T Terapia e profilassi i fil i antitrombotica nel DEA - - PowerPoint PPT Presentation

T i fil i Terapia e profilassi antitrombotica nel DEA antitrombotica nel DEA

Quali dati nella pratica clinica?

Dott Rita Bonfini

• Dott. Rita Bonfini

Definizione

AHA

AF is a supraventricular tachyarrhythmia with uncoordinated atrial activation and consequently

Definizione

AF is a supraventricular tachyarrhythmia with uncoordinated atrial activation and consequently ineffective atrial contraction. Electrocardiogram (ECG) characteristics include: 1) irregular R-R intervals (when atrioventricular [AV] conduction is present) [ ] p ) 2) absence of distinct repeating P waves 3) irregular atrial activity.

ESC

AF is defined as a cardiac arrhythmia with the following characteristics: (1) Th f ECG h ‘ b l t l ’ i l RR i t l (AF i th f ti (1) The surface ECG shows ‘absolutely’ irregular RR intervals (AF is therefore sometimes known as arrhythmia absoluta), i.e. RR intervals that do not follow a repetitive pattern. (2) There are no distinct P waves on the surface ECG. Some apparently regular atrial electrical activity may be seen in some ECG leads, most often in lead V1. electrical activity may be seen in some ECG leads, most often in lead V1. (3) The atrial cycle length (when visible), i.e. the interval between two atrial activations, is usually variable and ,200 ms (.300 bpm).

Classificazione 1 Classificazione 1

• Valvolari: correlabili a malattia reumatica

impianto di valvole

• Valvolari: correlabili a malattia reumatica - impianto di valvole.

ESC: valvular AF is used to imply that AF is related to rheumatic valvular disease (pre- dominantly mitral stenosis) or prosthetic heart valves

• Non valvolari:
• Non valvolari:

Classificazione 2 Classificazione 2

AIAC

• Di nuova insorgenza
• Ricorrente
• Parossistica
• Persistente – Persistente di lunga durata

Persistente Persistente di lunga durata

• Permanente
• Silente

Silente

• Secondaria
• Primitiva

Primitiva

Trattamento Trattamento

Controllo del ritmo - ripristino di ritmo sinusale

ESC 2010: An inappropriate ventricular rate and irregularity of the rhythm can cause symptoms and severe haemodynamic distress in AF rhythm can cause symptoms and severe haemodynamic distress in AF patients.

Controllo della frequenza – FC < 100

ESC 2010: Patients with a rapid ventricular response usually need acute control of their ventricular rate… In the acute setting, the target ventricular rate should usually be 80– 100 bpm…

Ripristino di ritmo sinusale Ripristino di ritmo sinusale

Farmacologica Cardioversione g Elettrica Studio elettrofisiologico ed ablazione

I farmaci I farmaci

Farmaco Dosaggio Raccomandazione Flecainide

• 2 mg/kg in 10‐20 min (max 150

mg) ‐ ev

• 200 – 300 mg singola dose ‐ os

Classe I Livello A Propafenone

2 mg/kg in 10‐20 min (max 150 mg) ‐ ev 450‐600 mg singola dose ‐ os

Classe I Livello A Ibutilide

1 mg in 10 min: dopo 10 min

Classe I Ibutilide

1 mg in 10 min: dopo 10 min ripetere se necessario 0.5‐1 mg in 10 min ‐ ev

Classe I Livello A Amiodarone

5‐7 mg/kg in 60 min, seguiti da 15 /k i 24 h

Classe IIb

mg/kg in 24 h – ev 600 mg/d x 2‐3 settimane (o 10 mg/kg x 10 gg) poi 200 mg die ‐

• s

Livello A Vernakalant

3 mg/kg in 10 min ripetibile 2 mg/kg dopo 15 min

Classe I Livello A

Cardioversione elettrica Cardioversione elettrica Indicazioni Indicazioni

FA di recente insorgenza (< 48 ore), in alternativa alla cardioversione farmacologica

I C

FA con compromissione emodinamica, indipendentemente dalla durata dell’aritmia*

I C

FA di durata > 48 in paziente già in appropriata terapia anticoagulante orale

I C I C

FA di durata > 48 ore, previa adeguata terapia anticoagulante orale per almeno 3 settimane**

I C

FA in presenza di preeccitazione ventricolare

IIa C

FA sintomatica quando i periodi di ritmo sinusale tra una CVE e l’altra sono di breve durata, nonostante trattamento farmacologico antiaritmico adeguato

III C III C

FA in presenza di ipokaliemia e intossicazione digitalica

III C

*Se durata dell’aritmia non databile o > 48 ore somministrare eparina frazionata e.v. o eparina a basso peso molecolare s.c. e contestualmente iniziare terapia anticoagulante orale. **Se FA recidivante, prima di eseguire nuovamente CVE, iniziare trattamento farmacologico antiaritmico.

