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FSM
ORGANO UFFICIALE
DELLA ASSOCIAZIONE ITALIANA
DI CARDIOLOGIA RIABILITATIVA
E PREVENTIVA (GICR-IACPR)
December 2013
Volume 80 Number 4
CARDIAC SERIES
ISSN 1122-0643
OFFICIAL JOURNAL OF THE ITALIAN ASSOCIATION FOR CARDIOVASCULAR PREVENTION,
REHABILITATION AND EPIDEMIOLOGY (GICR-IACPR)
F. Orso, R. Barucci, S. Fracchia, G. Mannarino, A. Pratesi, F. Fattirolli
Il trattamento di pazienti molto anziani con fibrillazione atriale non
valvolare. La preziosa opportunità offerta dai Nuovi Anticoagulanti
Orali, da usare con attenzione
Treatment of very old patients with non valvular atrial fibrillation. The
valuable opportunity offered by New Oral Anticoagulants, to be
cautiously used
VOLUME 80 • NUMBER 4. 2 0 1 3 • CARDIAC SERIES
INTERNATIONAL JOURNAL OF CARDIOPULMONARY MEDICINE AND REHABILITATION
ARCHIVES FOR CHEST DISEASE
MONALDI
Centro Studi
Fondazione Maugeri
V. Bianchi, A. Mezzani
Androgens and cardiac diseases
Androgeni e cardiopatie
S. Baldasseroni, A. Pratesi, F. Orso, C. Di Serio, A. Foschini, A.G. Marella,
N. Bartoli, M. Di Bari, S. Fumagalli, N. Marchionni, F. Tarantini
Epicardial adipose tissue and insulin resistance in patients with
coronary artery disease with or without left ventricular dysfunction
Tessuto adiposo epicardico e insulino resistenza in pazienti con
cardiopatia ischemica cronica con o senza disfunzione ventricolare
sinistra
L. Maresca, M. D’Agostino, L. Castaldo, A. Vitelli, M. Mancini, G. Torella,
R. Lucci, G. Albano, D. Del Forno, M. Ferro, V. Altieri, F. Giallauria,
C. Vigorito
Exercise training improves erectile dysfunction (ED) in patients with
metabolic syndrome on phosphodiesterase-5 (PDE-5) inhibitors
L’esercizio fisico migliora il grado di disfunzione erettile (ED) nei pazienti
con sindrome metabolica in terapia con inibitori della fosfodiesterasi-5
(PDE-5)
S.A. Di Fusco, N. Aspromonte, S. Aquilani, L. Mele, F. Colivicchi
Emergency reversal of vitamin-K antagonists related overanticoagulation: case report and brief overview on the role of
Prothrombin Complex Concentrate
Rapida correzione dell'eccessiva anticoagulazione da antagonisti della
vitamina K: caso clinico e breve inquadramento del ruolo del Complesso
Protrombinico Concentrato
B. Piovanelli, R. Rovetta, I. Bonadei, E. Vizzardi, A. D’Aloia, M. Metra
Nonbacterial Thrombotic Endocarditis in Pancreatic Cancer
Endocardite trombotica non batterica in associazione con una neoplasia
pancreatica
M. Correale, A. Totaro, A. Ferraretti, M. Di Biase, N. Daniele Brunetti
Sildenafil improves clinical and functional status of an elderly
postmenopausal female with ‘out of proportion’ PH associated
with left heart disease
Terapia con Sildenafil migliora clinica e stato funzionale di una anziana
donna con ipertensione polmonare associata a patologia del cuore sinistro
Periodico Trimestrale - No. 4 Dicembre 2013
Poste Italiane s.p.a.
Spedizione in Abbonamento Postale
D.L. 353/2003 (conv. in L. 27/02/2004 n. 46)
articolo 1, comma 1, LO/PV
Online full-text on www.gicr.it
MONALDI
ARCHIVES FOR CHEST DISEASE
An International Scientific Journal for Postgraduate Education in Cardiopulmonary Medicine and Rehabilitation
of the Fondazione Salvatore Maugeri, Care and Research Institute, Pavia, Italy.
Official Journal of the Italian Association for Cardiovascular Prevention, Rehabilitation and Epidemiology (GICR-IACPR)
PULMONARY MEDICINE AND REHABILITATION SERIES
CARDIAC REHABILITATION AND PREVENTION SERIES
Editors
Antonio Spanevello
Dept. of Pulmonary Rehab.
Fondazione Salvatore Maugeri
IRCCS
Dept. of Clinical Medicine
University of Insubria
Via Roncaccio 16
I-21049 Tradate (VA)
[email protected]
Editorial Office: [email protected]
Deputy Editors
Mirco Lusuardi
Dept. of Cardio-Pulmonary Rehab.
S. Sebastiano Hospital
AUSL Reggio Emilia
I-42015 Correggio (RE)
[email protected]
Executive Editors
Giuseppe Brunetti
IRCCS
Via Salvatore Maugeri 10
I-27100 Pavia
[email protected]
Associate Editors
R.W. Dal Negro
Bussolengo, Italy
Clinical Pharmacology
R. Trisolini
Bologna, Italy
Case Reports
N. Ambrosino
Pisa, Italy
V. Brusasco
Genova, Italy
G.W. Canonica
Genova, Italy
Bruno Balbi
IRCCS
Via per Revislate 13
I-28010 Veruno (NO)
[email protected]
Maurizio Luisetti
Laboratorio di Biochimica & Genetica
Clinica Malattie Apparato Respiratorio
IRCCS Policlinico San Matteo
Università di Pavia
Via Taramelli 5
I-27100 Pavia
[email protected]
Luca Bianchi
IRCCS
Via Mazzini 129
I-25066 Lumezzane (BS)
[email protected]
R. Dahl
Aarhus, Denmark
R.M. du Bois
London, UK
J.W. Fitting
Lausanne, CH
M.P. Foschino-Barbaro
Foggia, Italy
R.S. Goldstein
Toronto, Canada
P. Howard
Sheffield, UK
F. Meloni
Pavia, Italy
Editorial Board
P. Baiardi, Pavia, Italy
H. Burchardi, Goettingen, Germany
L. Casali, Perugia, Italy
M. Cazzola, Roma, Italy
A. Corsico, Pavia, Italy
I. Cerveri, Pavia, Italy
G. Cremona, Milano, Italy
G. D’Amato, Napoli, Italy
G. Di Maria, Catania, Italy
E.C. Flecther, Louisville, USA
G. Gialdroni Grassi, Pavia, Italy
C. Giuntini, Pisa, Italy
S.B. Gottfried, Montreal, Canada
V. Grassi, Brescia, Italy
R. Keller, Aarau, CH
G.B. Migliori, Tradate, Italy
G. Minuco, Veruno, Italy
Editors
Furio Colivicchi
Clinical Quality Management Unit
Cardiovascular Department
San Filippo Neri Hospital
Via Martinotti 20
I-00135 Roma
[email protected]
J.F. Muir
Rouen, France
S. Nardini
Vittorio Veneto, Italy
E. Pozzi
Pavia, Italy
M. Pistolesi
Firenze, Italy
An. Rossi
Bergamo, Italy
C.M. Sanguinetti
Roma, Italy
R. Sergysels
Bruxelles, Belgium
G. Moscato, Pavia, Italy
M. Neri, Tradate, Italy
D. Olivieri, Parma, Italy
C. Prefaut, Montpellier, France
R. Richmond, Sydney, Australia
J. Roca, Barcelona, Spain
G.A. Rossi, Genova, Italy
C. Roussos, Athens, Greece
M. Saetta, Padova, Italy
G. Scano, Firenze, Italy
G. Semenzato, Padova, Italy
N. Siafakas, Crete, Greece
J. Sorli, Golnik, Slovenia
S. Spinaci, Geneve, CH
C. Tantucci, Brescia, Italy
E. Wouters, Maastricht, NL
J. Zieli ński, Warsaw, Poland
Deputy Editors
Cesare Greco
Cardiac Rehabilitation Unit
S. Giovanni Addolorata Hospital
I-00184 Roma
[email protected]
Executive Editors
Pantaleo Giannuzzi
Dept. of Cardiac Rehabilitation
Institute for Clinical Care
and Research
I-28010 Veruno (NO)
[email protected]
Associate Editors
Maurizio Abrignani (Trapani)
Elisabetta Angelino (Torino)
Samuele Baldasseroni (Firenze)
Pompilio Faggiano (Brescia)
Francesco Giallauria (Napoli)
Scientific Board
M. Ambrosetti (Cunardo)
O. Bettinardi (Ponte dell’Olio)
P. Calisi (Arenzano)
R. Carlon (Cittadella)
V. Ceci (Roma)
S. Celardo (Caserta)
M. Chiatto (Trebisacce)
C. Chieffo (Napoli)
P. Clavario (Genova)
U. Corrà (Veruno)
L. Da Vico (Firenze)
S. De Feo (Peschiera del Garda)
T. Diaco (Crema)
G. Di Pasquale (Bologna)
G. Favretto (Motta di Livenza)
G. Furgi (Telese)
A. Galati (Roma)
M. Gattone (Veruno)
A. Genovesi Ebert (Livorno)
A. Giordano (Gussago)
P. Golino (Caserta)
P. Gremigni (Bologna)
M. Ferratini (Milano)
G.F. Ignone (Brindisi)
Francesco Fattirolli
Dept. Medical and Surgical Critical Care
Azienda Ospedaliero-Universitaria Careggi
Via delle Oblate 4
I-50141 Firenze
[email protected]
Oreste Febo
Institute for Clinical Care and Research
I-27040 Montescano (PV)
[email protected]
Carmine Riccio
Caserta Hospital
I-81100 Caserta
[email protected]
Raffaele Griffo (Genova)
Massimo Piepoli (Piacenza)
Pier Luigi Temporelli (Veruno)
Giovanni Pulignano (Roma)
Paolo Trambaiolo (Roma)
M.T. LaRovere (Montescano)
A. Maggioni (Firenze)
G. Majani (Montescano)
P. Maras (Trieste)
R. Marchioli (S.M. Imbaro)
G. F. Mureddu (Roma)
C. Opasich (Pavia)
S. Pirelli (Cremona)
M. Pistono (Veruno)
F. Rengo (Napoli)
G. Rosato (Avellino)
S. Scardi (Trieste)
M. Scherillo (Benevento)
C. Schweiger (Milano)
D. Scrutinio (Cassano Murge)
P. Stefàno (Firenze)
L. Tavazzi (Cotignola)
D. Temporelli (Veruno)
M. Volterrani (Roma)
M. Uguccioni (Roma)
S. Urbinati (Bologna)
D. Vanuzzo (Udine)
C. Vigorito (Napoli)
Chairman
Ernesto Catena
Inst. of Respiratory Medicine
2nd University of Napoli
V. Monaldi Hospital
I-80131 Camaldoli (NA)
AIMS AND SCOPE: Monaldi Archives for Chest Disease is an international scientific journal of the Fondazione Salvatore Maugeri IRCCS, Scientific Institute, Pavia, Italy, dedicated to the
advancement of knowledge in all fields of cardiopulmonary medicine and rehabilitation. It is published in two series: the “Cardiac Rehabilitation and Prevention Series” (volume, even numbers)
which, since 2002, is the official journal of the Italian Association for Cardiovascular Prevention, Rehabilitation and Epidemiology (GICR-IACPR); and the “Pulmonary Medicine and
Rehabilitation Series” (volume, odd numbers). Monaldi Archives for Chest Disease publishes original articles, new methodological approaces, reviews, opinions, editorials, position papers on
all aspects of cardiac and pulmonary medicine and rehabilitation, and, in addition, provides a forum for the inter-exchange of information, experiences and views on all issues of the cardiology
profession, including education. Accordingly, original contributions on nursing, exercise treatment, health psychology, occupational medicine, care of the elderly, health economics and other
fields related to the treatment, management, rehabilitation and prevention of cardiac and respiratory disease are welcome. Monaldi Archives for Chest Disease promotes excellence in the
profession of cardiology and pneumology through its commitment to the publication of research, support to continuous education, and encouragement and dissemination of ‘best practice’.
SUBSCRIPTION: Monaldi Archives for Chest Disease (ISSN 1122-0643) is published in two series: the Pulmonary Series, published quarterly (four issues per year), and the Cardiology
Series, also published quarterly (four issues per year). Monaldi Archives for Chest Disease is distributed by PI-ME Tipografia Editrice s.r.l., Via Vigentina 136A, 1-27100 Pavia, Italy,
E-mail: [email protected]. Annual subscription rate: a) Four quarterly issues of the Pulmonary Medicine and Rehabilitation Series: € 96.00 (US $ 124.80); b) Four quarterly
issues of the Cardiac Rehabilitation and Prevention Series: € 63.00 (US $ 81.90); c) Cumulative subscription: € 130.00 (US $ 169.00). Subscriptions should be addressed to: PI-ME
Tipografia Editrice s.r.l., Via Vigentina 136A, 1-27100 Pavia, Italy; Tel: +39 0382 572169; Fax: +39 0382 572102; E-mail: [email protected]. The issues of the Cardiology Series
of Monaldi Archives for Chest Disease are distributed free to all members of the Italian Association for Cardiovascular Prevention, Rehabilitation and Epidemiology (GICR-IACPR)
MONALDI ARCHIVES FOR CHEST DISEASE IS PUBLISHED (FULL-TEXT) ON-LINE ON THE WEB-SITE www.gicr.it
ADVERTISING REPRESENTATIVE: Segreteria GICR, ARISTEA International S.r.l., Via Roma 10, I-16121 Genova, Italy; Tel. (+39) 010-553591; Fax (+39) 010-5535970;
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Monaldi Archives for Chest Disease is cited in: Index Medicus - Medline, Pubmed and in Excerpta Medica - Embase [Monaldi Arch Chest Dis].
Registered as a journal at the Tribunal of Pavia, Italy, no. 418 July 17,1993 - Registro Stampe Periodiche - ROC 5756 - ISSN 1122-0643 © 1995. AlI rights reserved
Authors submitting manuscripts to the journal do so in the knowledge that copyright passes to Monaldi Archives for Chest Disease.
Monaldi Archives for Chest Disease
Volume 80, 4, Cardiac Series
December 2013
CONTENTS
INDICE
REVIEWS • RASSEGNE
F. Orso, R. Barucci, S. Fracchia, G. Mannarino,
A. Pratesi, F. Fattirolli
151 Il trattamento di pazienti molto anziani con fibrillazione
atriale non valvolare. La preziosa opportunità offerta
dai Nuovi Anticoagulanti Orali, da usare con attenzione
Treatment of very old patients with non valvular atrial
fibrillation. The valuable opportunity offered by New Oral
Anticoagulants, to be cautiously used
V. Bianchi, A. Mezzani
161 Androgens and cardiac diseases
ORIGINAL ARTICLES • ARTICOLI ORIGINALI
S. Baldasseroni, A. Pratesi, F. Orso, C. Di Serio,
A. Foschini, A.G. Marella, N. Bartoli, M. Di Bari,
S. Fumagalli, N. Marchionni, F. Tarantini
170 Epicardial adipose tissue and insulin resistance
in patients with coronary artery disease
with or without left ventricular dysfunction
Tessuto adiposo epicardico e insulino resistenza
in pazienti con cardiopatia ischemica cronica
con o senza disfunzione ventricolare sinistra
L. Maresca, M. D’Agostino, L. Castaldo, A. Vitelli,
M. Mancini, G. Torella, R. Lucci, G. Albano,
D. Del Forno, M. Ferro, V. Altieri, F. Giallauria,
C. Vigorito
177 Exercise training improves erectile dysfunction (ED)
in patients with metabolic syndrome on
phosphodiesterase-5 (PDE-5) inhibitors
L’esercizio fisico migliora il grado di disfunzione erettile
(ED) nei pazienti con sindrome metabolica in terapia
con inibitori della fosfodiesterasi-5 (PDE-5)
CASE REPORTS • CASI CLINICI
S.A. Di Fusco, N. Aspromonte, S. Aquilani,
L. Mele, F. Colivicchi
184 Emergency reversal of vitamin-K antagonists related
over-anticoagulation: case report and brief overview
on the role of Prothrombin Complex Concentrate
Rapida correzione dell'eccessiva anticoagulazione
da antagonisti della vitamina K: caso clinico e breve
inquadramento del ruolo del Complesso
Protrombinico Concentrato
B. Piovanelli, R. Rovetta, I. Bonadei, E. Vizzardi,
A. D’Aloia, M. Metra
189 Nonbacterial Thrombotic Endocarditis in Pancreatic Cancer
Endocardite trombotica non batterica in associazione
con una neoplasia pancreatica
M. Correale, A. Totaro, A. Ferraretti, M. Di Biase,
N. Daniele Brunetti
193 Sildenafil improves clinical and functional status of an
elderly postmenopausal female with ‘out of proportion’
PH associated with left heart disease
Terapia con Sildenafil migliora clinica e stato funzionale
di una anziana donna con ipertensione polmonare
associata a patologia del cuore sinistro
Monaldi Arch Chest Dis
2013; 80: 151-160
RASSEGNA
Il trattamento di pazienti molto anziani
con fibrillazione atriale non valvolare.
La preziosa opportunità offerta dai Nuovi
Anticoagulanti Orali, da usare con attenzione
Treatment of very old patients with non valvular atrial fibrillation.
The valuable opportunity offered by New Oral Anticoagulants,
to be cautiously used
Francesco Orso1, Riccardo Barucci1, Stefania Fracchia1,
Giulio Mannarino1, Alessandra Pratesi1, Francesco Fattirolli2
ABSTRACT: Treatment of very old patients with non valvular
atrial fibrillation. The valuable opportunity offered by New Oral
Anticoagulants, to be cautiously used. F. Orso, R. Barucci,
S. Fracchia, G. Mannarino, A. Pratesi, F. Fattirolli.
Atrial Fibrillation (AF) is the most frequent cardiac arrhythmia and its incidence increases with age reaching a
10% prevalence in the oldest old. Patients with AF have a
five-fold increase in the risk of stroke. Current guidelines on
AF management recommend the prescription of oral anticoagulant therapy in patients at medium and high risk of
thromboembolic events. Advanced age is a risk factor for
stroke in AF, but despite clear evidences a high rate of OAT
under prescription is reported and particularly in the oldest
old. Among the main causes of this phenomenon an enhanced risk of bleeding is often reported: this due to several
factors: risk of falls, the presence of comorbidity and polifarmacy and a reduction in compliance and adherence that
are common in the elderly. In recent years the international
scenario in the management of OAT has significantly
changed since the introduction of the new oral anticoagulants (NOA): Dabigatran, a direct thrombin inhibitor, and
two oral factor Xa inhibitors Rivaroxaban and Apixaban,
which have all been tested in randomized clinical trial
(RELY, ROCKET-AF e ARISTOTLE) which have demonstrated non inferiority compared to warfarin in the prevention of thromboembolic events with an optimal safety profile. NOA could be an important therapeutic opportunity for
stroke prevention in elderly patients with AF even if the substantial differences in mean age, anthropometric measures
and comorbidity of the patients enrolled in these trials compared with those of the real world setting, oblige some caution and discussion.
Keywords: atrial fibrillation, new oral anticoagulants,
warfarin, stroke, thromboembolic events, elderly.
Monaldi Arch Chest Dis 2013; 80: 151-160.
Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze e Azienda Ospedaliero Universitaria Careggi Firenze: 1 SOD
Cardiologia e Medicina Geriatrica; 2 SOD Riabilitazione Cardiologica.
Corresponding author: Prof. Francesco Fattirolli; Dipartimento Medicina Sperimentale e Clinica Università di Firenze e Azienda
Ospedaliero Universitaria Careggi, SOD Riabilitazione Cardiologica, Via delle Oblate 4, 50141 Florence, Italy; E-mail address:
[email protected]
La fibrillazione atriale: focus sull’oldest old
La fibrillazione atriale (FA) è la più comune aritmia cardiaca e la sua incidenza aumenta all’aumentare dell’età, raggiungendo una prevalenza del 10%
nei pazienti di età ≥ 80 anni e del 18% oltre gli 85 anni [1]; in base ai cambiamenti demografici in atto nei
paesi ad alto e medio reddito, entro il 2050 circa il
50% dei pazienti affetti da FA avrà un’età superiore
agli 80 anni. I pazienti affetti da FA presentano un rischio di essere colpiti da ictus cinque volte maggiore rispetto alla popolazione normale ed uno stroke su
cinque è attribuibile a tale aritmia. L’ictus ischemico
correlato a FA è spesso fatale ed i pazienti che sopravvivono presentano un elevato rischio di disabilità, nonché un maggior rischio di recidiva [2]. Le attuali Linee Guida sulla FA della Società Europea di
Cardiologia (ESC) raccomandano nei pazienti a medio ed alto rischio di eventi tromboembolici la terapia anticoagulante orale (TAO), mentre nei pazienti a
basso rischio risulta indicata la terapia antiaggregante con acido acetilsalicilico o nessuna terapia [2]. In
soggetti di età >75 anni affetti da FA il rischio annuo
di tromboembolismo si attesta attorno al 4%, per cui,
in assenza di un eccessivo rischio emorragico, viene
posta indicazione alla TAO, che in questi soggetti risulta prescritta in misura ampiamente ridotta.
I nuovi anticoagulanti orali (NAO) possono rappresentare una valida opzione terapeutica per pazienti anziani e molto anziani affetti da FA non valvolare. Lo scopo di questa rassegna è quello di analizzare le evidenze sull’impiego dei NAO in questa
categoria di pazienti, evidenziando i potenziali benefici ed anche i rischi legati al loro impiego.
