Clinical trial NCT00376272: GISSI-AF - Use of Valsartan an Angiotensin II AT1-Receptor Blocker in the Prevention of Atrial Fibrillation Recurrence
Official title: Randomized, Prospective, Parallel Group, Placebo-Controlled, Multi-Center Study on the Use of Valsartan an Angiotensin II AT1-Receptor Blocker in the Prevention of Atrial Fibrillation Recurrence
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Atrial Fibrillation
Keywords: atrial fibrillation,atrial remodeling,dysrhythmias,valsartan
Lead sponsor: Gruppo di Ricerca GISSI
Sponsor class: OTHER
First posted: 2006-09-14
Enrollment: 1442
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Study purpose The purpose of the study is to show that the addition of valsartan on top of established therapies can reduce the recurrence of atrial fibrillation in patients with a history of recent atrial fibrillation associated with cardiovascular diseases/comorbidities.

Primary objective To demonstrate that, in patients with history of recent atrial fibrillation treated with the best recommended therapies, the addition of valsartan 320 mg is superior to placebo in reducing atrial fibrillation recurrence.

Study design The GISSI-AF is a prospective, multicenter, randomized, double blind, placebo controlled study. Patients with a history of atrial fibrillation will be centrally randomized in a 1:1 ratio to receive either valsartan or placebo.

GISSI-AF will be a pragmatic trial, with broad selection criteria to mimic real clinical practice as much as possible. Since no special examinations or procedures are required for the trial, the economic impact on the National Health Service will be minimized and use of resources likely to be optimized. The enrollment period will last 12 months. The patients will be followed up for 12 months from study entry

All prescribed treatments for AF or for the underlying cardiovascular diseases, including ACE-inhibitors, amiodarone and betablockers, will be allowed:

* patients should be on a stable treatment for at least one month
* the current guideline for hypertension treatment should be applied
* patients should not be started on ARBs during the study

Detailed description: The protocol is sponsored by an independent organization and partially supported by Novartis

Eligibility criteria: Inclusion Criteria:

1. Male or female patients \>=40 years of age
2. Sinus rhythm
3. At least two ECG documented episodes of symptomatic AF in the previous 6 months or After a successful cardioversion for AF performed between 14 days and 48 hours before randomization
4. At least one of the following underlying cardiovascular diseases/comorbidities:

   * heart failure/documented history of LV dysfunction (defined as an EF \<40%)
   * history of hypertension \>=6 months with/without LVH
   * Type II diabetes mellitus
   * documented history of stroke or peripheral vascular disease
   * documented history of coronary artery disease
   * lone atrial fibrillation with documented LA dilation (LA diameter \>=45 mm for men and \>=40 mm for women)
5. Written informed consent to participate in the study prior to any study procedures

Exclusion Criteria:

1. Need for a continuous treatment with ARBs for any clinical reasons
2. Contraindications or known hypersensitivity to ARBs
3. Persistent standing systolic blood pressure \< 110 mmHg
4. Recent (\<6 weeks) acute myocardial infarction or bypass surgery, or percutaneous coronary intervention
5. Clinically significant valvular etiologies
6. Thyroid dysfunction
7. Indication for pacemaker or ICD implant or for an ablative treatment, recent (\<6 months) PM or ICD implant, previous ablative treatment
8. Planned cardiac surgery, expected to be performed within 3 months
9. Serum creatinine level above 2.5 mg/dL
10. Significant liver disease
11. Pregnant or lactating women or women of childbearing potential who are not protected from pregnancy by an accepted method of contraception
12. Any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety or be associated with poor adherence to the protocol
13. Presence of any non-cardiac disease (e.g. cancer) that is likely to significantly shorten life expectancy
14. Treatment with any investigational agent within 1 month before randomization
15. Currently decompensated heart failure