Linee guida AIAC 2010

Complicanze Complicanze

AF, whether paroxysmal, persistent, or permanent, and whether symptomatic or silent, i ifi tl i th i k f th b b li i h i t k N l l AF

AHA:

significantly increases the risk of thromboembolic ischemic stroke. Nonvalvular AF increases the risk of stroke 5 times and AF in the setting of mitral stenosis increases the risk of stroke 20 times over patients in sinus rhythm. Thromboembolism occurring with AF is associated with a greater risk of recurrent stroke, more severe disability, and mortality. is associated with a greater risk of recurrent stroke, more severe disability, and mortality. Silent AF is also associated with ischemic stroke.

ESC:

Stroke risk is a continuum and the predictive value of artificially categorizing AF patients into low, moderate, and high-risk strata only has modest predictive value for identifying the ‘high-risk’ category of patients who would subsequently suffer strokes.

AIAC:

La FA è responsabile del 15-18% di tutti i casi di stroke… il rischio annuale di stroke per i pazienti con FA parossistica (2.6-3.2%) è paragonabile a quello dei pazienti con FA permanente

Risk stratification schemes Risk stratification schemes

CHA2DS2 - CHA2DS2-VASC - HAS-BLED

AHA raccomendation – Class I AHA raccomendation Class I

In patients with AF, antithrombotic therapy should be individualized based on shared decision- making after discussion of the absolute and RRs of stroke and bleeding and the patient’s making after discussion of the absolute and RRs of stroke and bleeding, and the patient s values and preference. (Level of Evidence: C) Selection of antithrombotic therapy should be based on the risk of thromboembolism i ti f h th th AF tt i l i t t t (L l f In patients with nonvalvular AF, the CHA2DS2-VASc score is recommended for assessment of irrespective of whether the AF pattern is paroxysmal, persistent, or permanent. (Level of Evidence: B)

2 2

stroke risk. (Level of Evidence: B) For patients with AF who have mechanical heart valves, Warfarin is recommended and the target international normalized ratio (INR) intensity (2.0 to 3.0 or 2.5 to 3.5) should be based

• n the type and location of the prosthesis. (Level of Evidence: B)

For patients with nonvalvular AF with prior stroke, transient ischemic attack (TIA), or a CHA DS -VASc score of 2 or greater oral anticoagulants are recommended Options include: CHA2DS2-VASc score of 2 or greater, oral anticoagulants are recommended. Options include: Warfarin (INR 2.0 to 3.0) (Level of Evidence: A), Dabigatran (Level of Evidence: B), Rivaroxaban (Level of Evidence: B), or Apixaban. (Level of Evidence: B)

Casistica italiana Casistica italiana

• 295,906 pazienti 6.036 hanno presentato FA (0,16% 16-50 anni, 9,0% 76-85 anni, 10,7% ‡ 85

anni ) anni )

• Incidenza di fibrillazione atriale è stata 2,04% : 20,2% parossistica

4,3% persistente 55 5% t 55,5% permanente

• 91,5% dei pazienti aveva una comorbilità cardiaca

Il punteggio CHA2DS2: 0 per 12 1% Il punteggio CHA2DS2: 0 per 12,1% 1 per 25,3% 2 per 62,6%

46% dei pazienti ha assunto anticoagulanti 37,5% un farmaco antiaggregante piastrinico 16 5% non ha ricevuto alcuna terapia antitrombotica 16,5% non ha ricevuto alcuna terapia antitrombotica.

Studio ISAF (Italian Survey Atrial Fibrillation) - 2013

Casistica italiana 2 Casistica italiana 2

7148 pazienti con FA non valvolare Terapia antitrombotica: 55 5% d i i ti T i ti l t

Età avanzata abitudine alcoolica

• 55.5% dei pazienti – Terapia anticoagulante
• 35.8% dei pazienti – Terapia antiaggregante
• 8.7 % dei pazienti - Nessuna terapia

Età avanzata, abitudine alcoolica, procedure a rischio di sanguinamento, scarsa compliance, rischio di traumatismo sanguinamenti traumatismo, sanguinamenti ricorrenti, problematiche ematologiche SOLO IL 60% DEI PAZ CON PREGRESSO ICTUS O TIA HA RICEVUTO TERAPIA ANTICOAGULANTE