F. ORSO ET AL.
Gestione e trattamento farmacologico della
fibrillazione atriale nel paziente anziano
Malgrado le evidenze scientifiche ed i documentati benefici clinici, molti studi hanno dimostrato
che la TAO è poco prescritta nei pazienti in età geriatrica. Dati del registro REPOSI che includeva pazienti anziani ricoverati in reparti di medicina interna con diagnosi di FA all’ingresso, identificano l’età
avanzata (>80 anni) come predittore indipendente di
mancata prescrizione della terapia anticoagulante
[3]. Nello studio ATRIA [4] nei pazienti anziani con
FA non valvolare, la TAO era usata solo nel 60% degli individui tra 65-84 anni e solamente nel 35% di
quelli con più di 85 anni. Dati sostanzialmente sovrapponibili si ritrovano nel registro ATA-AF che,
pur suggerendo un’influenza del setting assistenziale nella sottoprescrizione della TAO in pazienti affetti da FA non valvolare ad alto rischio (46.5% medicina vs 65.9% cardiologia p< 0.001), riportano
una correlazione inversa tra prescrizione di TAO ed
età avanzata che è risultata essere anche in questo
caso fattore predittivo indipendente di non prescrizione (età ≥ 75 vs 65-74 anni p< 0.001) [5]. L’età
avanzata rappresenta dunque uno dei principali predittori di mancata profilassi con anticoagulanti [6],
sebbene questi siano generalmente ben tollerati ed
efficaci anche nella popolazione anziana e molto anziana nel prevenire gli eventi cerebrovascolari [7].
Spesso al posto della terapia anticoagulante orale
viene prescritta terapia antiaggregante con aspirina a
dosaggi variabili da 75 mg a 300 mg o con aspirina
associata a clopidogrel 75 mg. Nello studio BAFTA
(The Birmingham Atrial Fibrillation Treatment of the
Aged) nei pazienti in età >75 anni con FA, l’uso del
warfarin riduceva significativamente l’incidenza degli eventi primari (ictus, embolia sistemica) rispetto
all’aspirina, senza un significativo incremento dei
sanguinamenti maggiori [7]. Una metanalisi che ha
incluso quasi trentamila pazienti (età media 71 anni)
con FA non valvolare ha dimostrato una chiara superiorità del warfarin rispetto alla terapia antiaggregante nel ridurre la frequenza dell’ictus cardioembolico
(approssimativamente del 40%), con un minor rischio
di emorragie extracraniche [8] che, soprattutto a livello gastrointestinale, si associano ad una elevata
morbilità e mortalità nella popolazione anziana. Anche alla luce di questi dati le Linee Guida ESC sulla
gestione dei pazienti affetti da FA hanno ristretto l’indicazione all’utilizzo dell’aspirina nella prevenzione
degli eventi cardioembolici solo ai pazienti che rifiutano la terapia anticoagulante e come seconda scelta
rispetto all’associazione aspirina/clopidogrel nei pazienti con rischio di sanguinamento non basso [2].
Questa associazione, nello studio ACTIVE A, si è infatti dimostrata superiore rispetto al trattamento con
sola aspirina determinando una riduzione del 28%
nella frequenza di ictus ischemici anche se al prezzo
di un incremento significativo dei sanguinamenti
maggiori [9]. Tuttavia l’associazione aspirina/clopidogrel è risultata inferiore nello studio ACTIVE W
nel confronto con warfarin sulla prevenzione degli
eventi cardioembolici senza una significativa differenza in termini di sanguinamento nei due bracci di
trattamento, ed è quindi da considerare come seconda
scelta rispetto alla terapia anticoagulante [10].
152
La terapia anticoagulante
nei soggetti anziani: focus sulle motivazioni
principali della ridotta prescrizione
L’età avanzata rappresenta un fattore di rischio
indipendente di eventi trombotici, insieme alla presenza di ipertensione arteriosa, diabete mellito tipo
2, pregresso stroke/TIA, condizioni ad elevata incidenza nella popolazione anziana [11]. La correlazione tra età e rischio trombotico viene coerentemente
sottolineata nel principale score di rischio di eventi
tromboembolici utilizzato nei pazienti con FA non
valvolare (CHA2DS2-VASc), in cui all’età >75 anni viene assegnato un punteggio di 2, allo stesso livello dell’item “pregresso ictus/TIA” [12]. La conseguenza di questa valutazione del rischio dovrebbe
tradursi in una maggiore attenzione per la profilassi
anticoagulante nella popolazione anziana, mentre si
osserva un ridotto trattamento per le ragioni che sono illustrate di seguito.
Età e rischio di sanguinamento
Il rischio di sanguinamento è una delle motivazioni principali del non utilizzo di anticoagulanti nei
soggetti molto anziani. Una recente analisi retrospettiva di coorte condotta nel Regno Unito su oltre
ottantamila pazienti, mostra come l’età >80 anni risulti un fattore indipendentemente associato alla non
prescrizione di TAO [13]. I dati epidemiologici dimostrano che gli eventi emorragici hanno un’incidenza che aumenta con l’età [14], anche indipendentemente dalle terapie in corso [7, 15]; inoltre,
nello strumento di valutazione del rischio emorragico maggiormente utilizzato (HAS-BLED) l’età >65
anni aumenta di un punto il punteggio totale dello
score [16]. Nonostante ciò, i dati di letteratura non
sono concordi sulla presenza di una correlazione tra
età e rischio emorragico e solo alcuni degli studi disponibili hanno evidenziato una associazione di rischio indipendente tra età avanzata e incidenza di
sanguinamento. Le popolazioni studiate hanno incluso pazienti in terapia con warfarin, in terapia con
warfarin versus ASA e in terapia con warfarin versus altri anticoagulanti. In uno studio scandinavo
prospettico di coorte l’età avanzata e la presenza di
ulcera peptica risultavano essere gli unici due indicatori associati a sanguinamenti maggiori/fatali in
analisi multivariata, con un incremento per anno rispettivamente del 4% e del 5% [17], in accordo con
precedenti dati di metanalisi [18].
Evidenze più recenti sembrerebbero tuttavia
confutare l’esistenza di una associazione indipendente tra età e sanguinamenti. Sia lo studio BAFTA
[7], che il WASPO (The Warfarin versus Aspirin for
Stroke Prevention in Octogenarians with AF) [19] –
entrambi trial clinici randomizzati Warfarin versus
ASA – dimostrano come non vi sia una differenza
significativa nel rischio di emorragie maggiori anche nelle fasce di età rispettivamente >75 anni e >
80 anni. Un ampio studio prospettico condotto in
Italia (EPICA) su oltre quattromila ultraottantenni in
TAO, conferma che in analisi multivariata competitiva restano indipendentemente associati al rischio
di sanguinamento solo la presenza di neoplasia in fase attiva, la storia di pregressi sanguinamenti e la
storia di cadute, tanto che gli autori concludono che
L’UTILIZZO DEI NAO NEI PAZIENTI MOLTO ANZIANI CON FIBRILLAZIONE ATRIALE
l’età non è un fattore di rischio indipendente [20].
Anche in uno studio di coorte prospettico, condotto
in una popolazione simile per caratteristiche clinicoepidemiologiche [21], all’analisi multivariata l’età
non risultava associata a un maggior rischio di sanguinamento, a differenza di polifarmacologia, INR
fuori range, scarsa educazione alla terapia anticoagulante. La mancanza di omogeneità dei risultati di
questi studi lascia comunque ancora irrisolto il quesito dell’associazione indipendente tra età e sanguinamento.
Rischio di caduta e rischio di sanguinamento
Il rischio di caduta è un altro frequente motivo di
mancata prescrizione della terapia anticoagulante in
soggetti molto anziani con FA. In un ampio studio
retrospettivo nel quale sono stati arruolati circa 1200
pazienti ad elevato rischio di caduta e quasi 20.000
pazienti con FA [22] di cui il 48% in TAO, è stato
dimostrato che i pazienti ad elevato rischio di cadute mostravano una aumentata incidenza di emorragie intracraniche traumatiche rispetto a quelli a basso rischio. Inoltre, negli stessi pazienti, la mortalità
a 30 giorni dopo una emorragia intracranica era significativamente più elevata nei pazienti a cui era
stato prescritto il warfarin. Tuttavia, malgrado l’attesa associazione tra rischio di caduta ed emorragia
intracranica, gli stessi autori hanno osservato che i
pazienti a maggiore rischio di caduta e con un concomitante alto rischio tromboembolico beneficiavano della terapia anticoagulante con una riduzione del
rischio relativo del 25% per morte extraospedaliera,
ospedalizzazione per ictus ischemico, infarto miocardico ed emorragia.
In una metanalisi è stato dimostrato che per i
pazienti anziani con FA la scelta della terapia medica ottimale per la prevenzione dell’ictus ischemico
dipende da molti fattori tra cui l’ipertensione arteriosa, lo scompenso cardiaco, il diabete o un precedente attacco ischemico; tuttavia la propensione a
cadere non rientra tra questi [23]. In una persona
che assume warfarin, le emorragie subdurali correlate alle cadute sono ritenute estremamente infrequenti; nei pazienti anziani con FA e rischio cardioembolico maggiore del 6% all’anno, il beneficio
della terapia anticoagulante è decisamente superiore rispetto al rischio di sviluppare emorragie maggiori. È stato calcolato che un anziano dovrebbe cadere più di 300 volte all’anno per superare il beneficio clinico derivante dalla terapia con warfarin.
Anche in un recente studio prospettico [24] che ha
coinvolto pazienti con età media di 72 anni dimessi
con TAO, dei quali circa il 60% ad elevato rischio
di caduta, non corrispondeva un elevato rischio di
sanguinamenti maggiori a distanza di 12 mesi.
In ogni caso, una delle principali limitazioni di
questi studi risiede nel fatto di non definire in maniera univoca e sistematica il rischio di caduta.
Rischio emorragico e tromboembolico:
gli strumenti di valutazione
Rischio emorragico
Alcuni dei fattori di rischio per lo sviluppo di
emorragie maggiori sono l’età, la comorbilità e la
polifarmacoterapia: frequentemente gli eventi emor-
ragici maggiori sono causati da specifici fattori come l’uso di antiinfiammatori non steroidei, antiaggreganti, steroidi o abuso alcolico che, se evitati,
possono ridurre grandemente il rischio [1].
Nel corso degli anni sono stati sviluppati vari
strumenti per il calcolo del rischio emorragico; tra i
principali vi sono HAS-BLED [25], ATRIA [26] ed
HEMORR2HAGES [27].
HAS-BLED [Hypertension, Abnormal Liver/
Renal Function, Stroke History, Bleeding Predisposition, Labile INRs, “Elderly” (Age >65), Drugs/Alcohol Usage] deriva dall’analisi del rischio emorragico di una rilevante coorte di pazienti del registro
Euro Heart Survey on atrial fibrillation [28] della
ESC nel quale sono stati arruolati più di 5000 pazienti (età media 66 anni) sia ambulatoriali che
ospedalizzati, provenienti da 35 paesi, con un follow-up di circa un anno. La principale forza di questo strumento risiede nella facilità di utilizzo in
quanto le informazioni per il calcolo del punteggio
possono essere rapidamente disponibili. Le principali limitazioni [25] sono legate alla brevità del periodo di follow-up della survey, con una probabile
sottostima della frequenza di sanguinamento e dall’elevato numero di pazienti persi al follow-up (circa il 25%) costituiti da soggetti con comorbilità, trasferiti nelle nursing home o deceduti che, per quanto affermato dagli stessi autori, erano rappresentati
in prevalenza da soggetti molto anziani.
ATRIA (The AnTicoagulation and Risk Factors
In Atrial fibrillation study) derivato dall’omonimo
studio è uno score di rischio emorragico contenente
solamente cinque variabili (anemia, insufficienza
renale, età, ipertensione e anamnesi positiva per
emorragie maggiori) [15]. La frequenza dei sanguinamenti maggiori varia dallo 0,4% (0 punti) al
17,3% (10 punti) all’anno. Sono state sviluppate tre
categorie: pazienti a basso rischio (0-3 punti con
0,8% di frequenza di sanguinamento maggiore), rischio intermedio (4 punti, rischio 2,6%) e rischio
elevato (5-10 punti, rischio 5.8%) [15].
HEMORR2HAGES deriva dall’analisi del National Registry of Atrial Fibrillation [27]. È composto da 11 variabili a cui viene assegnato un punto ad
eccezione dell’anamnesi positiva per sanguinamenti
maggiori a cui viene dato un punteggio di 2.
Il confronto tra i tre strumenti effettuato su una
coorte di pazienti con FA arruolati nello studio
AMADEUS, ha dimostrato una modesta capacità
di predire eventi emorragici di tutti e tre gli score
nell’individuare il sanguinamento clinicamente rilevante, con una migliore qualità di HAS-BLED
che è l’unico ad avere una significativa performance predittiva per emorragia intracranica [29].
Questi risultati supportano l’indicazione ad utilizzare HAS-BLED come score di valutazione del rischio emorragico come raccomandato dalle ultime
Linee Guida ESC [2], con non marginali limitazioni per l’utilizzo nei molto anziani citata in precedenza.
Rischio tromboembolico
Anche l’identificazione di vari fattori di rischio per l’ictus cardioembolico in pazienti con
FA ha portato negli ultimi anni allo sviluppo di numerosi score di rischio. Il più semplice è il
153
F. ORSO ET AL.
CHADS2 [30], costituito da 5 variabili: Cardiac
failure, Hypertension, Age (>75 anni), Diabetes,
Stroke. Il punteggio massimo raggiungibile è 6,
con una frequenza di ictus cardioembolico per anno che va da 1,9% (0 punti) a 18,2% (6 punti). Negli studi di popolazione, l’applicazione di questo
punteggio ha generato un esteso gruppo di pazienti con rischio intermedio (circa il 60% del campione con punteggio 1-2) per cui si è reso necessario
un nuovo strumento che riuscisse a stratificare meglio questa categoria di soggetti. È stato elaborato
il CHA2DS2-VASc score [31] che include: Congestive heart failure, Hypertension, Age ≥75 (2 punti), Diabetes, Stroke (2 punti), Vascular disease,
Age 65-74, and Sex category (femmina). Analogamente al CHADS2, con un punteggio CHA2DS2VASc ≥ 2 è indicata la terapia anticoagulante orale,
con punteggio = 1 è da preferire la terapia anticoagulante orale, con punteggio = 0 aspirina o nessuna terapia; da sottolineare che nello strumento il
peso dell’item “età >75 anni” è di 2 punti.
I NAO nella fibrillazione atriale non valvolare
Negli ultimi due anni lo scenario internazionale
sulla gestione dell’anticoagulazione nella FA ha subito un significativo cambiamento, grazie alla commercializzazione dei Nuovi Anticoagulanti Orali:
Dabigatran, inibitore orale della trombina, Rivaroxaban ed Apixaban, inibitori orali del fattore Xa. I principali studi che hanno portato alla validazione di que-
sti farmaci (RELY per Dabigatran; ROCKET-AF per
Rivaroxaban; ARISTOTLE per Apixaban) [32-34]
sono stati condotti per dimostrare la non inferiorità
e/o superiorità in confronto al warfarin nella prevenzione dell’ictus nella FA non valvolare, escludendo
i pazienti portatori di protesi valvolare e valvulopatia reumatica. Gli end point primari di efficacia erano rappresentati dalla riduzione di stroke ed embolia
sistemica. I tre farmaci hanno dimostrato la non inferiorità rispetto al warfarin; ad esempio il Dabigatran, al dosaggio di 150 mg BID, ha dimostrato la
superiorità soprattutto sulla riduzione dell’ictus
ischemico e della mortalità per cause vascolari. Le
tre molecole sono risultate sicure, con riduzione dei
sanguinamenti maggiori soprattutto intracranici, di
facile somministrazione e gestione. Negli studi ARISTOTELE e RELY, l’outcome primario era il sanguinamento maggiore, mentre nel ROCKET-AF era
dato dall’associazione fra sanguinamenti maggiori e
minori. I criteri di inclusione/esclusione dei tre studi erano abbastanza omogenei e la popolazione dei
soggetti inclusi era simile per età, percentuale di
donne, peso medio e storia di pregresso infarto miocardico. I pazienti arruolati nell’ambito del
ROCKET-AF erano più comorbosi rispetto a quelli
inclusi negli altri trial come risulta dalla Tabella 1: la
quota di diabete mellito, insufficienza cardiaca e
pregressa malattia trombo-embolica era molto più
alta, con una percentuale elevata (87%) di pazienti
con CHADS2 ≥3. In questo gruppo di pazienti una
metanalisi [35] sembrava indicare un minor numero
Tabella 1. - Caratteristiche delle popolazioni arruolate nei trial sui NAO (RE-LY/Dabigatran; ROCKET-AF/Rivaroxaban;
ARISTOTLE/Apixaban)
Dabigatran
110 mg
Dabigatran
150 mg
Rivaroxaban
20 mg
Apixaban
5 mg
6015
6076
7131
9120
Età (anni + DS)
71.4±8.6
71.5±8.8
Mediana 73
69.1+9.6
Età > 75 anni*
41
43
31
Età > 80 anni*
17
25
NR
Peso Kg
82.9±19.9
82.5±19.4
82.1
82
Donne*
35.7
36.8
39.7
35.5
FA parossistica*
32.1
32.6
17.5
15.1
FA persistente/permanente*
67.8
67.4
81.1
84.9
Pregresso ictus/TIA*
19.9
20.3
54.9°
19.2°
Pregresso IMA*
16.8
16.9
16.6
14.5
Insufficienza cardiaca*
32.2
31.8
62.6
35.5
Diabete mellito*
23.4
23.1
40.4
25.0
Ipertensione*
78.8
78.9
90.3
87.3
CHADS2 score ≥ 3*
32.7
32.6
87.0
30.2
17
19
16.5
Caratteristiche
Arruolati
GFR < 50 ml/min*
*= %
154
di emorragie maggiori con Apixaban rispetto a Dabigatran e Rivaroxaban. La probabilità di interruzione del farmaco era sovrapponibile nei tre studi indipendentemente dal farmaco utilizzato: in un follow
up di 24 mesi la percentuale di interruzioni di terapia era del 21.2% per Dabigatran 150 mg (vs 16.6%
per warfarin), del 34.7% per Rivaroxaban (vs 33.5%
per warfarin) e del 25.3% per Apixaban (vs 27.5%
per warfarin). Alla luce di questi risultati i NAO sono stati inclusi nelle Linee Guida ESC [1] come anticoagulanti orali alternativi ai dicumarolici nella FA
non valvolare con CHA2DS2-VASc score ≥ 2 (IA) o
≥ 1 (IIaB), soprattutto nei pazienti con effetti collaterali ai dicumarolici o difficoltà nel mantenere o
monitorizzare il range terapeutico di INR.
I NAO negli oldest old: efficacia e sicurezza
Se confrontiamo le caratteristiche generali dei
pazienti arruolati nei tre grandi trial sui NAO con
quella dei pazienti dell’ampio registro italiano che
maggiormente si avvicina al mondo reale (ATA-AF)
[5] colpisce la differenza di età: nel registro ATA-AF,
l’età media è di 77 anni, con una elevata percentuale
di ultraottantenni che rappresentano più di un terzo
della casistica, mentre l’età media dei pazienti nei
trial è decisamente inferiore (70 anni, 71 anni e 73
anni circa rispettivamente per ARISTOTLE, RELY
e ROCKET AF) (Tabella 2). Questa osservazione
conferma la distanza che, in generale, intercorre tra
il “mondo degli studi clinici” ed il “mondo reale”
quando si considerano i risultati nella prospettiva
della applicabilità alla popolazione anziana. Anche
recentemente è stato calcolato come in oltre due terzi dei trial l’età media non superi i 73 anni, e che oltre il 75% dei soggetti vengono esclusi per comorbilità, di fatto la popolazione di anziani “fragili” che al
di sopra degli 80 anni può rappresentare dal 15 al
30% degli individui [36-37].
Allo scopo di valutare quanto i risultati siano applicabili anche agli anziani, i risultati sugli outcome
di efficacia (stroke/tromboembolismo) e sicurezza
(emorragie intracraniche e sanguinamenti maggiori)
di RELY, ARISTOTLE, ROCKET-AF, sono stati
confrontati con quelli ottenuti nel sottogruppo dei
pazienti ultra75enni e ultra80enni. I risultati generali sono sostanzialmente sovrapponibili a quelli ottenuti dai pazienti di età più avanzata: per l’efficacia è
mantenuta la superiorità o non inferiorità rispetto a
warfarin e per la sicurezza è mantenuta la superiorità
rispetto a warfarin nell’incidenza di emorragie intracraniche. Per quanto riguarda invece i sanguinamenti maggiori extracranici i risultati rimangono sovrapponibili in ARISTOTLE e ROCKET-AF mentre in
RELY i dati relativi agli anziani si discostano significativamente dai risultati generali dello studio: il rischio di emorragie maggiori extracraniche negli anziani è significativamente più elevato nel braccio
randomizzato a Dabigatran 150 mg BID rispetto a
warfarin; nel braccio Dabigatran 110 mg BID è
mantenuto solo un trend di significatività a favore di
warfarin su questo outcome di sicurezza. Da qui
l’indicazione a preferire la dose ridotta di Dabigatran per età >80 anni, ed a valutare l’indicazione a ridurre la dose in base al rischio individuale nei pazienti tra 75 e 80 anni. Tuttavia, nonostante queste
Tabella 2. - Caratteristiche delle popolazioni con FA arruolate in alcuni registri nazionali ed internazionali
Caratteristiche
PREFER
(47)
PREFER
Italia
RECORDAF
(48)
GARFIELD
(46)
AF-NET
(49)
EPICA
(20)
ATA-AF
(5)
Arruolati
7243
1888
5604
9288
7907
3015
7148
Età media anni
71,5
70,9
66
69,9
68,3
83
77
Età > 75 anni*
44,7
42,1
NR
34
Peso Kg/ BMI
NR
NR
NR
–/27,4
NR
NR
74+15/>25
Donne*
39,8
42,6
42,8
43
38,4
54.9
47
100
FA parossistica*
30
52,3
28
30,2
NR
24
FA persistente o permanente*
70
47,7
43
52,3
NR
76
Pregresso ictus/TIA*
8,4
6,5
5,7
14
10,5
19.6
14,6
Pregresso IMA*
10,7
11,3
NR
10
13,2
24.4
19,9
Insufficienza cardiaca*
21,3
19,4
25,9
21
36,9
27.4
27,7
Diabete mellito*
22,4
19,2
15,7
21
21,6
18.3
22,4
Ipertensione*
72
75,3
68
78
69,2
75.6
75,2
CHADS2 ≥ 2*
84,1
83,4
NR
55,4
NR
~84
64,2
10
9,3
NR
13
NR
NR
NR
GFR < 60*
NR = dato Non Riportato *= %
155
F. ORSO ET AL.
analisi tendenzialmente incoraggianti su efficacia e
sicurezza dei NAO, persistono perplessità per la
non totale applicabilità dei risultati nella pratica clinica [38]: i soggetti definiti “anziani” nei trial sono
diversi in quanto sostanzialmente “più sani” e più
“giovani” rispetto ai pazienti del mondo reale: queste differenze che riguardano in particolare il peso,
la presenza di comorbosità, di polifarmacoterapia e
soprattutto di insufficienza renale, possono determinare ampie variazioni nella risposta al trattamento con i NAO che devono essere valutate con molta
attenzione.