Primary outcomes:
measure: To demonstrate that, in patients with history of recent AF treated with the best recommended therapies, the addition of valsartan (titrated up to 320 mg daily) is superior to placebo in reducing over the whole follow-up:
timeFrame: Time to first AF recurrence
measure: First recurrence of AF,
timeFrame: time to first AF recurrence
measure: Rate of patients with more than one AF episode,
timeFrame: end of follow-up
Secondary outcomes:
measure: Number of AF episodes
timeFrame: end of fw-up
measure: Number of hospitalizations for CV reasons
timeFrame: end of fw-up
measure: Number of all-cause hospitalizations
timeFrame: end of fw-up
measure: Incidence of thromboembolic events
timeFrame: end of fw-up
measure: Number of patients who die or with non-fatal thromboembolic events
timeFrame: end of fw-up
measure: Number of patients in sinus rhythm at the time of each study visit
timeFrame: end of fw-up
measure: Number of patients in sinus rhythm who did not have any prior AF recurrence during the study
timeFrame: end of fw-up
measure: Duration and characteristics (ventricular rate) of the first recurrence of AF.
timeFrame: end of fw-up
Other outcomes:
Locations:
city: Cortona
country: Italy
facility: Ospedale Valdichiana Santa Margherita
state: AR
city: Asti
country: Italy
facility: Ospedale Cardinal Massaia
state: AT
city: Avellino
country: Italy
facility: Azienda Ospedaliera Giuseppe Moscati
state: AV
city: Bari - Carbonara
country: Italy
facility: Ospedale di Venere
state: BA
city: Bari
country: Italy
facility: Ospedale Consorziale Policlinico
state: BA
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo
state: BG
city: Bentivoglio
country: Italy
facility: Ospedale di Bentivoglio
state: BO
city: Bologna
country: Italy
facility: Ospedale Maggiore
state: BO
city: Bologna
country: Italy
facility: Ospedale Bellaria
state: BO
city: Brescia
country: Italy
facility: Casa di Cura Poliambulanza
state: BS
city: Chiari
country: Italy
facility: Ospedale Civile Mellini
state: BS
city: Bolzano
country: Italy
facility: Ospedlae Generale Regionale
state: BZ
city: Cagliari
country: Italy
facility: Azienda Ospedaliera G. Brotzu - S. Michele
state: CA
city: Aversa
country: Italy
facility: Presidio Ospedaliero Moscati
state: CE
city: Caserta
country: Italy
facility: Azienda Ospedaliera Sant'Anna e San Sebastiano
state: CE
city: Piedimonte Matese
country: Italy
facility: Ospedale Civile Ave Gratia Plena
state: CE
city: San Felice a Cancello
country: Italy
facility: Ospedale Ave Gratia Plena
state: CE
city: Santa Maria Capua Vetere
country: Italy
facility: Ospedale San Giuseppe e Melorio
state: CE
city: Cuneo
country: Italy
facility: Azienda Ospedaliera Santa Croce e Carle
state: CN
city: Saluzzo
country: Italy
facility: Ospedale Civile Saluzzo
state: CN
city: Crema
country: Italy
facility: Ospedlae Maggiore
state: CR
city: Cremona
country: Italy
facility: Istituti Ospitalieri di Cremona
state: CR
city: Cosenza
country: Italy
facility: Ospedale Santissima Annunziata
state: CS
city: Cosenza
country: Italy
facility: Presidio Ospedaliero Mariano Santo
state: CS
city: Paola
country: Italy
facility: Ospedale San Francesco di Paola
state: CS
city: Rogliano
country: Italy
facility: Ospedale Santa Barbara
state: CS
city: San Marco Argentano
country: Italy
facility: Presidio Ospedaliero San Marco Argentano
state: CS
city: Trebisacce
country: Italy
facility: Ospedale Civile "G. Chidichimo"
state: CS
city: Catania
country: Italy
facility: Ospedale Garibaldi - Nesima
state: CT
city: Catanzaro
country: Italy
facility: Ospedale Civile Pugliese
state: CZ
city: Lamezia Terme
country: Italy
facility: Ospedale Civile
state: CZ
city: Località Germaneto - Catanzaro
country: Italy
facility: Azienda Ospedaliera Mater Domini
state: CZ
city: Nicosia
country: Italy
facility: Ospedale G. Basilotta
state: EN
city: Ferrara
country: Italy
facility: Arcispedale Sant'Anna
state: FE
city: Bagno a Ripoli
country: Italy
facility: Ospedale Santa Maria Annunziata
state: FI
city: Firenze
country: Italy
facility: Nuovo Ospedale San Giovanni di Dio
state: FI
city: Genova-Sampierdarena
country: Italy
facility: Ospedali Civili di Sampierdarena
state: GE
city: Genova-Voltri
