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UNIVERSITATIS OULUENSIS MEDICA ACTA D D 1367 ACTA Antonino S. Rubino 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

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Page 1: OULU 2016 D 1367 UNIVERSITY OF OULU P.O. Box …jultika.oulu.fi/files/isbn9789526212289.pdfUNIVERSITY OF OULU P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS

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

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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

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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

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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

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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

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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.

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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.

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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

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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].

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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.

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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).

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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

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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.

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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

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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).

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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

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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].

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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.

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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].

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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.

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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].

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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].

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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].

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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].

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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].

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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

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[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

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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%

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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].

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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.

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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.

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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

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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).

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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

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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.

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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.

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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.

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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)

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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.

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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.

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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.

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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).

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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%.

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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).

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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

Page 65: OULU 2016 D 1367 UNIVERSITY OF OULU P.O. Box …jultika.oulu.fi/files/isbn9789526212289.pdfUNIVERSITY OF OULU P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS

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

.

Page 66: OULU 2016 D 1367 UNIVERSITY OF OULU P.O. Box …jultika.oulu.fi/files/isbn9789526212289.pdfUNIVERSITY OF OULU P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS

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).

Page 67: OULU 2016 D 1367 UNIVERSITY OF OULU P.O. Box …jultika.oulu.fi/files/isbn9789526212289.pdfUNIVERSITY OF OULU P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS

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.

Page 68: OULU 2016 D 1367 UNIVERSITY OF OULU P.O. Box …jultika.oulu.fi/files/isbn9789526212289.pdfUNIVERSITY OF OULU P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS

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.

Page 69: OULU 2016 D 1367 UNIVERSITY OF OULU P.O. Box …jultika.oulu.fi/files/isbn9789526212289.pdfUNIVERSITY OF OULU P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS

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).

Page 70: OULU 2016 D 1367 UNIVERSITY OF OULU P.O. Box …jultika.oulu.fi/files/isbn9789526212289.pdfUNIVERSITY OF OULU P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS

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).

Page 71: OULU 2016 D 1367 UNIVERSITY OF OULU P.O. Box …jultika.oulu.fi/files/isbn9789526212289.pdfUNIVERSITY OF OULU P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS

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

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1

0

Rece

nt m

yoca

rdia

l infa

rctio

n

2 (

1.1

) 1

1 (

2.9

) 0

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0

2

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3 (

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) 0.6

57

-4

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nic

pu

lmonary

dis

ease

2

0 (

11

.0)

27

(7

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41

15

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15

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raca

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rio

pa

thy

25

(1

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8.7

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5

2

2 (

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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

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3(1

.8)

0.6

57

-4

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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.

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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).

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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.

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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).

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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.

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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).

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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).

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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

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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

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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.

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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

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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

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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.

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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

)

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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.

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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).

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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.

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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%)

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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.

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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

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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.

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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

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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

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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

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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.

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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.

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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1352. Tuisku, Anna (2016) Tobacco and health : a study of young adults in NorthernFinland

1353. Forsman, Minna (2016) Histological characteristics and gene expression profilingof Dupuytren’s disease

1354. Moilanen, Jyri (2016) Functional analysis of collagen XVII in epithelial cancers anda mouse model

1355. Selkälä, Eija (2016) Role of α-methylacyl-CoA racemase in lipid metabolism

1356. Ohukainen, Pauli (2016) Molecular profiling of calcific aortic valve disease

1357. Oikarinen, Anne (2016) Effects of risk factor targeted lifestyle counsellingintervention on quality of lifestyle counselling and on adherence to lifestylechange in stroke patients

1358. Rannikko, Irina (2016) Change in cognitive performance and its predictors ingeneral population and schizophrenia in early midlife : The Northern Finland BirthCohort 1966 Study

1359. Lantto, Iikka (2016) Acute Achilles tendon rupture : Epidemiology and treatment

1360. Räsänen, Päivi (2016) Kotona asuvien ikääntyvien itsestä huolenpito :Hoitotieteen keskitason teorian ydinrakenteen testaaminen

1361. Hannila, Ilkka (2016) T2 relaxation of articular cartilage : Normal variation,repeatability and detection of patellar cartilage lesions

1362. Pihlaja, Juha (2016) Treatment outcome of zirconia single crowns and fixed dentalprostheses

1363. Moilanen, Jani (2016) The use of antipsychotic medication and its association withoutcomes and brain morphometry in schizophrenia – the Northern Finland BirthCohort 1966 Study

1364. Heikkilä, Vesa-Pekka (2016) New techniques and methods for decreasing healthytissue dose in prostate cancer radiotherapy, with special reference to rectaldoses

1365. Aro, Jani (2016) Novel load-inducible factors in cardiac hypertrophy

1366. Myllymäki, Mikko (2016) Hypoxia-inducible factor prolyl 4-hydroxylase-2 inTibetan high-altitude adaptation, extramedullary erythropoiesis and skeletalmuscle ischemia

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ubino

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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