Peso
Non ci sono evidenze per considerare valori
estremi di peso corporeo come fattore di rischio indipendente per sanguinamento o trombosi (negli
score di rischio emorragico e trombotico non viene
incluso), tuttavia rientra tra i fattori individuali che
influenzano la risposta alle terapie. È noto che l’ampiezza della risposta ai farmaci dipende anche dalla
concentrazione del farmaco al sito di azione, che a
sua volta è correlata al volume di distribuzione, direttamente proporzionale al peso corporeo. Maggiore è il volume di distribuzione, minore risulta la concentrazione del farmaco nei diversi distretti. Pertanto, per poter generalizzare i risultati dei trial clinici
al mondo reale, sarebbe necessaria una omogeneità
del peso corporeo (o del BMI) tra popolazione degli
studi e popolazione reale. Come si può osservare
nella Tabella 1 e nella Tabella 2, il peso medio delle
popolazioni dei trial è maggiore di quello della popolazione reale: in ATA-AF il peso medio era di 74
Kg, circa 8 Kg in meno rispetto ai trial sui NAO [5].
In RELY il peso non rientra direttamente nei criteri
di randomizzazione o di esclusione dallo studio, ma
è indirettamente considerato in quanto per il calcolo
della clearance della creatinina (CLcr) viene utilizzata la formula di Cockcroft-Gault (esclusi dallo studio i pazienti con CLcr< 30 m/min). Lo stesso avviene in ROCKET-AF (esclusi dallo studio i pazienti con CLcr< 30 m/min; pazienti con 30-49 ml/min
randomizzati a dose ridotta di rivaroxaban 15 mg
OD). Al contrario, in ARISTOTLE il peso rientra
direttamente nei criteri di riduzione della dose: i pazienti vengono randomizzati ad apixaban 2.5 mg
BID se presenti 2 criteri su 3 tra peso < 60 Kg,
età>80 anni e creatininemia>1.5 mg/dl, oppure se
Clcr 15-29 ml/min anche isolata.
Nelle attuali indicazioni al trattamento sono presenti le seguenti raccomandazioni per i 3 farmaci,
non derivanti tuttavia da specifiche osservazioni
sperimentali:
– Dabigtran: “non è necessario un aggiustamento
della dose, ma si raccomanda uno stretto controllo clinico in pazienti con peso < 50 Kg.”
– Rivaroxaban: “I valori estremi di peso corporeo
(< 50 kg o > 120 kg) hanno avuto solo un’influenza ridotta sulle concentrazioni plasmatiche
di rivaroxaban (meno del 25%). Non è necessario alcun aggiustamento della dose”.
– Apixaban: “la dose raccomandata è 2,5 mg due
volte al giorno per via orale nei pazienti con almeno due delle seguenti caratteristiche: età ≥ 80
anni, peso corporeo ≤ 60 kg, o creatinina sierica
≥ 1,5 mg/dl”.
156
Anche relativamente al peso corporeo, i risultati
dei trial vanno considerati con cautela proprio per la
mancanza di omogeneità tra le caratteristiche dei pazienti studiati e dei pazienti del mondo reale.
Comorbosità e polifarmacoterapia
I pazienti arruolati nei trial clinici sui NAO presentavano un limitato numero di comorbilità, caratteristica qualificante invece, assieme alla polifarmacoterapia, il profilo clinico degli oldest old. I fattori
di esclusione erano rappresentati oltre che dalle valvulopatie, dalla presenza di anemia, trombocitopenia, concomitante terapia antiaggregante e comorbilità tali da determinare ridotta aspettativa di vita rispetto alla durata del trial (solo in RE-LY), insufficienza renale severa oltre ad anamnesi positiva per
ictus a 14 gg di distanza e a 3/6 mesi nei casi di
stroke severo (quest’ultimo non presente per ARISTOTLE dove criterio di esclusione era la presenza
di stroke nei 7 gg precedenti). Per la terapia farmacologica, in ROCKET-AF vi sono limitate le informazioni sulla terapia farmacologica; i pazienti arruolati in RELY ed ARISTOTLE ricevevano farmacoterapia multipla, tuttavia dai dati pubblicati non
risulta chiaramente la reale entità della terapia in atto e delle combinazioni presenti [6, 38].
Non esistono dati circa la maggiore sicurezza ed
efficacia dei NAO nei pazienti con storia di sanguinamento intra o extracranico pregresso, in quanto tale dato anamnestico rappresentava un criterio di
esclusione dalla sperimentazione clinica di Dabigatran e Rivaroxaban (in ARISTOTLE il 16.7% dei
pazienti presentava anamnesi positiva per sanguinamento ma non ne viene specificata la tipologia e se
vi fossero criteri di esclusione per questo item).
Sempre nelle Tabelle 1 e 2 vengono sintetizzate le
comorbilità dei pazienti arruolati nei trial sui NAO e
nei vari registri che hanno incluso pazienti in età geriatrica.
Insufficienza renale
Numerosi studi hanno dimostrato che una peggior funzione renale è associata con un maggior rischio di sanguinamento durante terapia anticoagulante e ciò ha determinato la controindicazione all’utilizzo dei NAO in presenza di filtrato glomerulare al di sotto di 30 ml/kg/min. Nei pazienti anziani
l’età è notoriamente associata ad un progressivo
peggioramento della funzione renale [39]: infatti lo
score HASBLED include sia l’età che la funzione
renale e viene incluso come criterio di eleggibilità
all’utilizzo dei NAO e più in generale alla terapia
anticoagulante [16]. Nei trial la percentuale di pazienti con filtrato glomerulare (FG) <50 ml/Kg/min
era del 17% in ARISTOTLE, 19% in RELY, 20-22%
in ROCKET-AF [32-34], in accordo con l’età media
dei pazienti. Nel mondo reale la situazione è molto
diversa: nel registro EPICA, che ha incluso un elevato numero di pazienti ultraottantenni con FA, il
FG era in più del 60% dei casi <50 ml/Kg/min [3].
Uno dei principali problemi è quale sia il metodo
migliore per stimare il FG, sapendo che la creatininemia è sicuramente un parametro non sufficientemente attendibile [40] in particolare nel paziente anziano, in quanto le formule più utilizzate, CockroftGault formula (C-G), Modification of Diet in Renal
Disease (MDRD) equation [41] e Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI)
equation [42] non sono state validate nei soggetti in
età geriatrica. Sappiamo che nel paziente anziano la
C-G tende a sottostimare la funzione renale, mentre
l’MDRD a sovrastimarla nei casi di insufficienza renale moderata-severa; differenza che tende a ridursi
in caso di funzione renale conservata. Uno studio
[39] condotto su 1414 ultraottantenni, ha sottolineato che utilizzare MDRD invece che C-G come metodica per la valutazione del FG al fine di individuare
i pazienti cui somministrare Rivaroxaban o Dabigatran, ampliava il numero degli eleggibili a terapia
(+14,9% per Dabigatran, solo 0,3% per Rivaroxaban
con limite inferiore 15 ml/kg/min), ma anche il numero dei sanguinamenti. Inoltre, se veniva usato
MDRD c’era un alto numero di sovraddosaggio di
Rivaroxaban (+13,5%). Ciò a dimostrare che è necessario servirsi della più rigida formula di C-G per
individuare pazienti da escludere per il trattamento
con NAO, e in maniera indiretta che la funzione renale è correlata con un maggior rischio di sanguinamento soprattutto con questa categoria di farmaci
che hanno escrezione, anche e talora prevalentemente, renale. Gli autori suggeriscono anche che la
C-G non solo deve essere utilizzata nei pazienti di
età > 80 anni, ma anche nei pazienti di peso < 60 kg,
in cui spesso il calo ponderale è associato a perdita
di massa magra e a sarcopenia, condizioni che oltretutto conducono ad una riduzione della creatininemia e quindi ad una sottostima di una eventuale disfunzione renale.
Il profilo di sicurezza del warfarin è probabilmente maggiore nei pazienti con insufficienza renale. In realtà però, uno studio [40] condotto su pz ultraottantenni (range di età 80-102) ha dimostrato che
anche con dicumarolici l’insufficienza renale è correlata con un rischio di sanguinamento statisticamente significativa in pazienti con FG <30 ml/min
rispetto a quelli con FG >60 ml/min, indipendentemente dalla metodica di misurazione del FG. Inoltre,
nel caso fosse usata la FC-G anche un FG di 30-60
ml/min correlava con un rischio significativamente
più alto di sanguinamento maggiore.
In sintesi, le LG [2] raccomandano l’uso dei
NAO con le seguenti modalità:
– Dabigatran per filtrato >30 ml/min con riduzione
di dose a 110 QD con filtrato 30-49 ml/min.
– Rivaroxaban >30 ml/kg/min con riduzione di dose a 15 QD con filtrato 30-49 ml/min.
– Apixaban >30 ml/kg/min con riduzione di dose a
2.5 BID con filtrato 30-49 ml/min.
Viene raccomandata una valutazione basale della funzione renale con successive rivalutazione mediante misurazione del FG 2-3 volte l’anno. Risulta
controindicato l’uso dei NAO nei pazienti con FG
<30 ml/min [2] Al contrario, nelle recenti Linee
Guida AHA/ACC in pazienti con FG 15-30 ml/min
si possono utilizzare, oltre al warfarin, dabigatran 75
mg BID (dosaggio non disponibile in Italia) e rivaroxaban 15 mg QD [43].
Occorre tuttavia specificare che le indicazioni
date dalle Linee Guida AHA/ACC sono basate soltanto su estrapolazioni derivate dal profilo farmacocinetico dei NAO e non sulla base dei risultati dei
trial clinici.
Confronto tra NAO ed antagonisti della
vitamina K: vantaggi e svantaggi nell’oldest old
Se nei pazienti in terapia con antagonisti della
vitamina K la concentrazione ematica di farmaco
può essere monitorata mediante INR con i NAO ciò
non avviene. Le interazioni dei dicumarolici sul metabolismo di farmaci ed alimenti sono numerose e
ben conosciute, mentre non lo sono altrettanto per
quanto riguarda i NAO; è noto che essi sono substrato della glicoproteina P (P-GP, una proteina di
membrana con funzione di pompa di efflusso per xenobiotici coinvolta nei processi di resistenza multifarmaco) e che vengono in parte metabolizzati dal
gruppo CYP (superfamiglia enzimatica di emoproteine fondamentale per la detossificazione degli xenobiotici ed il metabolismo dei farmaci), che pertanto possono modificarne la concentrazione ematica. Esistono inoltre numerosi farmaci il cui metabolismo è modulato da P-GP, quali carvedilolo, amiodarone, clatritromicina, ciclosporina, altiazem, propafenone, simvastatina, verapamil, rosuvastatina,
paclitaxel; non è però noto quanto il metabolismo di
tali farmaci possa influenzare la biodisponibilità dei
NAO, in quanto non sono stati effettuati finora studi
al riguardo eccetto che per volontari sani, le cui caratteristiche in termini di farmacocinetica non sono
ovviamente paragonabili a quelle degli oldest old.
Un ulteriore aspetto che viene valorizzato è
quello della maggiore aderenza terapeutica con i
NAO. Tuttavia per quanto concerne il paziente geriatrico vi sono alcune riserve circa la facilitazione
di utilizzo: secondo scheda tecnica, Dabigatran non
può essere spezzato o “masticato” e questo può rappresentare una criticità nel paziente anziano affetto
da decadimento cognitivo; inoltre Dabigatran non
può essere somministrato per sondino naso-gastrico
o naso-enterico. L’assenza di indicazione a conservazione in comuni dispenser con gli altri farmaci
può infine ulteriormente ridurre la aderenza terapeutica in questa tipologia di pazienti. La breve emivita
di Dabigatran ed Apixaban ne richiede una duplice
assunzione giornaliera, come noto correlata con un
rischio aumentato di incostante assunzione della terapia: il salto di dose può comportare una instabilità
di efficacia terapeutica, i cui effetti possono essere
amplificati in considerazione della difficoltà al monitoraggio ematico del farmaco rispetto agli antagonisti della vitamina K [38]. Il monitoraggio della anticoagulazione che si può rendere necessario in condizioni di urgenza/emergenza è reso difficoltoso dalla notevole variabilità interindividuale della velocità
di eliminazione plasmatica dei NAO in quanto mancano dati farmacocinetici e farmacodinamici, soprattutto nei pazienti molto anziani. Infine, in considerazione della possibilità nell’oldest old di rapida
variazione della funzionalità renale, la mancanza del
monitoraggio dell’effetto anticoagulante potrebbe in
questi soggetti rappresentare un elemento aggiuntivo di rischio [38].
Il problema della aderenza alla terapia nei pazienti anziani si pone per qualsiasi farmaco e diventa prioritario in caso di farmaci salvavita e per di più
gravati da possibili severi effetti indesiderati, come
gli anticoagulanti. La scarsa aderenza alla terapia
farmacologica può essere secondaria a diversi fattori:
157
F. ORSO ET AL.
decadimento cognitivo, assenza di un care-giver, polifarmacologia, difficoltà pratiche nell’assunzione
(ipovisus; disfagia). La Tabella 3 mostra vantaggi e
svantaggi generali della terapia con warfarin, che risultano prioritari nel trattamento del paziente anziano, in quanto tendenzialmente meno compliante, comorboso, trattato con polifarmacologia. La Tabella 4
mostra vantaggi e svantaggi della terapia con NAO,
sempre con riferimento al paziente anziano.
Conclusioni
Deve essere considerata con molta attenzione la
possibilità di generalizzare i risultati dei trial ai pazienti molto anziani e si rendono necessari studi indipendenti di efficacia e sicurezza [44]. Attualmente sono in corso due registri post marketing sugli
outcome dei NAO nella popolazione reale: il GLORIA-AF [45] ed il GARFIELD [46]. Recentemente
la FDA ha pubblicato un primo report post marketing degli eventi emorragici in pazienti in terapia
con Dabigatran versus warfarin, ottenuto tramite dati amministrativi e dati delle assicurazioni: da queste
prime informazioni dal mondo reale non ci sarebbe
evidenza di un aumentato rischio emorragico del
Dabigatran versus warfarin [43].
Al momento attuale si ritiene di poter concludere, estrapolando le principali osservazioni riportate
dagli autorevoli Autori citati nella rassegna, che nell’oldest old:
– Se la terapia con warfarin è gestibile in modo
adeguato, non indicazione a switch a NAO.
– Dabigratan è preferibile se la clearance della
creatinina è > 50 ml/min.
– Apixaban è preferibile se la clearance della creatinina è 30-50 ml/min;
– Rivaroxaban può essere preferibile quando c’è
rischio di ridotta aderenza.
– Sono raccomandabili controlli frequenti della
funzione renale e per ogni variazione dello stato
clinico.
– È indispensabile una estrema cautela in presenza
di comorbilità e/o politerapia.
Riassunto
La Fibrillazione Atriale (FA) è la più comune
aritmia cardiaca e la sua incidenza aumenta all’aumentare dell’età, raggiungendo nell’oldest old
una prevalenza del 10%. I pazienti affetti da FA
presentano un rischio di essere colpiti da ictus cinque volte maggiore rispetto alla popolazione nor-
Tabella 3. - Vantaggi e svantaggi degli antagonisti della vitamina K nell’oldest old
VANTAGGI
SVANTAGGI
Compresse divisibili
Risposta scarsamente prevedibile
Esistenza di antidoto
Necessità di monitoraggio INR e finestra
terapeutica stretta (INR 2-3)
Possibile monitorare efficacia della terapia
con dosaggio INR
Interazioni con numerosi farmaci
Possibile monitorare compliance alla terapia
con dosaggio INR
Interazioni con numerosi cibi
Lenta insorgenza/termine di azione: vantaggio
per pazienti con aderenza non ottimale
Lenta insorgenza/termine di azione: svantaggio
per necessità di bridge therapy iniziale
Tabella 4. - Vantaggi e svantaggi dei NAO nell’oldest old
VANTAGGI
SVANTAGGI
Dosaggio fisso
Assenza di dati su possibilità
di dividere/frantumare le compresse
Non necessario monitoraggio
Assenza di test di laboratorio semplici
per monitorare aderenza alla terapia
Minori interazioni con cibi/farmaci (dati scarsi)
Assenza di antidoto
Rapida insorgenza/termine di azione: vantaggio
per non necessità di bridge therapy
Rapida insorgenza/termine di azione: svantaggio
per pazienti con aderenza non ottimale
Unico dializzabile
Somministrazione BID
Non divisibile (capsule); non dispensabile;
non dati su somministrazione per SNG e PEG
Somministrazione BID
Somministrazione OD
158
male. Le attuali Linee Guida sulla FA raccomandano nei pazienti a medio ed alto rischio di eventi
tromboembolici l’introduzione di terapia anticoagulante orale (TAO). L’età avanzata rappresenta un
fattore di rischio per eventi tromboembolici e malgrado chiare evidenze nei soggetti anziani e molto
anziani esiste una sottoprescrizione di TAO. Fra le
principali cause di questo fenomeno troviamo la
preoccupazione per l’aumentato rischio emorragico in questi pazienti legato a vari fattori quali un
maggior rischio di caduta, una ridotta compliance
e aderenza ai trattamenti, la presenza di comorbilità e polifarmacoterapia. Negli ultimi anni lo scenario internazionale sulla gestione dell’anticoagulazione nella FA ha subito un significativo cambiamento grazie alla disponibilità dei nuovi anticoagulanti orali (NAO): Dabigatran, un inibitore orale della trombina, e due inibitori orali del fattore
Xa, Rivaroxaban e Apixaban, che sono stati testati
in trial clinici randomizzati (RELY, ROCKET-AF e
ARISTOTLE) che hanno dimostrato la non inferiorità rispetto al warfarin nella prevenzione dell’ictus
cardioembolico con un ottimo profilo di sicurezza. I
NAO potrebbero essere un’importante risorsa terapeutica per la prevenzione dell’ictus tromboembolico nei soggetti anziani anche se le differenze in termini di età media, misure antropometriche e comorbilità dei soggetti anziani arruolati nei trial sopracitati e di quelli del mondo reale impongono
cautela e alcune attente riflessioni.
Parole chiave: fibrillazione atriale, nuovi anticoagulanti orali, warfarin, ictus, eventi tromboembolici, anziani.
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2013; 80: 161-169
REVIEW
Vittorio Bianchi1, Alessandro Mezzani2
ABSTRACT: Androgens and cardiac diseases. V. Bianchi,
A. Mezzani.
Although androgens have been considered deleterious
for the cardiovascular system, recent data have demonstrated favourable testosterone effects on cardiac and vascular remodeling and clinical outcome. However, the cardiovascular risk-benefit profile of testosterone therapy remains largely elusive due to lack of well-designed and adequately powered randomized clinical trials. In any case, a
large body of clinical evidence underlines that low plasma
testosterone levels should be considered a risk factor for
cardiovascular disease, and that the evaluation of sex
steroids should be included in the routine clinical evaluation
of cardiac patients. A better understanding of the mechanism regulating the effects of testosterone on cardiovascular
system could lead to novel therapeutic strategies in several
cardiac patient populations, such as chronic heart failure
patients and those who recently underwent cardiac surgery.
Keywords: testosterone, androgens, cardiac disease, cardiovascular risk.
1
2
Clinical Center Stella Maris - Exercise Physiology Laboratory - Falciano - Repubblica di San Marino.
Salvatore Maugeri Foundation, IRCCS - Scientific Institute of Veruno - Cardiac Rehabilitation Division - Exercise Pathophysiology
Laboratory - Veruno (NO) - Italy.
