 99: 524–530.
III Dalén M, Biancari F, Rubino AS, Santarpino G, Glaser N, De Praetere H, Kasama K, Juvonen T, Deste W, Pollari F, Meuris B, Fischlein T, Mignosa C, Gatti G, Pappalardo A, Svenarud P, Sartipy U (2016) Aortic valve replacement through full sternotomy with a stented bioprosthesis versus minimally invasive sternotomy with a sutureless bioprosthesis. Eur J Cardiothorac Surg 49: 220–227.
IV D'Onofrio A, Salizzoni S, Rubino AS, Besola L, Filippini C, Alfieri O, Colombo A, Agrifoglio M, Fischlein T, Rapetto F, Tarantini G, Dalèn M, Gabbieri D, Meuris B, Savini C, Gatti G, Aiello ML, Biancari F, Livi U, Stefàno PL, Cassese M, Borrello B, Rinaldi M, Mignosa C, Gerosa G; Italian Transcatheter Balloon-Expandable Registry and the Sutureless Aortic Valve Implantation Research Groups (In press) The rise of new technologies for aortic valve stenosis: A comparison of sutureless and transcatheter aortic valve implantation. J Thorac Cardiovasc Surg.
V Biancari F, Barbanti M, Santarpino G, Deste W, Tamburino C, Gulino S, Immè S, Di Simone E, Todaro D, Pollari F, Fischlein T, Kasama K, Meuris B, Dalén M, Sartipy U, Svenarud P, Lahtinen J, Heikkinen J, Juvonen T, Gatti G, Pappalardo A, Mignosa C, Rubino AS (2016) Immediate outcome after sutureless versus transcatheter aortic valve eplacement. Heart Vessels 31: 427–433.
VI Rubino AS, Biancari F, Caruso V, Lavanco V, Privitera F, Rinaldi I Sanfilippo M, Millan G, D’Urso LV, Castorina S, Mignosa C (2016) Hemodynamic assessment of the Perceval sutureless valve by dobutamine stress echocardiography (Manuscript)
Reprinted with permission from Elsevier (I, II, IV, VI), Oxford University Press
(III), Springer International Publishing AG (V).
Original publications are not included in the electronic version of the dissertation.
118
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Antonino S. R
ubino
OULU 2016
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Antonino S. Rubino
EFFICACY OF THE PERCEVAL SUTURELESS AORTIC VALVE BIOPROSTHESIS IN THE TREATMENT OF AORTIC VALVE STENOSIS
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;MEDICAL RESEARCH CENTER OULU;OULU UNIVERSITY HOSPITAL