country: Italy
facility: Ospedale San Carlo
state: GE
city: Monfalcone
country: Italy
facility: Ospedale Civile San Paolo
state: GO
city: Imperia
country: Italy
facility: Ospedale Civile
state: IM
city: Crotone
country: Italy
facility: Ospedale Civile San Giovanni di Dio
state: KR
city: Casarano
country: Italy
facility: Presidio Ospedaliero F. Ferrari
state: LE
city: Scorrano
country: Italy
facility: Ospedale Ignazio Veris Delli Ponti
state: LE
city: Cecina
country: Italy
facility: Ospedale Civile Bassa Val di Cecina
state: LI
city: Livorno
country: Italy
facility: Ospedali Riuniti
state: LI
city: Formia
country: Italy
facility: Ospedale del dono Svizzero
state: LT
city: Lucca
country: Italy
facility: Ospedale Civile Campo di Marte
state: LU
city: Milazzo
country: Italy
facility: Ospedale Civile
state: ME
city: Giussano
country: Italy
facility: Ospedale Carlo Borella
state: MI
city: Milano
country: Italy
facility: Ospedale San Raffaele
state: MI
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: MI
city: Sesto San Giovanni
country: Italy
facility: Multimedica SPA
state: MI
city: Modena
country: Italy
facility: Ospedale Policlinico
state: MO
city: Sassuolo
country: Italy
facility: Nuovo Ospedale Civile di Sassuolo
state: MO
city: Matera
country: Italy
facility: Ospedale Madonna delle Grazie
state: MT
city: Policoro
country: Italy
facility: Ospedale Civile
state: MT
city: Palermo
country: Italy
facility: Ospedale Buccheri La Ferla Fatebenefratelli
state: PA
city: Palermo
country: Italy
facility: A.R.N.A.S. Ospedale Civico e Benfratelli
state: PA
city: Palermo
country: Italy
facility: Ospedale V. Cervello
state: PA
city: Palermo
country: Italy
facility: Presidio Ospedaliero Villa Sofia
state: PA
city: Este
country: Italy
facility: Ospedale Generale Provinciale
state: PD
city: Penne
country: Italy
facility: Ospedale Civile San Massimo
state: PE
city: Città di Castello
country: Italy
facility: Ospedale Alta Valle del Tevere
state: PG
city: Foligno
country: Italy
facility: Nuovo Ospedale San Giovanni Battista
state: PG
city: Pordenone
country: Italy
facility: Azienda Ospedaliera S. Maria degli Angeli
state: PN
city: Fidenza
country: Italy
facility: Ospedale Civile
state: PR
city: Pesaro
country: Italy
facility: Azienda Ospedaliera San Salvatore
state: PU
city: Pavia
country: Italy
facility: IRCCS - Fondazione Salvatore Maugeri
state: PV
city: Pavia
country: Italy
facility: Ospedale Policlinico San Matteo IRCCS
state: PV
city: Cotignola
country: Italy
facility: Csa di Cura Villa Maria Cecilia
state: RA
city: Polistena
country: Italy
facility: Ospedale Santa Maria degli Ungheresi
state: RC
city: Reggio Calabria
country: Italy
facility: Policlinico Madonna della Consolazione
state: RC
city: Scilla
country: Italy
facility: Ospedale Scillesi D'America
state: RC
city: Albano Laziale
country: Italy
facility: Ospedali Riuniti Albano-Genzano
state: RM
city: Roma
country: Italy
facility: Ospedale San Filippo Neri
state: RM
city: Roma
country: Italy
facility: CTO
state: RM
city: Roma
country: Italy
facility: Ospedale San Giovanni
state: RM
city: Roma
country: Italy
facility: Ospedale San Camillo
state: RM
city: Roma
country: Italy
facility: Ospedale San Camillo
state: RM
city: Roma
country: Italy
facility: Ospedale Sant'Andrea
state: RM
city: Rimini
country: Italy
facility: Ospedale Infermi
state: RN
city: Porto Viro
country: Italy
facility: Casa di Cura Madonna della Salute
state: RO
city: Rovigo
country: Italy
facility: Presidio Ospedaliero
state: RO
city: Mercato San Severino
country: Italy
facility: Ospedale G. Fucito
state: SA
city: Vallo della Lucania
country: Italy
facility: Ospedale San Luca
state: SA
city: Sarzana - Loc. Santa Caterina
country: Italy
facility: Ospedale San Bartolomeo
state: SP
city: Pietra Ligure
country: Italy
facility: Ospedale Santa Corona
state: SV
city: Taranto
country: Italy
facility: Casa di Cura Villa Verde
state: TA
city: Taranto
country: Italy
facility: Ospedale SS. Annunziata
state: TA
city: Teramo
country: Italy
facility: Ospedale Civile G. Mazzini
state: TE
city: Cles
country: Italy
facility: Ospedale di Cles
state: TN
city: Trento
country: Italy
facility: Casa di Cura Villa Bianca
state: TN
city: Torino