Corresponding author: Dr. Vittorio Bianchi; Clinical Center Stella Maris - Exercise Physiology Laboratory; Strada Rovereta, 42;
I-47891 Falciano, Repubblica di San Marino; Fax: +39-0549942779; E-mail address: [email protected]
Androgens in normal humans
Human androgens comprise testosterone (T), dihydrotestosterone (DHT), androstenedione and dehydroepiandrosterone (DHEA) and its sulfate. Most
of T is secreted by the testis in males and by the
ovary in females. Approximately 5% of serum T is
transformed in DHTby a 5α-reduction process, with
DHT having a threefold greater affinity than T and a
15- to 30-fold greater affinity than adrenal androgens for androgen receptors. DHEA and dehydroepiandrosterone sulfate, the most abundant
adrenal steroids in humans, are precursors of the intracellular production of androgens and estrogens in
non-reproductive tissues. Most T is bound to plasma
proteins, namely, 40-50% to albumin and 50-60% to
sex hormone-binding globulin, with 1-2% being free
[1]. Part of T is converted by the aromatase enzyme
in estradiol, so that T is active through three ways: i)
by directly activating the androgen receptors, ii) by
indirectly activating the androgen receptors as DHT,
and iii) by activating the estrogen receptors α and β
(ERα and ERβ) after conversion to estradiol [2]
(Figure 1).
Androgens and aging
Many cross-sectional studies have demonstrated
lower concentrations of circulating and/or free T in
elderly men [3-6]. The study by Harman [7] is the
largest longitudinal evaluation of the effects of aging on male gonadal hormone function reported to
date, strongly supporting the concept of an age-re-
lated lowering of both total and bioavailable circulating T levels at a relatively constant rate, independently of obesity, illness, medications, cigarette
smoking and/or alcohol intake. Moreover, a
prospective cohort study about endocrine functioning in men found that the decline in total and free
serum T is associated not only to aging, but to
lifestyle as well [8], namely, nutrition and physical
activity. Of note, asymptomatic hypogonadism has a
high prevalence in the general US population, on average equal to 5.6% in men 30-79 years of age, and
increases with increasing age. Hence, the aging of
the western countries male population will likely
cause a large increase of androgen deficiency [9].
Androgens effects on cardiovascular system
Androgens and heart remodeling
Information about the important role played by
the androgen receptors system on cardiovascular
function has been gained by male androgen receptors-knockout mice. Experimental use of these mice
with inactivated androgen receptors has providedinsights into the functional activities of androgens in
adipocytes [10], brain [11], bone [12] and cardiovascular system [13].
Androgen receptors are present in cardiac myocytes of multiple species, including normal men
and women, allowing androgens to modulate the
cardiac phenotype and produce hypertrophy by direct, receptor-specific mechanisms [14]. The studies
of Ikeda [13] demonstrated that in male mice, the
androgen receptors system participates in normal
V. BIANCHI, A. MEZZANI
and platelets as well as in
coronary arteries of monkey
and man [28-31]. In rabbit
aorta, T was found to stimulate the expression of androgen receptors and to inhibit
neointimal plaque formation,
indicating autoregulatory effects [23].
The effects of androgenson vascular functionare still
controversial. It has long
been hypothesized that androgens promote atherosclerosis, and several in vitro and
in vivo studies have shown
that androgens increase expression of atherogenic factors [32-35]. Conversely,
other studies have demonstrated a correlation between
Figure 1. Pathways of testosterone action.
advanced atherosclerosis and
Testosterone directly activates the androgen receptors. In some organs rich of the 5α-reductase enzyme,
low T levels. Muller showed
such as prostate and hair follicles, the effect of testosterone is amplified after transformation in dihydrotethat serum free T concentrastosterone (DHT). Another pathway of testosterone action is through its aromatization into estrogen, that
tions were inversely related
interacts with estrogen receptors α and/or β.
to the mean progression of
intima-media thickness of
the common carotid artery, independently of cardiocardiac growth. Moreover, heart androgen receptors
vascular risk factors [36, 37]. Low plasma T levels
modulate adaptive hypertrophy and fibrosis during
were also associated with endothelial dysfunction
the process of cardiac remodeling under hyperand poor vasodilation of brachial artery in men [38].
trophic stress, and protect the heart from both anT-induced vasodilation was first reported in 1945
giotensin II-induced vascular remodeling [15] and
[39]. This effect involves primarily the vascular
doxorubicin-induced cardiotoxicity [16]. Androgen
smooth muscle cells without requiring the presence
receptors also exist in cardiomyocytes [17] and play
of endothelium, and the rapidity of the response evan important role in the modulation of cardiac hyidences that T acts through a non-genomic way. T
pertrophy and cardiac remodeling after myocardial
induces vasodilation in all arterial beds studied, ininfarction (MI) [18, 19]. Of note, when estrogen levcluding coronary, mesenteric, iliac, renal, and
els are reduced T worsens cardiac dysfunction and
femoral arteries [40], and thevasodilator responsiveremodeling [20]. Grohe [17] demonstrated that the
ness of coronary arteriesis reduced with age [41].
enzyme cyp450 aromatase is expressed in cardiac
The direct infusion of T causes acute coronary vamyocytes, and that the local estrogen biosynthesis in
sodilation, as demonstrated by intracoronary infuthe heart is effective to activate both the receptor
sion of T at physiological concentration in patients
ERα and ERβ. Accordingly, in the myocardium T
with coronary artery disease (CAD) [42, 43] and this
operates both by activation of androgen receptors
concept is supported by numerous experimental
and local aromatization in estradiol acting on ERα
findings both in animals and humans [32, 42, 44].
and ERβ. Many studies have demonstrated the preThe mechanism of T action is the arterial anventive effect of estrogens on myocardial hypertrodrogen receptors mRNA up-regulation, that reduces
phy, while androgens induced cardiac hypertrophy
neointimal plaque formation in male rabbits [23],
[20-22]. These studies evidenced that T and estroassociated with a 50% increase of the amount of angen interact physiologically modulating the effect
drogen receptor mRNA in the arterial segments
on cardiac hypertrophy and contractile function,
treated with T. The beneficial effects of T on postwhich underscores the need to evaluate both T and
injury plaque development underlines, at least in
estrogen circulating levels in the clinical setting.
males, the important role played by androgens in
the vascular system. Physiological levels of DHT
Androgens and vascular function
attenuated the development of atherosclerosis by
A direct effect of T on vascular function is mediandrogen receptor-mediated suppression of the forated by the expression of the androgen receptors in
mation of intimal foam cells by macrophages [45].
vascular cells, which has been demonstrated in rabThe pathophysiological role of androgen receptors
bits, dogs, monkeys and humans [23] in vascular
activity in the cardiovascular system has been studsmooth muscle cells, endothelial cells, macrophages,
ied in male androgen receptors-knockout mice unmegakaryocytes and platelets [24]. In addition, these
der vascular stress [15], that exhibited exaggerated
cells express aromatase and 17β-hydroxysteroid-deangiotensin II-induced medial thickening and
hydrogenase, so that also estradiol can be produced
perivascular fibrosis in the coronary arteries and
locally from both T and DHEA [25-27]. ERα, ERβ
aorta. Furthermore, physiological T supplementaand membrane estrogen receptors are expressed in
tion inhibited cholesterol-enriched diet-induced
endothelial cells, smooth muscle cells, macrophages
162
ANDROGENS AND CARDIAC DISEASES
fatty streak formation in mice with a deletion in the
gene encoding the classical androgen receptor [46].
These data suggest that androgen exerts an atheroprotective effect via androgen receptor-dependent
and -independent signaling.
Androgens and cardiac electrophysiology
The effects of T on cardiac electrophysiology
are poorly described, but evidence is accumulating
about the impact of sex steroids on human cardiac
rhythm and arrhythmias [47]. Charbit [48] showed
that the difference in QT-interval duration between
men and women might be explained by differences
in T levels. An involvement of gonadal steroids in
morphologic differences in ventricular repolarization between males and females has also been hypothesized [47, 49]. A reduced QT dispersion in
heart failure patients treated with T has been observed [50]. Lower QTc intervals in men with higher
serum T levels could be due to the association of
serum T with prolongation of the RR interval [51].
A non-genomic action of T and progesterone on cardiac ion channels likely contributes to gender differences in cardiac repolarization process [52]. Repolarization of canine ventricular myocardium is significantly modified by T, but not by estrogen, in
both genders. This effect is likely due to augmentation of expression of K+-channel proteins, and thus
may provide protection against arrhythmias via increasing the repolarization reserve [53]. The protective role of T in male hearts has been evidenced by
[54] and Bigi [55], who demonstrated a QTc interval
≤380 ms among professional bodybuilders abusing
of anabolic steroids.
Coronary risk factors
T plays an important role in metabolism regulation. Low T levels are associated with obesity,
metabolic syndrome and diabetes in men [56, 57],
and are now recognized as an independent risk factor for such diseases [58]. T replacement improves
glycemic control, visceral adiposity and hypercholesterolemia in hypogonadal men with type 2 diabetes [59]. High T levelsare associated to a low incidence of type 2 diabetes in men, but not in women
[60]. In a recent review, the current knowledge on
the metabolic actions of T, the effects of T deficiency on obesity, metabolic syndrome and type 2
diabetes and the role of T replacement are discussed
[61]. In older men, lower total T is associated with
insulin resistance independently of measures of
central obesity [62]. T is also involved in lipid
homeostasis in insulin-responsive tissues, such as
liver, adipose tissue and skeletal muscle [63].
Coronary artery disease and estrogens
CAD is the leading cause of death worldwide
for both men and women [64], with the prevalence
of CAD being significantly higher and the life expectancy significantly shorter in men as compared
to women [65]. Historically, the different prevalence of CAD between men and women has been
interpreted as an estrogen-induced protective effect
against atherosclerosis. This concept has been
challenged by randomized clinical trials testing the
effects of combined estrogen/progestin therapy in
post-menopausal women, that showed no benefits
as to CAD incidence [66, 67]. Furthermore, hormone replacement strategies in postmenopausal
women have been associated with an increased risk
of breast and endometrial malignancy and thromboembolic disease with resulting increased mortality. In a study conducted on 2763 postmenopausal
women, the treatment with oral conjugated equine
estrogen plus medroxyprogesterone acetate for 4.1
years did not reduce the overall rate of CAD events
[66]. In addition, a recent review showed that, in
elderly postmenopausal women with established
CAD, daily use of conjugated equine estrogen and
combination of medroxyprogesterone acetate plus
estrogen did not reduce the overall risk of MI and
coronary death during an average follow-up of 4.1
years [68]. In men, estrogen plasma level is related
to the incidence of CAD [69].
Coronary artery disease and androgens
The effects of androgens on CAD are even more
controversial. Previous studies have evidenced an
increased risk of cardiovascular risk in all ages in
men after administration of T [70-72]. A correlation
between the use of androgens and MI has been reported in body-builders using supraphysiological
doses of androgens [73-81]. Such doses of androgens were considered toxic on the cardiovascular
system [82, 83, 84], but no clear evidence about an
epidemic of acute cardiac events has been associated
with the increase of anabolic steroids abuse during
the last decades [85, 86].
Despite these reports, an increasing body of
literature indicates that men with CAD have significantly lower T levels than those without CAD.
An increased development of atherosclerosis has
been shown in male animals after castration and
reversedwith androgen replacement therapy [46]
(see above ‘Androgens and vascular function’).
The relationship between serum T level and CAD
in humans has been evaluated in a complete review by Wu [87]. Thirty-two cross-sectional studies were analyzed; in 16 studies, a lower level of T
was found in patients with CAD as compared to
controls, whereas other 16 studies showed no differences in T level between patients and controls.
The Caerphilly Heart Study enrolled 2512 men
[88], showing a modest reduction in T in survivors
of MI. The association, however, became not significant when adjusted for plasma insulin and
triglycerides. Conversely, Phillips [89] demonstrated a significant relationship between low free
T level and the degree of coronary occlusion in 55
men undergoing angiography. Another study on
900 men found that both total and bioavailable T
were significantly lower in men with CAD than in
those without [90]. Similar results were reported
by Dunajska [91], who showed that men with
CAD had lower total T levels, T/estradiol ratio and
free androgen index as compared to controls;
moreover, men with CAD were more insulin-resistant than controls and had an atherogenic lipid
profile. A positive association between low serum
androgen levels and severe internal carotid artery
163
atherosclerosis in men has been evidenced by Debing at al. [92], suggesting a protective role of
physiological levels of androgens from the development of atherosclerosis. Similar results have
been evidenced in the study of health in Pomerania [93] and further confirmed recently [94, 95].
In women, the relationship between androgen
level and CAD has been poorly investigated. In
women with polycystic ovary syndrome, two longterm longitudinal studies showed no significant increase of CAD incidence [96]. High free T and androstenedione levels within the physiological range
have also been correlated with reduced carotid
artery atherosclerosis in premenopausal and postmenopausal women [97]. More recently, in postmenopausal women decreased T levels have been
found to be associated with CAD independently of
other risk factors. Hormonal replacement therapy
tends to increase T level, which may further support
the beneficial role of hormone replacement therapy
in postmenopausal women [98]. Evidence of a positive association between low serum androgen levels
and severe internal carotid artery atherosclerosis in
postmenopausal women has been provided, and suggests that higher, but still physiological, levels of androgens in postmenopausal women have a protective role from the development of CAD [99]. He
[100] showed a more complex interaction between
sex hormones and CAD. In both men and postmenopausal women with angiographic CAD, there
were significant differences (relative to age-matched
control subjects) in sex hormone ratios, suggesting
that an abnormality in sex hormones could influence
coronary health. A lower estradiol-to-progesteron
ratio was associated with the predisposition to coronary atherosclerosis in males, whereas lower estradiol-to-progesteronand estradiol-to-T ratios were associated with the same condition in females.
Angina pectoris
Several studies have demonstrated the effect of
T therapy in angina pectoris and are reported in
Table 1. The first studies were reported in 1942 by
Hamm [101] and Walker [102]. These authors
showed that T supplementation in patients with
angina pectoris produced significant clinical improvement, reduced cardiac symptoms and increased time to ischemia. These date have been confirmed recently [103]. English [104] found that lowdose supplemental T reduces exercise-induced myocardial ischemia in men with chronic stable angina.
Long-term benefits of T therapy were observed during 12 months of treatment in men with low T levels and angina; T increased time to ischemia without
side effects [105]. In a randomized study on 50 men
with exercise-induced ST segment depression, Jaffe
[106] showed that a treatment with T cypionate, 200
mg intramuscularly weekly, significantly reduced
ST segment depression after 8 weeks of treatment;
no effects were observed in the placebo group. In a
crossover study, conducted on 62 men with ischemic
heart disease treated with T undecanoate or placebo
[107], angina pectoris was relieved by 77% and myocardial ischemia in ECG and Holter recordings was
reduced by 69% and 75%, respectively. Moreover,
administration of low doses of T in men with
chronic stable angina reduced exercise-induced myocardial ischemia [104], resulting in an increase in
time to 1-mm ST-segment depression after 12 weeks
of treatment.
Myocardial infarction
A limited number of studies are available on the
relationship between T levels and MI. After MI in
male patients, a transient decrease in T has been observed [112]. Chronic T administration showed no
detrimental effects on left ventricular remodeling
Table 1. - Effect of testosterone treatment in men with coronary artery disease
Chronic administration
Acute administration
Patient
n.
Dosage
Treatment
duration
Clinical
effect
Hamm L 101
7
75 mg/week
1/2 months
⇑
Walker TC 102
12
100 → 10 mg/day
4 months
⇑
Sigler LH 108
16
50 mg/week
6/7 weeks
⇑
Jaffe MD 106
50
200 mg/week
2 months
⇑
Wu SZ 107
62
40-120 mg/day
1 month
⇑
English KM 104
46
5 mg/day
3 months
⇑
Mathur A 105
15
1 g/3 months
12 months
⇑
Webb CM 109
14
2.3 mg i.v.
10 min
⇑
Rosano GM 110
14
2.5 mg i.v.
5 min
⇑
Thompson PD 111
32
2-6 times baseline
plasmatic level
20 min
–
The clinical effect cumulates the reduction of the number of anginal episodes and both the prolongation of time to and the
increase of heart rate at ischemic threshold during ergometric stress test.
⇑ = clinical improvement; - = no effect.
164
after MI [113]. In a study conducted on 65 regularly menstruating women aged 33-48 years with
recent MI, a significantly higher concentration of T
was found in women with a family history of CAD
than in those without [114]. Due to the young age
of these women, data are not conclusive and need
verification.
Chronic heart failure
Several authors have considered the effects of T
administration in chronic heart failure (CHF) patients at physiological doses, evidencing positive
clinical outcomes [115-119]. In patients with CHF, a
low level of plasma T has been observed [120-122].
Particularly, CHF due to idiopathic dilated cardiomyopathy is associated with a significant decrease in growth hormone, insulin-like growth factor 1 and T concentrations [122], underlying the
concept that a catabolic state is strictly related to this
clinical condition. Wehr [123] showed that low free
T level is independently associated with increased
CHF mortality, with no association with total T levels. The T treatment in men with CHF determined a
significant improvement in exercise capacity and
symptoms [115]. Anabolic hormones (T, DHEA sulfate, insulin-like growth factor 1) are related to
physical capacity in healthy men, and in CHF patients low circulating T are independent predictors
of exercise intolerance [124].
In a randomized double-blind placebo-controlled trial, T administration for a 12-month period
in men with moderate-to-severe CHF was associated to an improvement in exercise capacity and
symptoms, without changes in muscular strength
[115]. In a similar protocol, T replacement was studied in men with moderate-to-severe CHF; T therapy
improved exercise capacity and NYHA class compared with placebo [117]. Pugh [118] demonstrated
that the administration of T increases cardiac output
acutely, apparently via a reduction of left ventricular
afterload. In a recent review [125], T appears to be a
promising therapy to improve exercise capacity in
patients with CHF. Caminiti [116] showed that longacting T therapy improves exercise capacity, muscle
strength, glucose metabolism and baroreflex sensitivity in men with CHF. T therapy improved both
peak VO2 and ventilatory efficiency, as assessed by
the VE/VCO2 slope.
T benefits seem to be mediated by metabolic and
peripheral effects. Recently, T supplementation has
been used in a 12-week program of exercise rehabilitation in elderly male patients with CHF and a low
T status,positively impacting on a range of key
health outcomes [126]. Iellamo [119] showed that
women with stable CHF who received T transdermal patch, improved functional capacity, insulin resistance and muscle strength without side effects. In
a recent meta-analysis, Toma [125] observed that T
appears to be a promising therapy to improve exercise capacity in patients with CHF.
Testosterone and prognosis
Recent epidemiological studies revealed that
low T levels in men were associated with higher
cardiovascular mortality rates [90, 127-131]. Low
plasma level of T and estradiol predict mortality in
elderly men [129]. Furthermore, anti-androgen
therapy in men affected by prostate cancer is associated with significant increases in the risk of CAD
and incident heart failure [132]. Moreover, in men
treated by orchiectomy, a twofold increase of CAD
mortality over a 10-year period has been demonstrated [133].
Shores [134], using the Veteran’s Affairs clinical database, reported that men with low T level had
a 88% relative increase in all-cause mortality risk
when compared with those with normal T levels,
and concluded that hypotestosteronemia was a
marker of increased mortality risk. An increased
risk of death associated with the decline in anabolic
hormone levels during a 6-year follow-up was reported in the InChianty study [135]. Laughlin [128]
studied a group of 794 men for 20 years, and found
that the risk of death was 44% greater between the
lowest and highest quartiles of total T after adjusting for age, adiposity and lifestyle choices. The European Prospective Investigation in Norfolk [127]
investigated all-cause and cardiovascular mortality
in 11606 healthy men between 40 and 79 years of
age, observing a statistically significant association
between baseline serum T level and all-cause, cardiovascular- and cancer-related death. The authors
concluded that T concentrations are inversely related to cardiovascular and all-cause mortality. Recently, Malkin [90] followed 930 men with angiographycally proven CAD over a 7-year period, and
found that in androgen-deficient men the mortality
was 21% versus 12% in the eugonadal group. Furthermore, the biological available T – and not total
T – was significantly associated to all-cause and
cardiovascular mortality (Figure 2). This data suggest that bioavailable T is the most sensitive assay
for mortality risk stratification.
Figure 2. - Survival curves of all-cause mortality based on bio-available
testosterone (Bio-T) levels.
The solid line represents patients with baseline Bio-T less than 2.6 nmol/l,
the broken line represents patients with Bio-T greater than 2.6 nmol/l.
Follow-up duration was 6.9±2.1 years.
HR = hazard ratio.
Reproduced with permission from Malkin [90].
165
Conclusions
Although androgens have been considered deleterious for the cardiovascular system, recent data
have demonstrated favorable T effects on cardiac and
vascular remodeling and clinical outcome. However,
Ruige [136] in a recent review affirms that the cardiovascular risk-benefit profile of T therapy remains
largely evasive in view of a lack of well-designed
and adequately powered randomized clinical trials.
Discrepancies between studies might be explained
by differences in methodology, dose and duration of
T administration, and effects of other important hormones, such as estrogens and insulin-like growth
factor 1. In any case, a large body of clinical evidence underlines that low plasma T levels should be
considered a risk factor for cardiovascular disease,
and that the evaluation of sex steroids should be included in the routine clinical evaluation of cardiac
patients. A better understanding of the mechanism
regulating the effects of T on cardiovascular system
could lead to novel therapeutic strategies in several
cardiac patient populations, such as CHF patients
and patients who recently underwent cardiac surgery.
2.
3.
4.
5.
6.
7.
8.