ATA-AF study (international Journal of cardiology – 2012)

Studi clinici Studi clinici

ACTIVE-W: Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular

Events

ACTIVE-A: Clopidogrel + Aspirina versus Aspirina RE-LY: Randomized Evaluation ol Long term anticoagulation therapy (Dabigatran

versus Warfarin)

ROCKET-AF: Rivaroxaban versus Warfarin in NVAF ARISTOTLE: Apixaban versus Warfarin in pazienti con NVAF AVERROES: Apixaban versus Aspirina per pazienti non idonei a Warfarin AVERROES: Apixaban versus Aspirina per pazienti non idonei a Warfarin

Warfarin Warfarin

Agisce su diversi fattori della coagulazione. Se mantenuto nella finestra terapeutica (INR 2-3) costituisce un valido alleato nella prevenzione delle complicanze tromboemboliche costituisce un valido alleato nella prevenzione delle complicanze tromboemboliche . MA: - Interazioni con numerosi farmaci ed alimenti;

• Effetto dose dipendente;
• Necessità di controlli continui per dosaggio.

Dabigatran etexilato Dabigatran etexilato

Dabigatran is the first new oral anticoagulant approved by the U S Food and Drug Dabigatran is the first new oral anticoagulant approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF, and is a direct thrombin inhibitor. Dabigatran was compared with Warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which was an open-label randomized comparison of Dabigatran (110 mg or 150 mg twice daily in a blinded fashion) with adjusted-dose Warfarin in 18,113 patients over a median follow-up period of 2 years. The mean CHADS2 score was 2.1 and the primary outcome was stroke (of any type) and systemic embolism with any major hemorrhage being the primary safety any type) and systemic embolism, with any major hemorrhage being the primary safety

• utcome. Half of the patients were naïve to oral anticoagulants. The mean TTR for those

randomized to Warfarin was 64%. The primary

• utcome

was assessed first for noninferiority followed by superiority. For the primary outcomes, dabigatran 150 mg twice daily was superior to warfarin, and dabigatran 110 mg twice daily was noninferior to warfarin. Compared with warfarin, the risk of hemorrhagic strokes was also significantly lower (74% lower) with both the 110 mg and 150 mg doses. Major bleeding was significantly decreased with the 110 mg dose but not with the 150 mg dose decreased with the 110 mg dose but not with the 150 mg dose.

Dabigatran etexilato Dabigatran etexilato

• Inibitore diretto della trombina (fattore IIa)- Profarmaco lipofilo
• Metabolismo intestinale-epatico
• Picco plasmatico in 2 h
• Biodisponibilità e farmacocinetica aumentano dopo la singola dose
• Somministrazione per 2/die

p

• Interazioni con IPP

Rapida fase di distribuzione

• Rapida fase di distribuzione
• Escrezione renale 80% (riduzione dose nell’Insufficienza renale)

Dabigatran etexilato Dabigatran etexilato

Ottobre 2015: FDA approva Idarucizumab antagonista specifico di Dabigatran che mostra g g immediata, completa e duratura inversione nell’effetto anticoagulante Somministrazione di 5 g di Idarucizumab (due infusioni separate di 2.5 g) in 15 minuti

• Nelle emorragie incontrollabili in pazienti in trattamento con Dabigatran
• Nelle emorragie incontrollabili in pazienti in trattamento con Dabigatran
• Nelle terapie chirurgiche urgenti in paz trattati con Dabigatran
• Effetto terapeutico massimo entro 4 h

Rivaroxaban Rivaroxaban

The second new oral anticoagulant approved by the FDA for reduction of risk of stroke and The second new oral anticoagulant approved by the FDA for reduction of risk of stroke and systemic embolism in patients with nonvalvular AF. The evidence leading to approval was based

• n

the ROCKET AF (Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation) trial, which was an RCT comparing rivaroxaban (20 mg once daily, 15 mg once f C C / / ) f OC daily if CrCl was 30 mL/min to 49 mL/min) with warfarin among 14,264 patients. ROCKET AF differed from RE-LY in that it selected higher-risk patients with AF (≥2 risk factors for stroke compared with 1 risk factor)… the primary hypothesis was noninferiority…The trial demonstrated noninferiority for rivaroxaban compared with warfarin; however in the intention- demonstrated noninferiority for rivaroxaban compared with warfarin; however, in the intention to-treat analysis, superiority was not achieved (p=0.12). Major bleeding was similar for rivaroxaban and warfarin, but less fatal bleeding and less intracranial hemorrhage, were found for rivaroxaban. At the end of the trial, patients transitioning to open-label therapy had t k ith i b th ith f i Th i k f t k i il f ti t more strokes with rivaroxaban than with warfarin…. The risk of stroke was similar for patients assigned to rivaroxaban and warfarin