country: Italy
facility: Ospedale Evangelico Valdese
state: TO
city: Terni
country: Italy
facility: Azienda USL 4 Terni
state: TR
city: Trento
country: Italy
facility: Ospedale Santa Chiara
state: TR
city: Trieste
country: Italy
facility: Azienda Servizi Sanitari N. 1 Triestina
state: TS
city: Trieste
country: Italy
facility: Azienda Ospedaliera - Univ. Ospedali Riuniti
state: TS
city: Conegliano Veneto
country: Italy
facility: Ospedale De Gironcoli
state: TV
city: Conegliano Veneto
country: Italy
facility: Ospedale Santa Maria dei Battuti
state: TV
city: Palmanova
country: Italy
facility: Ospedale di Ialmicco - Palmanova - Udine
state: UD
city: San Daniele del Friuli
country: Italy
facility: Ospedale S. Antonio
state: UD
city: Udine
country: Italy
facility: Santa Maria della Misericordia
state: UD
city: Varese
country: Italy
facility: Azienda Ospedaliera e Universitaria
state: VA
city: Mestre
country: Italy
facility: Ospedale Civile Umberto I
state: VE
city: Mirano
country: Italy
facility: Ospedale Civile
state: VE
city: Bovolone
country: Italy
facility: Ospedale Civile San Biagio
state: VR
city: San Bonifacio
country: Italy
facility: Ospedale G. Fra Castoro
state: VR
city: Soriano Calabro
country: Italy
facility: Presidio Ospedaliero
state: VV
city: Vibo Valentia
country: Italy
facility: Ospedale Civile G. Jazzolino
state: VV
city: Giugliano in Campania
country: Italy
facility: Ospedale Generale di Zona
city: Napoli
country: Italy
facility: Azienda Ospedaliera Vincenzo Monaldi
city: Napoli
country: Italy
facility: Policlinico Universitario Federico II
city: Pozzuoli
country: Italy
facility: Ospedale Santa Maria delle Grazie
city: Lugano
country: Switzerland
facility: Cardiocentro Ticino
Study officials:
affiliation: Gruppo di Ricerca GISSI
name: Marcello Disertori, MD
role: STUDY_CHAIR
affiliation: Gruppo di Ricerca GISSI
name: Roberto Latini, MD
role: STUDY_CHAIR
References:
citation: Disertori M, Latini R, Maggioni AP, Delise P, Di Pasquale G, Franzosi MG, Staszewsky L, Tognoni G; GISSI-AF Investigators. Rationale and design of the GISSI-Atrial Fibrillation Trial: a randomized, prospective, multicentre study on the use of valsartan, an angiotensin II AT1-receptor blocker, in the prevention of atrial fibrillation recurrence. J Cardiovasc Med (Hagerstown). 2006 Jan;7(1):29-38. doi: 10.2459/01.JCM.0000199778.85343.08.
citation: GISSI-AF Investigators; Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, Maggioni AP, Lucci D, Di Pasquale G, Tognoni G. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med. 2009 Apr 16;360(16):1606-17. doi: 10.1056/NEJMoa0805710.
citation: Disertori M, Franzosi MG, Barlera S, Cosmi F, Quintarelli S, Favero C, Cappellini G, Fabbri G, Maggioni AP, Staszewsky L, Moroni LA, Latini R; GISSI-AF investigators. Thromboembolic event rate in paroxysmal and persistent atrial fibrillation: data from the GISSI-AF trial. BMC Cardiovasc Disord. 2013 Apr 15;13:28. doi: 10.1186/1471-2261-13-28.
citation: Staszewsky L, Wong M, Masson S, Raimondi E, Gramenzi S, Proietti G, Bicego D, Emanuelli C, Pulitano G, Taddei F, Nicolis EB, Correale E, Fabbri G, Bertocchi F, Franzosi MG, Maggioni AP, Tognoni G, Disertori M, Latini R; GISSI-AF Investigators. Left atrial remodeling and response to valsartan in the prevention of recurrent atrial fibrillation: the GISSI-AF echocardiographic substudy. Circ Cardiovasc Imaging. 2011 Nov;4(6):721-8. doi: 10.1161/CIRCIMAGING.111.965954. Epub 2011 Sep 16.
citation: Disertori M, Lombardi F, Barlera S, Maggioni AP, Favero C, Franzosi MG, Lucci D, Staszewsky L, Fabbri G, Quintarelli S, Bianconi L, Latini R. Clinical characteristics of patients with asymptomatic recurrences of atrial fibrillation in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation (GISSI-AF) trial. Am Heart J. 2011 Aug;162(2):382-9. doi: 10.1016/j.ahj.2011.05.008. Epub 2011 Jul 7.
citation: Disertori M, Lombardi F, Barlera S, Latini R, Maggioni AP, Zeni P, Di Pasquale G, Cosmi F, Franzosi MG; GISSI-AF Investigators. Clinical predictors of atrial fibrillation recurrence in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation (GISSI-AF) trial. Am Heart J. 2010 May;159(5):857-63. doi: 10.1016/j.ahj.2010.02.016.