Riassunto
Sebbene gli androgeni siano stati considerati
dannosi per il sistema cardiovascolare, dati recenti
hanno dimostrato effetti favorevoli del testosterone
sul rimodellamento cardiaco e vascolare e sulla
prognosi. Tuttavia, il rapporto rischio-beneficio
cardiovascolare della terapia con testosterone rimane elusivo per la mancanza di trial clinici randomizzati ben disegnati e dotati di adeguata potenza statistica. In ogni caso, una notevole evidenza
clinica suggerisce che bassi livelli di testosterone
plasmatico dovrebbero essere considerati un fattore
di rischio cardiovascolare, e che il dosaggio degli
steroidi sessuali dovrebbe essere incluso nella routine clinica dei pazienti cardiopatici. Una miglior
comprensione dei meccanismi che regolano gli effetti del testosterone sul sistema cardiovascolare
potrebbe condurre a nuove strategie terapeutiche in
molte popolazioni di pazienti cardiopatici, quali
quelli con scompenso cardiaco cronico e quelli recentemente sottoposti a cardiochirurgia.
Parole chiave: testosterone, androgeni, cardiopatia, rischio cardiovascolare.
9.
10.
11.
12.
13.
14.
15.
ABBREVIAZIONI
T = testosterone
DHT = dihydrotestosterone
DHEA = dehydroepiandrosterone
ERα = estrogen receptors α
ERβ = estrogen receptors β
MI = myocardial infarction
CAD = coronary artery disease
NYHA = New York Heart Association
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ORIGINAL ARTICLE
Epicardial adipose tissue and insulin resistance
in patients with coronary artery disease
with or without left ventricular dysfunction
Tessuto adiposo epicardico e insulino resistenza
in pazienti con cardiopatia ischemica cronica
con o senza disfunzione ventricolare sinistra
Samuele Baldasseroni, Alessandra Pratesi, Francesco Orso, Claudia Di Serio,
Alice Foschini, Andrea Giosafat Marella, Nadia Bartoli, Mauro Di Bari, Stefano Fumagalli,
Niccolò Marchionni, Francesca Tarantini
ABSTRACT: Epicardial adipose tissue and insulin resistance
in patients with coronary artery disease with or without left
ventricular dysfunction. S. Baldasseroni, A. Pratesi, F. Orso,
C. Di Serio, A. Foschini, A.G. Marella, N. Bartoli, M. Di Bari,
S. Fumagalli, N. Marchionni, F. Tarantini.
Background. Epicardial adipose tissue (EAT) is a visceral fat that fulfills two important functions: lipid-storage
and secretion of adipokines with pro-inflammatory and
pro-atherogenic properties. It has been suggested that EAT
may affect the pathogenesis of atherosclerosis and the clinical course of coronary artery disease (CAD). In patients
with obesity, diabetes and metabolic syndrome, the epicardial adipose tissue is enlarged. Little is known about the
role of EAT in left ventricular dysfunction. Aim of this
study was to evaluate the ability of insulin resistance to predict EAT thickness in patients with significant CAD and
systolic dysfunction.
Methods. We enrolled 114 subjects diagnosed with CAD
by angiography. The majority underwent revascularization
after an acute coronary syndrome. Patients were considered
affected by significant left ventricular dysfunction when EF
was )40%. Three indexes of insulin resistance, the HOMA IR
index, the insulin sensitivity QUICKI index, and the novel
adiponectin/resistin index (ADIPO-IRAR) were calculated and
correlated to EAT thickness. Epicardial fat was measured by
echocardiography according to standardized methods.
Results. Subjects with diabetes and with a history of hypercholesterolemia had thicker EAT compared to controls.
Potassium levels and all three indexes of insulin resistance
were the best independent predictors of EAT in the study
population as a whole and in the subset of patients with left
ventricular dysfunction. In the latter group the novel
ADIPO-IRAR index displayed the strongest predictivity.
Conclusion. Insulin resistance is an independent predictor of EAT thickness in patients affected by CAD, also in the
presence of significant left ventricular dysfunction
Keywords: epicardial fat, insulin resistance, coronary
artery disease, adipokine, left ventricular dysfunction.
Department of Clinical and Experimental Medicine, Geriatric Cardiology and Medicine Unit, University of Florence; Azienda
Ospedaliero-Universitaria Careggi, Florence (Italy).
Corresponding author: Samuele Baldasseroni MD, PhD; Department of Heart and Vessels; Geriatric Cardiology and Medicine
Unit; University of Florence and Azienda Ospedaliero-Universitaria Careggi; Viale Morgagni 85, I-50134 Florence, Italy; Phone:
+39 0554271472; Fax: +39 0554271469; E-mail address: [email protected]
Introduction
Epicardial adipose tissue (EAT) is a visceral fat
located between the outer layer of the myocardium
and the visceral pericardium. It is mainly concentrated in the atrioventricular and interventricular
grooves, along the major branches of the coronary
arteries, and, to a minor extent, around the atria,
over the free wall of the right ventricle and the apex
of the left ventricle [1]. In physiologic conditions,
EAT fulfills two important distinct functions: lipidstorage and secretion of hormones and peptides. Indeed, EAT may be considered an endocrine organ,
capable of producing and releasing several bioactive
adipokines, as well as pro-inflammatory and proatherogenic cytokines [2]. However, EAT also pro-
duces anti-inflammatory and anti-atherogenic
adipokines [3]. It is well known that EAT shares
with the myocardium the same microcirculation
and, given its proximity to the heart muscle and to
the adventitia of the coronary arteries, it is believed
to affect the pathogenesis of atherosclerosis and the
clinical course of coronary artery disease (CAD) [4].
In healthy people, epicardial fat has been measured with different radiological tools. Iacobellis et
al. [5] using standardized echocardiography found
that thickness of epicardial fat, measured at any
site over the right ventricular free wall, varied between 1.8 and 16.5 mm. EAT can be assessed also
by Multidetector Computerized Tomography and
by Magnetic Resonance Imaging (MRI) which, despite a lower spatial resolution and higher costs, is
EPICARDIAL ADIPOSE TISSUE AND INSULIN RESISTANCE IN PATIENTS WITH CORONARY ARTERY DISEASE WITH OR WITHOUT LEFT VENTRICULAR DYSFUNCTION
considered the gold standard [6]. EAT assessed by
echocardiography correlates well with the extent of
visceral fat evaluated by MRI, but it is only weakly
related to body mass index or waist circumference
[6, 7].
In the general population, EAT correlates negatively with markers of insulin sensitivity [8] and
positively with markers of insulin resistance [7]; in
addition, it is significantly more abundant in subjects with metabolic syndrome [6, 7].
As mentioned above, emerging evidence suggests that EAT could play a role as risk factor for the
development of CAD, its severity and vulnerability
of atherosclerotic plaques [9, 10]. However, little is
known about the role of epicardial fat in left ventricular dysfunction. Studies on healthy subjects
have demonstrated that more abundant EAT correlates significantly with greater left ventricular mass
[11]. In a study evaluating epicardial fat volume
(EFV) with CT scan, subjects with left ventricular
dysfunction had significantly lower EFV than subjects with preserved function [12]. Even when EAT
was assessed volumetrically by cardiovascular MRI,
subjects with ventricular dysfunction showed lower
amount of EAT compared to healthy controls [13].
Aims of this study were: 1) to evaluate three different indexes of insulin resistance for their ability
to predict EAT thickness in patients with CAD and
2) to test their predictive power in a subgroup of patients with left ventricular dysfunction.
Methods
Study subjects: 114 patients referred to the Cardiac and Diabetic Outpatient Clinic of the Geriatric
Cardiology and Medicine Unit of Careggi Academic Hospital (Florence, Italy) were enrolled, provided that they met the following inclusion criteria:
willing to give written informed consent, previously diagnosed with CAD by angiography (with at
least one *75% stenosis of a major epicardial
branch), clinically stable (Canadian Cardiovascular
Society Angina score )1) with no hospitalization
for worsening HF or need for an increased dosage
of the current cardiac drug therapy, during the last
two months. The study was approved by an institutional review committee, according to the Helsinki
declaration.
Clinical and instrumental data: patients underwent a thorough clinical history, including reporting of symptoms needed to define New York Heart
Association (NYHA) class, physical examination
with measurement of height and weight to calculate
body mass index (BMI) and waist circumference,
12-lead electrocardiogram (ECG), and 6-minute
walking test (6-WT) according to the Guyatt’s protocol [14]. A standard echocardiographic study was
carried out following the American Society of
Echocardiography recommendations [15]. Heart
failure (HF) was considered to be overt in the presence of positive European Society of Cardiology
criteria [16], associated with a Boston score *5
[17], and significant left ventricular systolic dysfunction was defined as ejection fraction (EF)
)40%. Type 2 diabetes mellitus was diagnosed according to ADA-WHO criteria [18].
Biochemical data: venous blood samples were
drawn in the fasting state to measure glycaemia, insulinemia, glycated hemoglobin (HbA1c) - determined by high liquid pressure chromatography
method (Menarini Diagnostics, Florence, Italy; upper normal limit 5.9%), hemoglobin, electrolytes,
uric acid, serum albumin, total and fractional cholesterol, and triglycerides. Glomerular filtration rate
was estimated according to the Modification of Diet
in Renal Disease (MDRD) Study method (eGFR).
Adipokines and indexes of insulin resistance:
circulating plasma resistin and total adiponectin
were determined, in duplicate, by ELISA (Linco Research, Missouri, USA). Three insulin resistance indexes were calculated, the HOMA IR index [19], the
insulin sensitivity QUICKI index [20], and the novel
adiponectin/resistin index (ADIPO-IRAR) [21] defined as follows:
Log10 (I0*G0)+ [Log10 (I0*G0) Log10 (R0/A0)
where I0 is fasting serum insulin, G0 fasting plasma
glucose, R0 fasting resistin level and A0 total fasting
adiponectin level.
Measurement of EAT thickness: each subject underwent two-dimensional transthoracic echocardiography (Acuson Sequoia 512® Ultrasound with 3
MHz transducer; Siemens, Mountain View, California, USA); standard parasternal and apical views
were obtained in the left lateral decubitus position.
Epicardial fat was identified as the echo-free space
between the linear echo-dense parietal pericardium
and the right ventricular epicardium and its thickness was measured perpendicularly on the free wall
of the right ventricle, at end-systole, in three cardiac
cycles, according to Jacobellis method [5].
Statistical analysis: data were analyzed using
SPSS® software (version 18); results are expressed
as mean±SD and as percentage for continuous or
categorical variables, respectively. Statistical comparisons were carried out with Student t-test or with
chi-square test when necessary. Correlations were
analysed with Pearson R-test for variables with normal distribution and with Spearman R-test for those
with not normal distribution. Variables significantly
associated with EAT thickness at univariate analysis, were entered in three multivariable stepwise
backward linear regression models, one for each
predefined index of insulin resistance (HOMA,
QUICKI, and ADIPO IRAR indexes). Among variables with independent predictive value but similar
clinical significance, only one was introduced in the
model, to avoid co-linearity; parameters comprised
in the mathematical formula of insulin resistance indexes were excluded. Multivariable models were
tested in the study population as a whole and in the
subgroup of patients with left ventricular systolic
dysfunction. A p value less than 0.05 was considered statistically significant.
Results
Clinical characteristics of the study population
are reported in Table 1. Fifty percent of the subjects
had type 2 diabetes mellitus; 15% was in NYHA
class III-IV. Mean EAT thickness was 7.8 mm. Renal function and biohumoral variables were within
normal, or near normal, range (Table 1).
171
S. BALDASSERONI ET AL.
Table 1. - Clinical, echocardiographic and biohumoral
characteristics of the study population: continuous
variables are expressed as mean ± SD and categorical
variables as number (percentage)
n=114
Age, yrs
66.7 ± 10.7
Female gender
16 (14.0)
BMI (Kg/m2)
27.3 ± 4.1
Waist circumference (cm)
100.9 ± 11.8
Previous myocardial infarction
93 (81.6)
Previous angina
50 (43.9)
Previous stroke
8 (7.0)
The glycometabolic profile of the study population is summarized in Table 2. Mean values of insulinemia, glycated hemoglobin, plasma adipokines
concentrations and insulin resistance indexes are in
agreement with 50% of the population being affected by diabetes.
Subjects with diabetes (Figure 1) and with a history of hypercholesterolemia (Figure 2) had significantly higher values of EAT thickness when compared to non-diabetics and non-hypercholesterolemic control subjects.
Table 2. - Glycometabolic profile of the study population
n=114
Hypertension
80 (70.2)
Glycemia (mg/dl)
122.1 ± 48.4
Hypercholesterolemia
83 (72.8)
Insulinemia (pmol/l)
19.4 ± 30.1
Smokers
59 (51.6)
Previous CABG
33 (29.8)
Previous PCI
90 (78.9)
Left main coronary artery pathology
12 (10.5)
Three vessels disease
Atrial fibrillation
Hb1AC (%)
6.8 ± 1.3
Resistin level (ng/ml)
10.7 ± 5.7
Total adiponectin level (ng/ml)
8.9 ± 6.7
43 (37.7)
HOMA index
5.7 ± 7.9
20 (17.5)
QUICK index
0.32 ± 0.04
Diabetes
57 (50.0)
ADIPO-IRAR index
COPD
12 (10.5)
PAD
19 (16.6)
ADIPO-IRAR, Adipose tissue Insulin Resistance adiponectin/
resistin index; Hb1AC, glycated hemoglobin; HOMA-IR,
HOmeostatic Model Assessment- Insulin Resistance; QUICKI,
QUantitative Insulin sensitivity ChecK Index.
Distance at 6-WT (m)
NYHA class III-IV
436.8 ± 170.2
3.6 ± 1.4
17 (14.9)
Echocardiographic variables
Septal thickness (mm)
9.8 ± 2.1
Posterior wall thickness (mm)
10.2 ± 3.2
LV end systolic volume (ml/m2)
82.0 ± 28.7
LV end diastolic diameter (ml/m2)
47.9 ± 26.6
Ejection fraction (%)
44.9 ± 15.2
IVRT (msec)
90.2 ± 23.9
E/A ratio
1.2 ± 1.0
Tdec (msec)
245.0 ± 277.3
Myocardial mass (gr/m2)
126.3 ± 36.5
EAT thickness (mm)
7.8 ± 3.1
Biohumoral variables
eGFR (ml/min/1.73m2)
74.0 ± 24.8
Hemoglobin (g/dl)
13.6 ± 1.5
Potassium (meq/l)
Sodium (meq/l)
Uric acid (mg/dl)
Albumin (gr/l)
EAT, epicardial adipose tissue
4.3 ± 0.6
139.7 ± 10.1
6.6 ± 5.6
3.8 ± 0.5
Total cholesterol (mg/dl)
169.3 ± 37.9
HDL cholesterol (mg/dl)
44.8 ± 12.6
LDL cholesterol (mg/dl)
96.2 ± 30.6
6-WT, 6-minute walking test; BMI, body mass index; CABG,
coronary artery by-pass graft; COPD, chronic obstructive
pulmonary disease; EAT, epicardial adipose tissue; IVRT,
isovolumic relaxation time; LV, left ventricular; NYHA, New
York Heart Association; PAD, peripheral artery disease; PCI,
percutaneous coronary intervention; Tdec, deceleration time.
172
Figure 1. - Difference of EAT thickness (mm) between diabetic and
non-diabetic patients.
Figure 2. - Difference of EAT thickness (mm) between hypercholesterolemic and non-hypercholesterolemic patients.
EAT, epicardial adipose tissue
Univariate analysis: clinical, echocardiographic and biohumoral variables that showed a
significant association with EAT thickness are reported in Table 3. Insulinemia, adiponectinemia and
all three indexes of insulin resistance showed a significant association with EAT, with adiponectinemia and QUICKI index displaying an inverse correlation (Table 4).
Table 3. - Association between clinical, echocardiographic and biohumoral variables and EAT thickness
R
p
BMI
0.31
0.001
Waist circumference
0.34
<0.001
6-WT
–0.26
0.005
Potassium
0.28
0.005
Septal thickness
0.24
0.011
Tdec
0.20
0.041
6-WT, 6-minute walking test; BMI, body mass index; Tdec,
deceleration time.
Table 4. - Association between glycometabolic variables
and EAT thickness
R
p
Insulinemia
0.38
<0.001
Total adiponectin
–0.19
0.023
HOMA index
0.26
0.008
QUICKI index
–0.33
0.001
ADIPO-IRAR index
0.28
0.006
ADIPO-IRAR, Adipose tissue Insulin Resistance adiponectin/
resistin index; HOMA-IR, HOmeostatic Model AssessmentInsulin Resistance; QUICKI, QUantitative Insulin sensitivity
ChecK Index.
Multivariable analysis: the multivariable regression models for the population as a whole (Panel A)
and for patients with left ventricular dysfunction
(Panel B) are reported in Table 5. At multivariate
analysis, all three indexes of insulin resistance maintained their independent predictive value in both
populations. When we considered the study population as a whole (Panel A), plasma potassium level
was an independent predictor of EAT thickness,
whereas in the subset of subjects with left ventricular dysfunction (Panel B), potassium maintained its
predictive power only in Model 3; deceleration time
of mitral E wave (Tdec) was an independent predictor of EAT thickness in Models 1 and 2.
Discussion
In our population, the mean value of EAT thickness was 7.8 mm, significantly higher than that
found by Eroglu et al. [22] who established a value
of 5.2 mm as the cut-off of epicardial fat thickness
for association with CAD. Nevertheless, if we consider their subgroup of patients with significant
coronary artery disease (two and three-vessel disease), which is more similar to our study population,
the two values are almost identical.
However, unlike other reports [23], we did not
find an association between epicardial fat thickness
and severity of CAD defined by the number of coronary arteries affected by at least 75% stenosis or by
the number of site of percutaneous/grafting revascularization. This result confirms that the role of EAT
as a marker of CAD severity is everything but established and, probably, is greatly influenced by the
method used to define disease severity itself [23].
Nonetheless, it is highly likely that epicardial fat
may influence the evolution of coronary atherosclerosis, through the production of many pro-atherogenic cytokines able to modify plaque composition,
vulnerability and stability [9, 32].
We found that diabetic patients had a higher
EAT thickness compared to those without diabetes.
This data is in accordance with several literature reports which also show that increased EAT thickness
in diabetic subjects is related to the presence of
higher visceral adiposity and body mass index, and
longer waist circumference [24].
We also clearly demonstrated that, independently from the type of index we used to define the
glycometabolic profile, insulin resistance and serum
potassium level were the strongest, independent predictors of EAT thickness, irrespective to the presence of diabetes. This result is not surprising if we
consider that kalemia is strictly linked to peripheral
insulin sensibility, since insulin stimulates K+ cellular uptake in skeletal muscles and other tissues, including liver and adipose tissue [25].
The association of EAT thickness with insulin
resistance has been recognized already in obesity
and type 2 diabetes [8]; in addition, the power of
EAT to predict the presence of metabolic syndrome
has been well established [7] in a large observational
study of 246 patients, undergoing standardized
echocardiography, in which waist circumference
and HOMA-IR index were the best predictors of
epicardial fat thickness.
The correlation between insulin resistance and
epicardial fat in patients with CAD, with or without
myocardial revascularization, has been less studied.
Ahn et al. [26], in a large Asian population affected
by CAD in which the severity of disease was established by coronary angiography, found that HOMA
score displayed only a weak association with EAT;
conversely, a good correlation was found with visceral adiposity. However, in that study patients with
prior myocardial revascularization, heart failure,
cardiomyopathy and acute myocardial infarction
were excluded, and the HOMA score was tested
only in non-diabetic patients. In our study, three different indexes of insulin resistance were tested in a
Caucasian population with CAD, almost entirely
revascularized and with a large percentage of type 2
diabetic patients. Insulin resistance showed a strong
correlation with EAT, independently from the type
of index we used to define it. Moreover, this is the
first time that the new ADIPO-IRAR index was
173
Table 5. - Multivariable stepwise backward linear regression models (EAT thickness as continuous dependent variable) Panel A (whole study population)
Model 1
R2=0.25,
Model 2
R2=0.29
Model 3
R2=0.28
Beta; p value
Beta; p value
Beta; p value
Age
0.06; p=0.682
0.16; p=0.164
0.03; p=0.843
Gender
–0.02; p=0.866
0.04; p=0.736
0.03; p=0.840
Waist circumference
0.06; p=0.652
0.01; p=0.952
0.05; p=0.787
Type 2 diabetes
0.09; p=0.466
0.03; p=0.805
0.18; p=0.169
0.08; p=0.514
0.04; p=0.751
0.09; p=0.436
Potassium
0.42; p<0.001
0.40; p<0.001
0.35; p=0.005
6-WT
–0.15; p=0.211
–0.08; p=0.566
–0.24; p=0.047
Septal thickness
0.12; p=0.311
0.10; p=0.374
0.12; p=0.313
Tdec
0.16; p=0.177
0.13; p=0.226
0.14; p=0.244
HOMA index
0.26; p=0.021
QUICKI index
–0.34; p=0.002
ADIPO-IRAR index
0.28;p=0.016
6-WT, 6-minute walking test; ADIPO-IRAR, Adipose tissue Insulin Resistance adiponectin/resistin index; HOMA-IR, HOmeostatic
Model Assessment- Insulin Resistance; QUICKI, QUantitative Insulin sensitivity ChecK Index; Tdec, deceleration time.
Table 5. - Multivariable stepwise backward linear regression models (EAT thickness as continuous dependent variable) Panel B (patients with left ventricular systolic dysfunction, EF )40%)
Model 1
R2=0.32
Model 2
R2=0.38
Model 3
R2=0.35
Beta; p value
Beta; p value
Beta; p value
Age
–0.21;p=0.680
–0.18; p=0.738
0.29; p=0.241
Gender
–0.25; p=0.342
–0.27; p=0.291
–0.34; p=0.188
Waist circumf.
–0.23; p=0.323
–0.14; p=0.597
–0.28; p=0.184
Type 2 diabetes
0.18; p=0.508
0.20; p=0.439
0.03; p=0.911
–0.18; p=0.505
–0.23; p=0.429
0.05; p=0.834
Potassium
0.08; p=0.848
0.07; p=870
0.61; p=0.016
6-WT
–0.28; p=0.353
–0.27 p=0.295
–0.04; p=0.966
Septal thickness
–0.36; p=0.123
–0.20; p=0.374
–0.03; p=0.913
Tdec
0.47; p=0.061
0.51; p=0.038
0.24; p=0.294
HOMA index
0.47; p=0.060
QUICKI index
ADIPO IRAR index
–0.54; p=0.028
0.69; p=0.008
6-WT, 6-minute walking test; ADIPO-IRAR, Adipose tissue Insulin Resistance adiponectin/resistin index; HOMA-IR, HOmeostatic
Model Assessment- Insulin Resistance; QUICKI, QUantitative Insulin sensitivity ChecK Index; Tdec, deceleration time.
174
demonstrated to predict epicardial fat thickness. In
our opinion, this index is quite attractive because
hypo-adiponectinemia and hyper-resistinemia have
been associated with the glycometabolic profile and,
recently, also with CAD [27]; therefore, this index
summarizes well the contribution of both adipokines
to the insulin resistance biological profile.
Another critical finding of our study is that insulin resistance still remains the main contributing
factor to EAT thickness, even in patients with left
ventricular dysfunction. Previous data have demonstrated that impaired insulin sensibility is related to
both systolic [28] and diastolic [29] left ventricular
dysfunction, and several molecular mechanisms may
be invoked to explain this association. In fact, hyperinsulinemia may contribute to the sympathetic nervous system hyperactivity that unfavorably impacts
the progression towards left ventricular dysfunction
[30]; moreover, it has been clearly proved that insulin resistance potentiates the effect of angiotensin
II on cardiomyocyte hypertrophy and collagen production, leading to myocardial hypertrophy and fibrosis which are responsible for the unfavorable cardiac remodeling observed in ischemic heart disease
[31]. Based on our findings, an additional hypothesis
may be generated to explain the link between insulin
resistance, EAT thickness and left ventricular dysfunction: the detrimental effect of insulin resistance
on myocardial cells could be mediated by EAT
through a harmful, paracrine secretory profile. This
hypothesis seems to be supported by the recent work
of Greulich et al. [32]: these Authors clearly demonstrated that epicardial fat tissue can have a direct influence on cardiomyocyte metabolism and function.
They showed that adult rat cardiomyocytes, incubated with conditioned media obtained from EAT
biopsies of patients with type 2 diabeteshave a significant reduction in sarcomere shortening, cytosolic
calcium-flux, and insulin-mediated phosphorylation
of target proteins, with a consequent myocardial dysfunction. This is the first demonstration of a direct,
active pathophysiological contribution of epicardial
fat to myocardial dysfunction.
In conclusion, insulin resistance, measured with
different standardized indexes, independently predicts EAT thickness in patients affected by CAD.
Moreover, its predictive power also persists in patients with left ventricular dysfunction. In subjects
with CAD, the association of EAT with increased
body mass index and waist circumference is mediated by the presence of reduced insulin sensibility, a
feature of the metabolic syndrome.
Study limitations. The study presents all limitations of a cross-sectional design. Sample size is limited, although the population is quite homogeneous
in terms of management of CAD and left ventricular
dysfunction, because it was enrolled by a single center. Evaluation of EAT thickness was carried out by
an expert cardiologist, but not in a blinded manner.
Riassunto
Razionale. Il grasso epicardico (GE) è un grasso viscerale che compie due principali funzioni: di
deposito di grasso e di secrezione di adipochine con
proprietà pro-infiammatorie e pro-aterogene. È sta-
to suggerito che il GE possa contribuire alla patogenesi dell’aterosclerosi e influenzare la storia clinica della coronaropatia. Nei pazienti con obesità,
diabete mellito di tipo 2 e sindrome metabolica il
GE è maggiormente rappresentato. Poco si sa sul
ruolo del GE nella disfunzione del ventricolo sinistro. Scopo di questo studio è valutare la capacità
dell’insulino-resistenza di predire lo spessore del
GE nei pazienti con coronaropatia e disfunzione sistolica del ventricolo sinistro.
Materiali e metodi. Abbiamo arruolato 114 pazienti con diagnosi di coronaropatia effettuata mediante angiografia, la maggior parte dei quali sottoposti a rivascolarizzazione dopo una sindrome coronarica acuta. La disfunzione ventricolare sinistra
è stata considerata significativa per frazione di eiezione ) 40%. Sono stati calcolati tre indici di insulino-resistenza: HOMA-IR index, QUICKI, e il nuovo
adiponectin/resistin index (ADIPO-IRAR); questi
successivamente sono stati correlati con lo spessore
del GE. Il GE è stato misurato tramite ecocardiografia secondo i criteri di Iacobellis.
Risultati. I soggetti con diabete mellito di tipo 2
e storia di ipercolesterolemia avevano un GE più
spesso rispetto ai controlli. I livelli di potassiemia e
tutti e tre gli indici di insulino-resistenza sono risultati essere i migliori predittori indipendenti dello
spessore del GE sia nella popolazione totale che nei
pazienti con disfunzione ventricolare sinistra. In
quest’ultimo gruppo il nuovo ADIPO-IRAR index ha
mostrato il maggior valore predittivo.
Conclusioni. L’insulino-resistenza è un predittore indipendente dello spessore del GE nei pazienti
affetti da coronaropatia, anche in presenza di una
significativa disfunzione del ventricolo sinistro.
Parole chiave: grasso epicardico, insulino resistenza, cardiopatia ischemica cronica, adipochine,
disfunzione ventricolare sinistra.
ACRONYMOS
ADIPO-IRAR = Adipose tissue Insulin Resistance adiponectin/
resistin index
BMI = Body Mass index
CAD = Coronary artery Disease
EAT = Epicardial Adipos Tissue
ECG = electrocardiogram
EF = Ejection Fraction
EFV = Epicardial Fat Volume
ELISA = Enzyme-Linked Immuno-Sorbent Assay
HF = Heart failure
HOMA-IR = HOmeostatic Model Assessment- Insulin Resistance
MRI = Magnetic Resonance Imaging
NYHA = New York Heart Association
QUICKI = QUantitative Insulin sensitivity ChecK Index
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ORIGINAL ARTICLE
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(ED) in patients with metabolic syndrome
on phosphodiesterase-5 (PDE-5) inhibitors
L’esercizio fisico migliora il grado di disfunzione erettile (ED)
nei pazienti con sindrome metabolica in terapia con inibitori
della fosfodiesterasi-5 (PDE-5)
Luigi Maresca1,*, Mariantonietta D’Agostino1,*, Luigi Castaldo3, Alessandra Vitelli1,
Maria Mancini1, Giorgio Torella1, Rosa Lucci1,Giovanna Albano1, Domenico Del Forno2,
Matteo Ferro3, Vincenzo Altieri3, Francesco Giallauria1,4, Carlo Vigorito1
ABSTRACT: Exercise training improves erectile dysfunction (ED) in patients with metabolic syndrome on phosphodiesterase-5 (PDE-5) inhibitors. L. Maresca, M. D’Agostino,
L. Castaldo, A. Vitelli, M. Mancini, G. Torella, R. Lucci,
G. Albano, D. Del Forno, M. Ferro, V. Altieri, F. Giallauria,
C. Vigorito.
Introduction. Erectile dysfunction (ED) affects about
50% of males aged 40-70 years old. ED shares with atherosclerotic disease several common risk factors; therefore, it
may be considered a surrogate marker of atherosclerosis.
Sincephosphodiesterase-5 inhibitors are well known pharmacologic agents capable of significant improvement in ED,
we designed this study to evaluate whether exercise training
is of added value in patients with ED who are already on
PDE-5 inhibitors.
Methods. We recruited 20 male patients affected by ED
with metabolic syndrome.At baseline, all patients underwent Cardio-Pulmonary Exercise Testing (CPET) and the
International Index of Erectile Function (IIEF) test.After
the initial evaluation, patients were subdivided into two
groups: tadalafil group (group T, n=10), who were maintained only on tadalafil therapy, and a tadalafil/exercise
training group (T/E group, n=10)who continued tadalafil
but in addition underwent a2-month structured exercise
training program.
Results. Basal anthropometric characteristics of study
population showed no significant differences. Although bothgroups showed at 2 months an improvement of the IIEF
score, thiswas more evident in the T/E group (T group: 11.2
vs 14.2, P=0.02; T/E group: 10.8 vs 20.1, P<0.001). There was
an improvement of oxygen consumption at peak exercise
(VO2peak) only in the T/E group patients (T group:
13.63±2.03 vs 14.24±2.98 mL/kg/min; P=0.521; T/E group:
13.41±2.97 vs 16.58±3.17 mL/kg/min; P=0.006). A significant
correlation was found between the changes in VO2peak and
the modifications in IIEF score (r=0.575; P=0.001).
Conclusion. Exercise training in ED patients treated
with PDE-5 inhibitors is of added valuesincefurther improves ED, as evaluated by IIEF score, and increases functional capacity.
Keywords: erectile dysfunction, exercise training, metabolic
syndrome, phosphodiesterase-5, erectile dysfunction therapy.
* Both Authors contributed equally to this work.
Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
Department ofMedicine and Surgery, University of Salerno Medical School, Salerno, Italy.
School of Science and Technology, University of New England, Armidale, NSW 2351, Australia.
1
2
3
4
Corresponding author: Luigi Maresca, M.D.; Cardiac Rehabilitation Unit, University of Naples “Federico II”; via Pansini 5, I-80131
Naples (Italy); E-mail address: [email protected]
Introduction
Erectile dysfunction (ED) affects about 50% of
males aged 40-70 years old, and is in this age
range one of the most important aspectaffecting
quality of life [1]. ED shares with atherosclerotic
disease several common risk factors, such as hypertension, hypercholesterolemia, obesity or
sedentary habits, diabetes and cigarette smoking
[2-5]; therefore, ED is a surrogate marker of atherosclerotic disease [6]. Phosphodiesterase-5 inhibitorsare well known pharmacologic agents ca-
pable of significant improvement in ED [7]. Recent studies, including some small randomized
controlled trials and one meta-analysis [8] have
demonstrated that alsolife-style changes, including exercise and/or diet, alone or in combination,
have a favorable effect on ED and cardiovascular
riskfactors in patients with ED and impairedcardiovascular risk profile [8-11]. In particular, exercise training, alone or as core component of cardiac rehabilitation programs,exerts beneficial effects on cardiovascular system, including an improvement in vascular endothelial function [12-14],
L. MARESCA ET AL.
global atherosclerotic risk profile [15], beta-receptor signaling [16, 17], free radical expression [18],
inflammation [19], cardiovascular functional capacity [20-24] and other several cardiovascular
outcomes [25, 26]. However, only 2 studies analyzed separately the effect of an exercise intervention on ED in patients with obesity [9] or hypertension [11], both showing significant although
modest improvement in ED.Moreover, in none of
these studies the studypatient population was on
therapy with PDE-5 Inhibitors. Hence, the potential additive effects of exercise training in patients
with ED who arealready on PDE-5 inhibitors are
still unknown.Therefore, in this study we evaluated whether exercise training is capable of a further improvement in ED in patients who are already on PDE-5 inhibitors.
Methods
Study population and protocol
Twenty male patients affected by ED andmetabolic syndromeaddressed to a firstout-patient evaluation at the urological ambulatory (age 68.5 ±3.2
years)were enrolled into the study. Exclusion criteria were: inducible ischemia at the routine stress
testing, previous cardiovascular event, known
coronary artery disease ornon-organic ED (psychogenic, iatrogenic, etc.). At baseline, all patients
underwent Cardio-Pulmonary Exercise Test
(CPET) and International Index of Erectile Function (IIEF) test, a validated test for the evaluation
of ED [27]. Tadalafil 5 mg/die (Cialis®; Eli Lilly,
Indianapolis, Indiana, USA) was administeredfor
treating ED at patient enrollment. After the initial
evaluation,patients were subdividedinto two
groups: a T group (n = 10 patients) was treated
with tadalafil 5 mg/die (Control Group), whereas a
T/E group (n = 10 patients) was treated with
tadalafil 5 mg/die and was enrolled in a 2-month
structured exercise training program (Training
Group). Demographic and cardiovascular risk profiles of the study populationwere given in Table 1:
there were no significant differences between the
two groups at baseline.According to the 2005
AHA/NHLBI scientific statement, all patients satisfied the diagnostic criteria for metabolic syndrome [28]. Structured exercise training programwas carried out on a hospital outpatient-based
regimen. The training program consisted on 3 exercise sessions per week under continuous electrocardiographic monitoring and undersupervisionof
a cardiologist and a physiotherapist. Each session
was preceded by a 5-min warm-up and followed by
a 5-min cool-down. Exercise was performed for 30
min on a bicycle ergometer or on a treadmill with
the heart rate target of 65% of the maximal oxygen
consumption (VO2peak) achieved at the initial cardiopulmonary exercise test. The heart rate was
monitored by a wearable device. Exercise workload was gradually increased until the achievement
of the predefined target. The T group received only
generic information on the usefulness of exercise.
After 2 months, all patients repeatedthe CPET and
the IIEF.
Cardiopulmonary Exercise Test (CPET)
All patients performed an incremental wattramp symptom-limited cardiopulmonary exercise
test protocol on a bicycle ergometer. Before each
test, oxygen and carbon dioxide analyzers and a
flow mass sensor were calibrated by use of available precision gas mixtures and a 3-liter syringe, respectively. To stabilize gas measurements, patients
were asked to remain still on the ergometer for at
least 3 min before starting exercise. After1-min
warm-up period at 0 Watt workload, a ramp protocol of 15 Watt/min was started and continued until
exhaustion. The pedaling was kept constant at 55-65
revolutions per minute. A 12-lead electrocardiogram was monitored continuously during the test,
and arm blood pressure was manually recorded
every 2 min. Respiratory gas exchange measurements, that is minute ventilation (VE), oxygen consumption (VO2) and carbon dioxide production
(VCO2), were obtained breath by breath with the
Table 1. - Demographic and cardiovascular risk profile of the study population
Total
Population
(n = 20)
Tadalafil
Group
(n = 10)
Tadalafil + Exercise
Training Group
(n = 10)
P value
(between
groups
Age (years)
68.5 ± 3.2
68.0 ± 3.6
69.0 ± 2.8
0.498
Systolic Blood Pressure (mmHg)
138.7 ± 4.1
139.5 ± 4.4
137.9 ± 3.9
0.401
Diastolic Blood Pressure (mmHg)
90.7 ± 5.5
90.0 ± 5.3
91.4 ± 5.8
0.580
Glycemia (mg/dL)
107.0 ± 7.9
107.8 ± 8.5
106.1 ± 7.5
0.641
Total Cholesterol (mg/dL)
214.5 ± 21.3
212.2 ± 21.6
216.8 ± 21.9
0.641
LDL Cholesterol (mg/dL)
145.4 ± 21.2
143.1 ± 21.0
147.7 ± 22.2
0.634
HDL Cholesterol (mg/dL)
32.9 ± 4.7
32.8 ± 5.1
32.9 ± 4.5
0.963
Triglycerides (mg/dL)
181.3 ± 16.6
181.7 ± 19.1
180.8 ± 14.8
0.908
Waist circumference (cm)
103.2 ± 3.8
102.5 ± 3.6
103.9 ± 4.0
0.418
178
EXERCISE TRAINING AND ERECTILE DYSFUNCTION
use of a computerized metabolic cart (Vmax 29C;
Sensormedics, Yorba Linda, California). VO2peak
was recorded as the mean of VO2 during the last 20
sec of the test, evidenced by a failure for VO2 to increase further despite an increase in work rate, and
was expressed in millimeters per kilogram per
minute. At the end of the cardiopulmonary exercise
test, patients were asked to identify the primary reason for stopping. Peakoxygen consumption
(VO2peak) and oxygen consumption at anaerobic
threshold (VO2AT) were measured and compared
with maximal predicted VO2 by use of a sex-, age-,
height-, and weight-adjusted and protocol specific
formula; and ventilatory anaerobic threshold (AT)
was detected by use of the V-slope methodas detailed elsewhere [29, 30]. The VE vs. VCO2 relationship was measured by plotting VE against
VCO2 obtained every 10 sec of exercise
(VE/VCO2slope); both VE and VCO2 were measured in liters per minute. The VE/VCO2slope was
calculated as a linear regression function, excluding
the nonlinear part of the relationship after the onset
of acidotic drive to ventilation.
International Index of Erectile Function (IIEF)
The International Index of Erectile Function
test represents an efficient and useful tool for the
multidimensional assessment of the sexual function in male population [27]. In 1999it was recommended as a primary endpoint by the “First International Consultation on Erectile Dysfunction” and
sponsored by the World Health Organization for
the diagnostic evaluation of ED. It consists of a
validated and reliable 15-item questionnaire that is
self-administered by the patient himself. It addresses the relevant domains of male sexual function (that is, erectile function, orgasmic function,
sexual desire, intercourse satisfaction, and overall
satisfaction), is psychometrically sound, and has
been linguistically validated in 32 languages. Erectile function is explored by the questions 1, 2, 3, 4,
5 and 15, with an overall score of 30. These questions are able to quantify the degree of erectile dysfunction, which may be classified as: severe (6-10
score), moderate (11-16), mild (17-25) or normal
(26-30) (see Table 2).
Statistical analysis
Data are expressed as percentages for discrete
variables and mean± standard deviation for continuous variables. Comparisons between groups at
randomization were performed by unpaired t test,
Table 2. - Classification of ED depending on IIEF test
results
IIEF Test Score
ED Classification
6 - 10
SEVERE
11 - 16
MODERATE
17 - 25
MILD
26 - 30
ABSENCE OF ED
χ2 or Fisher’s exact test as required. The distribution of continuous variables was analyzed by Kolmogorov-Smirnov test of normality. The comparison between the control and the experimental
group in biochemical and ventilatory function data
was performed by the Student’s t test for paired
data. The bivariate correlations procedure was used
to compute Pearson’sor Spearman’s correlation coefficients. A p value <0.05 was considered statistically significant. All statistical analyses were performed using the software package SPSS, version
15.0 (SPSS Inc., Chicago, IL, USA).
Results
The results of CPET and of the IIEF are shown
in Table 3. Both groups showed an improvement of
the IIEF score: groupT remained within the moderate degree ED score (11.2 vs 14.2 score, P = 0.02);
whereas group T/E, undergoing 2 monthsmedical
therapy plus exercise training showed a significant
improvement in IIEF score shifting from a basal
moderate ED to a mild impairment (10.8 vs 20.1
score, P< 0.0001) (Fig. 1 and Table 3). Furthermore,
the percentage enhancement of the IIEF score was
40% in the T group and 100% in the T/E group, revealing a statistically significant difference between
the two groups at the end of the 2 months treatment
(p<0.001 between the 2 groups at 2-months results).The improvement of oxygen consumption at
peak exercise (VO2peak) was statistically significant
only in the T/E group patients (VO2peak = 13.41 ±
2.97 vs 16.58 ± 3.17 mL/kg/min; P = 0.006);
whereas in the T group (controls) the VO2peak improvement was not significant (VO2peak = 13.63 ±
2.03 vs 14.24 ± 2.98 mL/kg/min; P = 0.521). In addition, in the entire study population, a significant
positive correlation (r = 0.574; P = 0.001; Fig. 2)
was found between ΔVO2peak and ΔIIEF. However,
after 2 months, T/E group patients did notshowa significant improvement of the metabolic risk profile
(Table 4).
Table 3. - CPET and IIEF test results
Tadalafil
group
(n = 10)
Tadalafil + exercise
training group
(n = 10)
VO2peak
(Basal; mL/kg/min)
13.63 ± 2.03
13.41 ± 2.97
VO2peak
(After 2 months;
mL/kg/min)
14.24 ± 2.98
16.58 ± 3.17
0.521
0.006
IIEF Test Score
(Basal)
11.2 ± 2.1
10.8 ± 2.0
IIEF Test Score
(After 2 months)
14.2 ± 2.2
20.1 ± 2.3
0.01660
< 0.00001
P value
P value
179
L. MARESCA ET AL.
Figure 1. - IIEF Test Score in both Groups (T group: P=0.01660; T/E group: P<0.00001).
(T Group:
(T/E Group:
basal: 11.2 ± 2.1
basal: 10.8 ± 2.0
2th month: 14.2 ± 2.2)
2th month: 20.1 ± 2.3)
Figure 2. - Correlation between changes in DIIEF score (x) vs. changes in DVO2peak(y) in the entire study population(n=20; r=0.575; P=0.001).
Discussion
The most important observation of our study
was that, in addition to the expected improvement
of ED in patients on Tadalafil only, the improvement of the ED was markedly increased in patients
180
who practiced exercise training and were already on
Tadalafil therapy. Indeed, the IIEF test significantly
improved in the T/E group patientscompared to the
T group. The association between the implementation of a training program and the improvement of
the erectile function in this patient population is
Table 4. - Cardiovascular risk profile at baseline and after 2 months
Tadalafil
Group
(Baseline)
Tadalafil
Group
(After 2 months)
P Value
Training Group
(Baseline)
Training Group
(After 2 months)
P Value
Systolic Blood
Pressure (mmHg)
139.5 ± 4.4
137.5 ± 5.0
0.141
137.9 ± 3.9
136.0 ± 4.1
0.184
Diastolic Blood
Pressure (mmHg)
90.0 ± 5.3
87.8 ± 6.2
0.211
91.4 ± 5.8
89.5 ± 6.0
0.076
Glycemia
(mg/dL)
107.8 ± 8.5
108.9 ± 9.6
0.712
106.1 ± 7.5
104.7 ± 6.4
0.618
Total Cholesterol
(mg/dL)
212.2 ± 21.6
208.2 ± 26.0
0.558
216.8 ± 21.9
210.9± 20.3
0.206
LDL Cholesterol
(mg/dL)
143.1 ± 21.0
136.8 ± 26.5
0.412
147.7 ± 22.2
143.5± 19.5
0.367
HDL Cholesterol
(mg/dL)
32.8 ± 5.1
32.7 ± 5.9
0.868
32.9 ± 4.5
33.9 ± 4.0
0.317
Triglycerides
(mg/dL)
181.7 ± 19.1
193.5 ± 23.8
0.168
180.8 ± 14.8
177.7 ± 19.4
0.545
Waist circumference
(cm)
102.5 ± 3.6
103.4 ± 4.1
0.487
103.9 ± 4.0
103.3 ± 4.3
0.217
also suggested by the significant correlationamong
the changes in IIEF test score and in the VO2peak in
the T/E group after two months of exercise training.
At the present, there are not literature clarifying the
mechanism(s) of the additional benefit of exercise
training on the erectile dysfunction in patients already on PDE-5 inhibitors therapy. In the metaanalysis by Gupta et al. [8], showing a beneficial
effect of life style changes on ED, only 2 of the included studies analyzed separately the effect of an
exercise intervention only on ED in patients with
obesity [9] or hypertension [11], both showing only
modest improvement in ED. However, in none of
these studies the included patient population was on
PDE-5 inhibitors. Therefore, we could not exclude
that the beneficial effect of exercise training in
these two studies would not be observed in other
patients already on PDE-5 inhibitors. On the opposite, in our patients we foundan incremental value
of exercise training on EDimprovement. Interestingly, the mean increment in IIEF score of 4.0 with
exercise in the paperby Esposito et al. [31] and of
3.6 in the paperby Lamina et al. [11] are similar to
the additional value of 5.9 observed in our study as
the added value of exercise training on ED score in
our patients assuming tadalafil. To this regard, it
must be underscored that only the association of
tadalafil and exercise training increased the IIEF
score in our patients with baseline moderate ED by
a value (mean 9.3 increment) to be considered as
clinically relevant (i.e. 5 points improvement in
IIEF score) [32], while the mean score increase
of3.0 in the tadalafil group was not sufficient to
achieve this goal.Therefore, our study underlines
that the synergic action of a structured program of
exercise training added to the pharmacological therapy with tadalafil in patients with a chronic moder-
ate ED could amplify the pharmacological effect of
the PDE-5 inhibitor. This magnified effect could
improve ED up toclinical relevant values.
In addition to the effects on ED, exercise training also induced a global improvement in functional
capacity, expressed as an increase of the oxygen
consumption at peak exercise (VO2peak), which represents a strong prognostic predictor of cardiovascular disease and death [33], in this case not accompanied by an improvement of the cardiovascular risk
profile, probably due to the very small number of
study patients.The mechanisms underlying the
favourable effects of exercise training include an
improvement of vascular endothelial function, a reduction of peripheral resistances and an increase of
the O2 consumption by the peripheral muscles [13].
The significant correlation found between exerciseinduced changes in IIEF score and in VO2peak suggests that common mechanisms, such as an improvement in vascular endothelial function, are at
the base of the favorable improvement of these parameters.In fact, ED represents an early sign of endothelial dysfunction and arterial stiffness [34]. The
PDE-5 inhibitors are pharmacological agents able to
augment the NO/cGMP pathway and to determine
dilationof the smooth muscle [37]. Previously, the
peripheral vasodilatation mediated by the action of
PDE-5 inhibitorshas been identified as the main factor enhancing VO2peak in patients with chronic heart
failure [38, 39]. and in patients with metabolic syndrome [40]. However, as in our study tadalafil alone
did not led to a significant increase of the VO2peak,
we suggest that the pharmacological effect of the
PDE-5 inhibitors on this essential functional parameter is particularly evident in chronic heart failure
patients,who present a severe compromise ofsystemic and pulmonary hemodynamicsand of en181
L. MARESCA ET AL.
dothelial function. On the contrary, in patients with
metabolic syndrome and without cardiovascular
structural disease, such as those included in our
study,VO2peakwas not significantly affected by
PDE-5 inhibitors. In this patient population exercise
training becomes of remarkable importance in improving cardiovascular capacity.
12.
Conclusions
14.
Structured exercise training in patients with ED
and on PDE-inhibitors is of added valuefor improvingED compared to PDE-5 inhibitors therapy
alone. Future trialsare mandatory in order to confirm
the additional benefits of exercise training in a largerED population and to establish the global benefit
of these programs in ED patient.
Author’s contributions: CV, FG and VA designed
the study. MD, LC, RL, MF and GT performed the CPET
and the IIEF test.LM, DDF, GA and MM collected the
data. LM, AV and MM took blood samples. LM, MD
and FG analyzed the data. LM, MD and CV prepared the
manuscript. CV and VA gave suggestions for this work.
We thank Mr. Mario Aurino for his technical support
during the training programs.
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2013; 80: 184-188
CASE REPORT
Emergency reversal of vitamin-K
antagonists related over-anticoagulation:
case report and brief overview on the role
of Prothrombin Complex Concentrate
Rapida correzione dell'eccessiva anticoagulazione da antagonisti
della vitamina K: caso clinico e breve inquadramento del ruolo
del Complesso Protrombinico Concentrato
Stefania Angela Di Fusco1, Nadia Aspromonte1, Stefano Aquilani1,
Luca Mele2, Furio Colivicchi1
ABSTRACT: Emergency reversal of vitamin-K antagonists
related over-anticoagulation: case report and brief overview on
the role of Prothrombin Complex Concentrate. S.A. Di Fusco,
N. Aspromonte, S. Aquilani, L. Mele, F. Colivicchi.
Oral anticoagulation is a widely used treatment and
atrial fibrillation (AF) is the most frequent indication. We review the therapeutic options on an important clinical challenge: rapid reversal anticoagulation in the setting of an urgent invasive procedure. We report a case of a 71-year-old
man treated with warfarin who was over-anticoagulated
when presented to the emergency department for syncope
due to severe bradiarrhythmia and needed temporary pacing.
Intravenous infusion of vitamin-k was not adequate for rapid
reversal over anticoagulation whereas the administration of a
Prothrombin Complex Concentrate (PCC) was able to quickly
reverse anticoagulant activity and allowed the performance of
an urgent invasive procedure without hemorrhagic complication. The aim of this paper is to draw attention to possible
therapeutic strategies to reduce the risk of bleeding related to
over-anticoagulation with vitamin-K antagonists (VKAs) in
case of urgent invasive procedure, emphasizing the role of
PCC in keeping with national and international guidelines.
Keywords: vitamin-K antagonist; reversal of over-anticoagulation, Prothrombin Complex Concentrate.
From 1 Cardiovascular Department and 2 Transfusion Medicine Department, San Filippo Neri Hospital, Roma, Italy.
Corresponding author: Stefania Angela Di Fusco; Cardiovascular Department, San Filippo Neri Hospital; Via G. Martinotti 20;
I-00135 Roma, Italy; Fax: 39-06-33062489; Telephone: 39-06-33062467; E-mail address: [email protected]
Case report
A 71-year-old male was admitted to the emergency department of our hospital because of syncope with contusive head trauma, and previous recurrent episodes of dizziness. The patient had a past
medical history of arterial hypertension, chronic
renal failure, and persistent AF. He was treated
with amiodarone for rhythm control, warfarin for
thrombo-embolic prevention (CHA2DS2-ASc 2;
HASBLED 3), and angiotensin-converting-enzyme
inhibitor for hypertension. On admission, the patient’s blood pressure was 130/70mmHg and his pulse
rate was 60 bpm.
A thorough physical examination revealed no
abnormal findings besides an epistaxis which was
resolved quickly with direct pressure. The neurological examination revealed no neurological deficits
and a brain computed tomography excluded structural abnormalities related to syncopal episode.
The electrocardiogram (ECG) at admission
showed sinus rhythm, left bundle branch block and
first degree atrio-ventricular block, with a PR inter-
val of 220 msec (Fig. 1). Initial laboratory evaluation was remarkable for an international normalized
ratio (INR) of 8.05, a high creatinine level (2.65
mg/dl) with serum electrolytes within normal range
and mild anemia (hemoglobin value 13g/dl). Due to
the high risk of bleeding related to the high level of
INR and the head trauma, Vitamin K 10 mg was administered by slow intravenous infusion to reverse
anticoagulation.
During observation in the emergency department a few hours later, the patient experienced a further episode of dizziness. The ECGs performed immediately after revealed a total atrio-ventricular
block, junctional rhythm with the same QRS morphology as sinus rhythm and isorhythmic atrial ectopic activity, with a heart rate of 30 beats per
minute (Fig. 2). The blood pressure was 110/70
mmHg. Due to the persistent severe bradycardia despite the use of atropine bolus and isoprenaline infusion, and with the patient symptomatic for deep asthenia, temporary transcutaneous pacing was applied and the patient was scheduled for urgent implantation of temporary transvenous pacing. Before
REVERSAL VITAMIN-K OVER-ANTICOAGULATION
Figure 1. - ECG at admission showing a sinus rhythm, left bundle branch block and first degree
atrio-ventricular block.
performing the invasive procedure
coagulation parameters were reassessed. The INR was 4.65 with a
Prothrombin Time (PT) equal to
16%. For the purpose of reducing
procedural hemorrhagic risk, we
discussed the case with a consultant
hematologist and opted for a therapeutic intervention to immediately
reverse the patient’s over-anticoagulation. We administered a three
factor Prothrombin Complex Concentrate (PCC), a combination of
concentrates of factors II, IX and
X, supplemented with small
amounts of heparin. One hour after
administration of PCC at a dose of
35UI/Kg (equal to a total amount of
2800 UI), the INR was 1.93. The
dose was established, according to
the formula proposed on the label:
body weight (kg) x desired PT level
rise x 1.2. The desired PT level rise
was calculated as: target level of
PT minus the present level of PT,
and our target PT was 45% equivalent to an INR value of 1.8.
A transvenous temporary pacing electrode was promptly inserted via the right femoral vein. In
order to reduce the risk of complications an ultrasound-guided approach to central venous cannulation was used. The pacing lead was
advanced under fluoroscopic guidance and placed in the right ventricular apex. No implant-related
complications were observed during the procedure. The next day the
temporary pacing was replaced by
a permanent pacing with a subsequent course uncomplicated.
Discussion
Figure 2. - ECG during symptoms: total atrio-ventricular block, junctional rhythm with the same
QRS morphology as sinus rhythm and isorhythmic atrial ectopic activity (a. preceding QRS, b.
following QRS) with heart rate of 30 beats per minute.
We report a case of perioperative management of over-anticoagulation in a patient with a history
of AF who required immediate reversal of anticoagulant activity. AF
is the most frequent indication for
anticoagulation and according to a
recent nationwide observational
study, it is estimated that 2% of the
Italian population has a diagnosis
of AF, and 46% of these patients
receive anticoagulant therapy [1]
and vitamin K antagonists (VKAs)
are still the most commonly prescribed oral-anticoagulants despite
the introduction in the market of
novel oral-anticoagulant (NAO).
In patients who need urgent
surgery or an invasive procedure
the optimal strategy to reverse anticoagulation has not been clearly
185
S.A. DI FUSCO ET AL.
defined. The therapeutic strategy described here, intravenous administration of Vitamin K followed by
PCC infusion, was performed successfully with a
favorable outcome. At present, therapeutic options
to reverse over-anticoagulation with vitamin-k antagonists include: omission of a dose of VKA, administration of an oral or intravenous dose of vitamin K, use of fresh frozen plasma (FFP), administration of PCC, or recombinant factor VIIa. The
clinical setting (major bleeding, need of urgent
surgery, etc) in addition to the patient’s INR value
must be taken into account to establish the most appropriate strategy to reverse anticoagulation in each
case. The first two options are inadequate in emergency cases since they require several hours for the
full recovery of coagulation factors. Human plasma
has traditionally been the keystone of treatment for
reversing over-anticoagulation in most emergency
cases. PCC, which was originally developed to treat
hemophilia B (Factor IX deficiency) [2], is now indicated as first choice treatment for emergency reversal of anticoagulant therapy in life threatening
major bleeding and in perioperative settings, although fewer studies support the latter indication.
Commercially available PCCs, depending on their
content of clotting factors, are referred as three-factor PCC, which contains significant levels of factors II, IX, and X, or four-factor PCC, which also
contains factor VII in significant amounts. The
place of recombinant activated factor VIIa in the
setting of emergency reversal of anticoagulation
needs further evaluation because its risk-benefit
profile is not clear [3]. According to the Italian Federation of Centres for the Diagnosis of Thrombosis
and Monitoring of Antithrombotic Therapies
(FCSA), PCC is the treatment of choice for acute
reversal of oral VKAs in both cases of major bleeding and urgent surgery [4]. Liumbruno et al. [5], as
Italian Society of Transfusion Medicine and Immunohaematology Working Party, suggest a 2C+
grade of recommendation for PCC as anticoagulation therapy reversion. These recommendations are
in accordance with other international guidelines.
The American College of Chest Physicians’ guidelines also suggest rapid reversal of anticoagulation
with four-factor PCC rather than with plasma in
case of major bleeding, however they don’t give
clear recommendations for the treatment of patients
who need urgent surgery [6]. The recently updated
consensus guidelines of the Australasian Society of
Thrombosis and Haemostasis state that in the setting of urgent surgery PCC can be used to reverse
anticoagulant effect [7]. Despite these recommendations, the use of PCC in clinical practice remains
limited for various reasons such as the prevalent accessibility of FFP, and possible inconsistent application of guidelines. PCC has several advantages
over FFP (Table 1). Cost-effectiveness analysis
shows that PCC compared to FFP is a more cost-effective strategy in several scenarios [8]. PCC requires a shorter time for administration, and time is
critically important in emergency cases. Before FFP
can be administered, compatibility testing is required and the plasma must be thawed and then
warmed. In contrast to FFP, PCC contains higher
amounts of the vitamin K-dependent clotting factors per unit of volume. Indeed, the overall clotting
factor concentration is approximately 25 times
higher than in FFP [9]. Therefore smaller volumes
of PCC are necessary to achieve an increase in coagulation factor level, therefore minimizing the risk
of fluid overload and decreasing the infusion’s
time. PCC is associated with lower risks of infectious agents’ transmission because it undergoes viral inactivation, whereas most FFP products are not
virally inactivated.
In spite of such clear advantages, there is still a
lack of expert consensus on the optimal dose of
PCC to use. Literature data indicates that individualized dosing, based on body weight, basal INR,
and target INR in each clinical case, is more effective at reversing anticoagulation than a standard
dose. In the majority of studies, the dose of threefactor PCC (expressed as units of the factor IX
component) used was 25-50 units/kg [10]. The
dosage prescribed in our case was established according to the formula suggested by the label, considering that an infusion of 1 UI/Kg of PCC increases the PT by 1%. The dosage so calculated was
lower than that recommended by FCSA [4] (Table
2). In fact, our target was an INR between 1.5 and
2, whereas in the FCSA practical guide the goal of
the proposed treatment is an INR <1.5. However,
the dose administered in our case was consistent
Table 1. - Main differences between PCC and FFP
PCC
FFP
Immediate
After compatibility testing and thawing
• Infusion volume
Small
Large
• Risk of infection
Minimal
Higher
II, VII*, IX, X
All
• Risk of TRALI
Unlikely
Present
• Risk of thrombotic complications
Present
Not significant
• Time for the administration
• Coagulation Factors contained
FFP, fresh frozen plasma; PCC, Prothrombin Complex Concentrate; TRALI, transfusion-related acute lung injury.
* In significant amounts only in 4-factor PCC.
186
REVERSAL VITAMIN-K OVER-ANTICOAGULATION
Table 2. Suggested dose of PCC to reverse the anticoagulant effect of VKAs according to patient’s initial INR in case
of urgent surgery
Author, year (reference)
Initial INR
PCC dose
Limbruno, 2009 (5)
INR <2
INR 2-4
INR >4
20 IU/kg
30 IU/kg
50 IU/kg
Crippa, 2010 (4)
INR 1.5-2
INR 2.1-3.9
INR 4-5.9
INR >6:
20 IU/kg
30 IU/kg
40 IU/kg
50 IU/kg
Colomina, 2012 ( 10)
INR 2-3.9
INR 4-S.9
INR >6
25 IU/kg
35 IU/kg
50 IU/kg
INR, international normalized ratio; PCC, Prothrombin Complex Concentrate; VKA: vitamin-K antagonist.
with that proposed by Colomina et al. in their review on perioperative use of PCC [10]. Considering
the long anticoagulant effect of warfarin and the
shorter half-life of coagulation factor concentrates,
to treat vitamin-k dependent over-anticoagulation
the PCC should always be used in association with
vitamin-k supplement [4, 5, 6, 7, 10, 11].
This case highlights the difficulties faced by
physicians in emergency perioperative management
of patients treated with oral anticoagulant. In each
case the risk of thrombotic complication due to
treatment with haemostatic agents has to be weighed
against the potential benefit of rapid reversal of the
effect of VKAs (risk of intraoperative bleeding or
the consequences of procedure deferral). The routine clinical use of NOAs is changing the therapeutic landscape (Fig. 3). According to the European
Heart Rhythm Association practical guide, the administration of PCC can be considered in patients
with life-threatening bleeding, whereas unfortunately, there are insufficient data available to optimally guide management of patients undergoing an
urgent surgical intervention [12].
Riassunto
La terapia anticoagulante orale è ampiamente
utilizzata in diversi contesti clinici e la fibrillazione
atriale è la più comune indicazione. Nel presente articolo riesaminiamo le opzioni terapeutiche in un
contesto clinico molto critico: la rapida correzione
di una eccessiva anticoagulazione con antagonisti
della vitamina K, in caso di necessità di procedura
invasiva urgente. Riportiamo il caso clinico di un
uomo di 71 anni, in profilassi antitrombotica con
warfarin che presentava
un INR sopra-terapeutico
quando è giunto in
Pronto soccorso in seguito ad episodio sincopale dovuto ad una importante bradiaritmia che
richiedeva il posizionamento di un pacemaker
temporaneo transvenoso.
L’infusione di vitamina K
non è stata sufficiente a
correggere rapidamente
l’anticoagulazione, mentre la somministrazione di
Complesso Protrombinico Concentrato (PCC)
ha permesso una rapida
correzione dell’anticoagulazione. È stata quindi
eseguita la procedura invasiva urgente senza
complicanze emorragiche. Nella discussione
Figure 3. - The coagulation cascade, action site of oral anticoagulant drugs, and factors contained in PCC.
viene posta l’attenzione
sulle possibili strategie
VKAs, vitamin-K antagonists; NOA, novel oral anticoagulants; PCC, Prothrombin Complex Concentrate.
187
S.A. DI FUSCO ET AL.
terapeutiche volte a correggere rapidamente l’anticoagulazione in caso di procedure invasive urgenti,
sottolineando il ruolo del PCC in accordo con le linee guida nazionali ed internazionali.
4.
ABBREVIATIONS AND ACRONYMS
5.
AF: atrial fibrillation
CHA2DS2-ASc: congestive heart failure or left ventricular dysfunction, hypertension, age *75 (doubled), diabetes, stroke
(doubled)-vascular disease, age 65-74 and sex category (female)
ECG: electrocardiogram
FCSA: Italian Federation of Centres for the Diagnosis of
Thrombosis and Monitoring of Antithrombotic Therapies
FFP: fresh frozen plasma
HASBLED: hypertension, abnormal renal/liver function,
stroke, bleeding history or predisposition, labile INR, elderly
age, drugs/alcohol concomitantly
INR: international normalized ratio
NOA: novel oral-anticoagulant
PCC: Prothrombin Complex Concentrate
PT: Prothrombin Time
VKA: vitamin-K antagonist.
6.
7.
8.
References
9.
1.
2.
3.
188
Zoni-Berisso M, Filippi A, Landolina M, et al. Frequency, patient characteristics, treatment strategies, and resource usage of atrial fibrillation (from the Italian Survey
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Key NS, Negrier C: Coagulation factor concentrates:
past, present, and future. Lancet 2007, 370: 439-448
Rosovsky RP, Crowther MA. What is the evidence for the
off-label use of recombinant factor VIIa (rFVIIa) in the
acute reversal of warfarin? ASH evidence-based review
2008. Hematology Am Soc Hematol Educ Program 2008;
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12.
Crippa L, Erba N, Falanga A et al. Pazienti in terapia anticoagulante orale, che cosa fare in caso di: Emorragia intracranica, Emorragie maggiori, Chirurgia di emergenza,
Emorragie minori (con o senza eccessiva anticoagulazione), Correzione di eccessiva anticoagulazione in assenza
di emorragie. FCSA, Settembre 2010.
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Rossetti G; Italian Society of Transfusion Medicine and
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prothrombin complex concentrates. Blood Transfus 2009;
7(4): 325-34.
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Guest JF, Watson HG, Limaye S. Modeling the cost-effectiveness of prothrombin complex concentrate compared with fresh frozen plasma in emergency warfarin reversal in the United kingdom. Clin Ther 2010; 32(14):
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Colomina MJ, Díez Lobo A, Garutti I, Gómez-Luque A,
Llau JV, Pita E. Perioperative use of prothrombin complex
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Europace 2013; 15(5): 625-51.
2013; 80: 189-192
CASE REPORT
Nonbacterial Thrombotic Endocarditis
in Pancreatic Cancer
Endocardite trombotica non batterica in associazione
con una neoplasia pancreatica
Barbara Piovanelli, Riccardo Rovetta, Ivano Bonadei,
Enrico Vizzardi, Antonio D’Aloia, Marco Metra
ABSTRACT: Nonbacterial Thrombotic Endocarditis in
Pancreatic Cancer. B. Piovanelli, R. Rovetta, I. Bonadei,
E. Vizzardi, A. D’Aloia, M. Metra.
Nonbacterial thrombotic endocarditis (NBTE), known
as marantic endocarditis, is a phenomenon due to hypercoagulability with a complex pathogenesis. Originally described by Ziegler, the lesions of NBTE were considered to
be fibrin thrombi deposited on normal or superficially degenerated cardiac valves [1]. Numerous reports have identified the relationship between NBTE and a variety of different inflammatory states, including chronic diseases like malignancy and autoimmune disease [2, 3]. NBTE is a serious
manifestation of prothtombotic state that is characterized by
the deposition of thrombi on previously undamaged heart
valves in the absence of a bloodstream bacterial infection and
by the increased frequency of arterial embolic events in patients with chronic debilitating diseases. Although hypercoagulability is often seen in patients with pancreatic cancer,
NBTE has rarely been reported antemortem. We report a
case of marantic endocarditis in patient with pancreatic cancer, in which neurological symptoms preceded the diagnosis
of pancreatic cancer.
Keywords: Nonbacterial thrombotic endocarditis, pancreatic cancer, echocardiography .
Department of Experimental and Applied Medicine, Section of Cardiovascular Diseases, University of Brescia.
Corresponding author: Riccardo Rovetta; Piazzale Spedali civili, 1; I-25100 Brescia; Italy; Tel: +39 030 3995575; Fax: +39 030 3995018;
E-mail address: [email protected]
Background
Since the seminal observation by Armand
Trousseau in 1865 4, numerous studies have confirmed the common association between cancer and
thromboembolism. The etiology of the hypercoagulable state in cancer is multifactorial. Contributing
factors include procoagulant alterations associated
with the malignancy (tissue factor and cancer procoagulant expression by tumor cells, vascular compression by tumor masses) and the host’s inflammatory response (monocyte tissue factor expression,
increased levels of factor VIII, fibrinogen, and von
Willebrand factor). Although venous thromboembolism is the most common manifestation, cancerassociated thrombophilia may also present as a migratory superficial thrombophlebitis (the original
syndrome described by Trousseau), arterial thrombosis, disseminated intravascular coagulation (DIC),
a thrombotic microangiopathy or nonbacterial
thrombotic endocarditis (marantic endocarditis).
Case presentation
A 48-year-old woman with no significant past
medical history, previously asymptomatic, who
suddenly showed a lowered level of consciousness,
was admitted to department of intensive care unit
for stroke. She had no history of tobacco use, con-
sumed an occasional alcoholic beverage, and did
not have any recent nonsteroidal anti-inflammatory
drug use. The computer tomography (CT) of the
bran confirmed multiple embolic infarctions
throughout both cerebral hemispheres and cerebellum. The distribution of the signal abnormalities
was compatible with multiple embolic infarcts.
Cardiovascular examination revealed intact carotid
and distal pulses without any bruits, regular rhythm
with no cardiac murmurs. ECG showed normal sinus rhythm with no ischemic changes. Chest x-ray
was normal. Transthoracic and transesophageal
echocardiography were significant for multiple
vegetations on a trileaflet aortic valve associated
with moderate aortic regurgitation (Fig. 1 and Fig
2). During hospitalization, the patient had worsening neurological and repeated CT of brain control
with evidence of new ischemic lesions with embolic origin, despite she was treated with iv heparin. Findings were consistent with a new embolization resulting in multiple infarcts. Given the
worsening of the clinical condition the patient underwent CT of the abdomen/pelvis (Fig. 3) that
showed presence of a mass in the tail of the pancreas. Initial laboratory data were notable for a
complete blood count, basic metabolic panel, liver
function test, coagulation studies, amylase, lipase,
cardiac enzymes, triglycerides, and erythrocyte
sedimentation rate: all within normal limits.
B. PIOVANELLI ET AL.
Figure 1. - Short axis view of trileaflet aortic valve with mobile vegetations.
Figure 2. - Long axis view of aortic root showing mobile formation on
one leaflet.
Workup for bacterial endocarditis was negative, including multiple sterile blood cultures. In suspected
endocarditis associated with antiphospholipid syndrome, the patient has performed immunological
tests, but they was negative for antinuclear, anticardiolipin, antimitochondrial, and antismooth muscle
antibodies. Additional laboratory findings showed
CEA of 660 ng/mL, CA 19.9 of 47 U/mL and CA
125 level of 721 U/mL. Pancreatic enzymes, erythrocyte sedimentation rate, C-reactive protein, remained within normal limits. The diagnosis of
marantic endocarditis was made.
The patient required admission to the intensive
care unit for stroke. She was treated with aspirin,
beta blocker therapy, and unfractionated heparin.
Definitive therapy includes antitumor therapy directed at the underlying malignancy and indefinite
anticoagulation with unfractionated or low molecular weight heparin. Vitamin K antagonists such as
warfarin are ineffective and should not be employed
in management. In our experience, prompt diagnosis
and treatment with heparin and treatment of the patient’s pancreatic cancer may prevent catastrophic
neurological events and decrease morbidity.
The patient continued on heparin iv and neurological symptoms worsened. Unfortunately, she continued to deteriorate from the pancreatic cancer and
died 6 weeks after this hypercoagulable state was diagnosed. This case demonstrates a rare presentation
of advanced pancreatic adenocarcinoma. Marantic
endocarditis is likely underreported and underdiagnosed. Cancer is associated with a significant hypercoagulable state that increases the risk of thromboembolism fivefold. NBTE is an uncommon but
devastating manifestation of malignancy-associated
thrombophilia. NBTE should be considered in any
cancer patient suffering an episode of arterial thromboembolism. TEE is useful imaging modality in the
diagnosis of NBTE. The long-term outcome for most
patients with malignancy-associated NBTE is poor,
because it is typically associated with disseminated
and incurable malignancies. Health care professionals should be alert to the possibility of marantic endocarditis in any patient with cancer, especially pancreatic cancer, who presents with symptoms of neurological dysfunction or an arterial thrombotic event.
Discussion
Figure 3. - Abdominal CT showing a mass in the tail of the pancreas.
190
NBTE is a phenomenon due to hypercoagulability from an underlying cause. Clinical presentation is most often a sudden neurological deficit. It
has been associated with a variety of inflammatory
states including malignancy. It is the result of a
prothrombotic condition characterized by deposition of sterile fibrin and platelet-rich thrombi on
previously undamaged heart valves. Cardiac function is generally unaffected. Associated morbidity
and mortality are due to increased frequency of arterial embolic events, specifically in the central
nervous system [5]. NBTE is characterized by the
presence of an amorphous mixture of platelets and
fibrin on a valve leaflet in the absence of inflammation or micro-organisms, or destruction of the
underlying cardiac valve [6]. It is most often diagnosed only at postmortem examination because
NONBACTERIAL THROMBOTIC ENDOCARDITIS IN PANCREATIC CANCER
the small, friable vegetations frequently embolize,
leaving remnants too small to be identified by
echocardiography. Vegetations caused by NBTE
are found in approximately 1.2% of patients during autopsy. Although the reported incidence of
systemic emboli varies widely, on average 42% of
patients embolize [7]. Arterial embolization most
frequently involves the spleen, kidney, brain, and
heart, respectively [8]. It is also the major cause of
morbidity and mortality in these patients. The
most common sites of vegetations are on the mitral
and aortic valves along the coaptation line [9].
However, the tricuspid and pulmonary valves as
well as bivalvular involvement have been identified [10, 11]. The great majority of underlying
neoplasms associated with NBTE are adenocarcinomas of the pancreas, colon, lung, and prostate.
The pathogenesis of NBTE is incompletely understood. The lesions of NBTE are classically found
in areas of high flow on valvular leaflets; therefore, blood flow likely contributes to the location
if not the initiation of these valvular lesions. Elevated levels of circulating cytokines associated
with cancers, such as tumor necrosis factor or interleukin-1 may also result in local tissue damage
that instigates vegetation formation. In addition,
the interaction between these cells activates the
coagulation cascade leading to the generation of
thrombin and thrombosis [12]. While NBTE has
been reported in every age group, it most commonly affects patients between the fourth and
eighth decades of life. No sex predilection has
been reported [13]. Therefore, if a diagnosis of endocarditis is made, but the cultures and serology
are negative, and there is no response to antibiotic
treatment, then NBTE should be strongly considered. Patients with newly acquired murmurs
should be evaluated with two-dimensional
echocardiography to elucidate the presence of
valvular vegetations. The preferred diagnostic test
for NBTE is a TEE, which is more sensitive in the
detection of valvular vegetations than the transthoracic approach [14]. Although no established
treatment strategies exist for tumor related NBTE
and DIC, there are limited data supporting the use
of anticoagulation in these patients. The most effective anticoagulant appears to be unfractionated
heparin, which has been shown to be effective in
reducing the incidence of recurrent episodes of
thromboembolism [15, 16]. When delivered in
therapeutic doses, both i.v. and s.c. heparin therapy has been effective. In contrast to heparins, vitamin K antagonists such as warfarin should not be
used in patients with malignancy-associated
NBTE, as recurrent thromboembolic events while
on warfarin are common. A multicenter, randomized trial by Lee et al. [17] demonstrated low-molecular weight heparin was more effective than
warfarin in reducing the risk of recurrent thromboembolism in patients with cancer without increasing the risk of bleeding. Although the exact
reason for warfarin’s inability to control the coagulopathy associated with NBTE is not precisely
known, the presence of non-vitamin K dependent
agents that induce the thrombotic coagulopathy
has been suggested by some investigators [18].
Anticoagulation must be continued indefinitely in
patients suffering from NBTE, because recurrent
thromboembolism has occurred in patients following discontinuation of heparin therapy. Although
no trial has compared unfractionated heparin with
low-molecular weight heparin in patients with tumor associated NBTE, a multicenter double-blind
trial published by Sakuragawa et al. [19] demonstrated that low-molecular weight heparin can be
used as an alternative to unfractionated heparin in
patients with DIC. Although most patients do not
require surgery to address NBTE valvular lesions,
cardiac surgery is a reasonable intervention in selected circumstances where the risk-benefit balance is favorable.
Riassunto
L’endocardite trombotica non batterica (NBTE),
nota anche come endocardite marantica, è un fenomeno conseguente ad uno stato di ipercoagulabilità
con una patogenesi complessa. Originariamente descritta da Ziegler, le lesioni della NBTE sono considerati trombi di fibrina depositata su valvole cardiache normali o degenerate [1]. Numerosi casi
hanno identificato il rapporto tra la NBTE e una varietà di diversi stati infiammatori, comprese le malattie croniche come tumori e malattie autoimmuni
[2, 3]. La NBTE è una grave manifestazione di uno
stato protrombotico che si caratterizza per la deposizione di trombi sulle valvole cardiache precedentemente intatti in assenza di una infezione batterica
nella circolazione sanguigna e da eventi embolici
arteriosi nei pazienti con malattie croniche debilitanti. Sebbene lo stato di ipercoagulabilità è spesso
visto in pazienti con cancro del pancreas, la NBTE
è stato raramente segnalata antemortem. Riportiamo un caso di endocardite marantica in una paziente con neoplasia del pancreas, in cui i sintomi
neurologici hanno preceduto la diagnosi di carcinoma pancreatico.
References
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2.
3.
4.
5.
6.
7.
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Ziegler E. Ueber den Bau und die Entstehung der endocarditis chen Efflorescenzen. Ver Kong Inn Med 1888; 7:
339-343.
Ferrans VJ, Rodriguez ER. Cardiovascular lesions in collagen-vascular diseases. Heart Vessels Suppl 1985; 1:
256-261.
Hughson MD, McCarty GA, Sholer CM, et al. Thrombotic cerebral arteriopathy in patients with the antiphospholipid syndrome. Mod Pathol 1993; 6: 644-653.
Trousseau A. Clinique Médicale de l’Hôtel-Dieu de Paris.
Paris: Ballière; 1865. Phlegmasia alba dolens; p. 654-712
El-Shami K, Griffiths E, Streiff M. Nonbacterial thrombotic endocarditis in cancer patients: pathogenesis, diagnosis and treatment. Oncologist 2007; 12: 518-523.
Otten HM, Prins MH. Venous thromboembolism and
occult malignancy. Thromb Res 2001; 102: V187-V194.
Lopez JA, Ross RS, Fishbein MC, et al. Nonbacterial
thrombotic endocarditis: A review. Am Heart J 1987;
113: 773-784.
Rosen P, Armstrong D: Nonbacterial thrombotic endocarditis in patients with malignant neoplastic diseases. Am
J Med 1973; 54: 23-29.
Deppisch LM, Fayemi AO: Non-bacterial thrombotic
endocarditis. Am Heart J 1976; 92: 723-729.
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Biller J, Challa VR, Toole JF, et al. Nonbacterial thrombotic endocarditis. A neurologic perspective of clinicopathologic correlations of 99 patients. Arch Neurol 1982;
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Reagan TJ, Okazaki H. The thrombotic syndrome associated with carcinoma. A clinical and neuropathologic
study. Arch Neurol 1974; 31: 390-395.
Bick RL: Cancer-associated thrombosis. N Engl J Med
349: 109-111, 2003
Lopez JA, Ross RS, Fishbein MC, et al. Nonbacterial
thrombotic endocarditis: A review. Am Heart J 1987;
113: 773-784.
Dutta T, Karas MG, Segal AZ, Kizer JR. Yield of transesophageal echocardiography for nonbacterial thrombotic
endocarditis and other cardiac sources of embolism in
cancer patients with cerebral ischemia. Am J Cardiol
2006; 97: 894-898.
Rogers LR, Cho ES, Kempin S, et al. Cerebral infarction
from non-bacterial thrombotic endocarditis: Clinical and
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pathological study including the effects of anticoagulation. Am J Med 1987; 83: 746-756.
Sack GH Jr., Levin J, Bell WR. Trousseau’s syndrome
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1977; 56: 1-37.
Lee AYY, Levine MN, Baker RI, et al: Low molecularweight heparin versus a coumarin for the prevention of
recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146-153.
WR, Starksen NF, Tong S, et al. Trousseau’s syndrome.
Devastating coagulopathy in the absence of heparin. Am J
Med 1985; 79: 423-430.
Sakuragawa N, Hasegawa H, Maki M, et al: Clinical
evaluation of low-molecular weight heparin (FR-860) on
disseminated intravascular coagulation (DIC) - a multicenter co-operative double-blind trial in comparison with
heparin. Thromb Res 1993; 72: 475-500.
2013; 80: 193-194
CASE REPORT
Sildenafil improves clinical and functional
status of an elderly postmenopausal female
with ‘out of proportion’ PH associated
with left heart disease
Terapia con Sildenafil migliora clinica e stato funzionale
di una anziana donna con ipertensione polmonare associata
a patologia del cuore sinistro
Michele Correale, Antonio Totaro, Armando Ferraretti,
Matteo Di Biase, Natale Daniele Brunetti
ABSTRACT: Sildenafil improves clinical and functional status
of an elderly postmenopausal female with ‘out of proportion’
PH associated with left heart disease. M. Correale, A. Totaro,
A. Ferraretti, M. Di Biase, N. Daniele Brunetti.
We report a case of an elderly woman with heart failure with preserved ejection fraction and pulmonary hyper-
tension (HFpEF-PH), refractory to conventional therapy for
left heart failure and successfully treated by sildenafil.
Keywords: sildenafil, pulmonary hypertension, left heart
failure, diastolic heart failure.
Department of Cardiology, University of Foggia, Foggia, Italy.
Corresponding author: Michele Correale, Department of Cardiology; “Ospedali Riuniti”OO.RR; viale L Pinto, 1; I-71100 Foggia,
Italy; Tel 0881733652; Fax 0881745424; E-mail address: [email protected]
Case
A seventy-two years old woman, with arterial
hypertension, diabetes mellitus, permanent atrial
fibrillation and previous mitral commisuroplasty for
rheumatic mitral stenosis, was admitted to our Department, after a new decompensated heart failure
(WHO functional class III-IV).
An echocardiographic examination showed dilated right chambers, left ventricle with D-shaped
configuration, moderate mitral stenosis (mean PG: 9
mmHg), moderate aortic regurgitation, severe tricuspid regurgitation and the continuous-wave
Doppler showed a peak velocity consistent with a
pressure gradient of 95 mmHg and a pulmonary arterial systolic pressure (PAsP) of 115 mmHg.
Right heart catheterization showed a high mean pulmonary arterial pressure (mPAP 80mmHg) and high
pulmonary arterial wedge pressure (PWP 30mmHg)
with transpulmonary gradient (TPG) >12 mmHg
(mean PAP - mean PWP: 50 mmHg). She performed
the six minutes walking test and walked 230 meters
(53% of predicted value).
In ambulatory setting, the therapy for left heart
failure was most titrated; however, she remained in
WHO functional class III and she refused cardiac
surgery evaluation. So, we started therapy with sildenafil 10 mg die (with slow titration up to 60 mg die).
After one month of sildenafil therapy, she began to
improve functional and clinical status (260 m at the
6MWT and WHO functional class II-III) with a reduction of the PAsP (95 mmHg). After four months
of therapy, she received up to sildenafil 60 mg die
and further functional status improved (WHO functional class II). After 6 months no major events (hospitalization, cardiac death, death) was observed.
Discussion
Pulmonary hypertension with elevated TPG occurs in patients with mitral stenosis, and is significantly more common in females [1].
Most of the advances in the treatment of PH have
been made in PAH, while a few progress has been
made for the PH due to left heart diseases. Despite
the lack of data, drugs with proven efﬁcacy in PAH
are increasingly being used for other forms of PH.
Recent studies suggest the usefulness of sildenafil,
a phosphodiesterase-5 inhibitor in particular subgroups. In fact, sildenafil appears to be well tolerated
and can improve markers of cardiovascular and pulmonary function in patients with HF. So, the PDE5 inhibitors may be a therapeutic option for patients who
cannot tolerate standard therapy for HF or who remain
symptomatic with standard therapy, as in this case [2].
Sildenafil improves exercise capacity and quality of life in patients with systolic HF with secondary PH [3] and improves left ventricular diastolic function, cardiac geometry, and clinical status
in patients with stable systolic heart failure [4].
M. CORREALE ET AL.
However, contrast data come from subgroup
with HFpEF. In fact, in a multicenter, double-blind,
placebo-controlled, parallel-group, randomized clinical trial with 216 stable outpatients with HFpEF, the
authors showed administration of sildenafil for 24
weeks, compared with placebo, did not result in
significant improvement in exercise capacity or
clinical status [5].
Instead, we report a case of an elderly postmenopausal female with residual mitral stenosis
post-commissurotomy and permanent atrial fibrillation, where the therapy for left heart failure was
most titrated, but, she remained in WHO functional
class III. So, sildenafil therapy was performed and
she began to improve functional and clinical status
with a reduction of the PAsPs. After four months of
therapy, she received up to sildenafil 60 mg die and
further functional status improved (WHO functional class II).
Over the last decade there has been growing interest in using phosphodiesterase-5 (PDE-5) inhibitors in HF associated with group 2 pulmonary
hypertension (PH), with benefits reported on pulmonary haemodynamic and functional status only
in a single-centre trials [3], however our data seem
to confirm it.
zione ed ipertensione polmonare, refrattario alla
terapia convenzionale per lo scompenso cardiaco
sinistro e trattato con successo con sildenafil.
References
1.
2.
3.
4.
5.
Further studies to assess sildenafil efficacy and
tolerability in patients with HF and evidence of
group 2 PH are necessary, so recently, a randomized,
placebo-controlled multinational trial designed to
assess this aim in patients with HF (WHO functional
class II or III) and evidence of group 2 PH was designed and we looking forward the results [6].
Riassunto
Riportiamo il caso di una donna anziana con
scompenso cardiaco a preservata frazione d’eie-
194
6.
Hart SA, Krasuski RA, Wang A, Kisslo K, Harrison
JK, Bashore TM. Pulmonary hypertension and elevated
transpulmonary gradient in patients with mitral stenosis. J
Heart Valve Dis 2010 Nov; 19(6): 708-15.
Cvelich RG, Roberts SC, Brown JN. Phosphodiesterase
type 5 inhibitors as adjunctive therapy in the management
of systolic heart failure. Ann Pharmacother 2011 Dec;
45(12): 1551-8.
Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves
exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension.
Circulation 2007 Oct 2; 116(14): 1555-62.
Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic
function, cardiac geometry, and clinical status in patients
with stable systolic heart failure: results of a 1-year,
prospective, randomized, placebo-controlled study. Circ
Heart Fail 2011 Jan; 4(1): 8-17.
Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee
KL, Lewis G, LeWinter MM, Rouleau JL, Bull
DA, Mann DL, Deswal A, Stevenson LW, Givertz
MM, Ofili EO, O’Connor CM, Felker GM, Goldsmith
SR, Bart BA, McNulty SE, Ibarra JC, Lin G, Oh JK, Patel MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom
KJ, Hernandez AF, Mascette AM, Braunwald E; RELAX
Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with
preserved ejection fraction: a randomized clinical trial.
JAMA 2013 Mar 27; 309(12): 1268-77.
Cooper TJ, Guazzi M, Al-Mohammad A, Amir O, Bengal
T, Cleland JG, Dickstein K. Sildenafil in Heart failure
(SilHF). An investigator-initiated multinational randomized controlled clinical trial: rationale and design. Eur J
Heart Fail 2013 Jan; 15(1): 119-22.
www.gicr.it • www.aristea.com/gicr2014

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