Rivaroxaban Rivaroxaban

• Inibitore diretto selettivo del fattore Xa
• Non ha effetti sull’aggregazione piastrinica

Non ha effetti sull aggregazione piastrinica

• Effetto inibente di durata 8-12 h dopo singola dose per dosi >5mg
• Monosomministrazione giornaliera (ritorno a valori iniziali in 24 h)
• Assorbito per os
• Picco di concentrazione in 2-4 h
• Metabolismo epatico (no insufficienza epatica)
• Cautela nell’insufficienza renale e nel basso peso – Controindicato nell’insufficienza renale

grave

Apixaban Apixaban

The third new oral anticoagulant approved by the FDA. In the ARISTOTLE (Apixaban Versus Warfarin in Patients With Atrial Fibrillation) trial, Apixaban (5 mg twice daily) was compared with warfarin in a double-blind RCT of 18,201 patients with AF and a mean CHADS2 score of 2.1. warfarin in a double blind RCT of 18,201 patients with AF and a mean CHADS2 score of 2.1. Apixaban was significantly better than warfarin, with fewer overall strokes (both ischemic and hemorrhagic), systemic embolism, and major bleeding events. Patients treated with apixaban had significantly fewer intracranial bleeds, but gastrointestinal bleeding complications were similar. Patients treated with apixaban had fewer deaths than those on warfarin In ARISTOTLE apixaban’s Patients treated with apixaban had fewer deaths than those on warfarin. In ARISTOTLE, apixaban s benefit was independent of type of AF, risk profile, CHADS2 or CHA2DS2-VASc score, and whether there was a prior stroke. Apixaban was compared with aspirin in the AVERROES study. The mean CHADS2 score was 2 and 36% f th bj t h d CHADS f 0 t 1 Aft f ll f 1 1 th t d 36% of the subjects had a CHADS2 score of 0 to 1. After a mean follow-up of 1.1 years, the study was prematurely terminated owing to the superiority of apixaban compared with aspirin for preventing the occurrence of any stroke or systemic embolism, whereas bleeding risk was similar. Patients with severe and end-stage CKD (serum creatinine >2.5 mg/dL or CrCl <25 mL/min) were g ( g ) excluded from the ARISTOTLE and AVERROES trials. Based on new pharmacokinetic profiles in a limited data set, apixaban prescribing recommendations were revised for use in patients with end- stage CKD maintained on stable hemodialysis with the recommended dose of 5 mg twice daily with a reduction in dose to 2.5 mg twice daily for either ≥80 years of age or body weight ≤60 kg. For reduction in dose to 2.5 mg twice daily for either ≥80 years of age or body weight ≤60 kg. For patients with severe or end-stage CKD not on dialysis a dose recommendation was not provided. There are no published data for the use of apixaban in these clinical settings.

Apixaban Apixaban

• Agisce selettivamente sul fattore Xa
• Assorbito rapidamente in stomaco ed intestino
• Picco di concentrazione 1-3 h
• Basso potenziale di interferenza con altri farmaci
• Emivita 8-15 h
• Eliminazione renale 25% - il resto intestino/bile

Peso del paziente dipendente (<50 >120 necessita aggiustamento di dose)

• Peso del paziente dipendente (<50->120 necessita aggiustamento di dose)

Casistica italiana Casistica italiana

• 295,906 pazienti 6.036 hanno presentato FA (0,16% 16-50 anni, 9,0% 76-85 anni, 10,7% ‡ 85

anni ) anni )

• Incidenza di fibrillazione atriale è stata 2,04% : 20,2% parossistica

4,3% persistente 55 5% t 55,5% permanente

• 91,5% dei pazienti aveva una comorbilità cardiaca

Il punteggio CHADS2: 0 per 12,1% 1 per 25,3% 2 per 62,6%

46% dei pazienti ha assunto anticoagulanti 37,5% un farmaco antiaggregante piastrinico , gg g p 16,5% non ha ricevuto alcuna terapia antitrombotica.

Studio ISAF (Italian Survey Atrial Fibrillation) - 2013

16,5% non assunto alcuna terapia antitrombotica

In patients with nonvalvular AF, the CHA2DS2-VASc score is recommended for assessment of stroke risk. (Level of Evidence: B) For patients with nonvalvular AF with prior stroke, transient ischemic attack (TIA), or a CHA2DS2-VASc score of 2 or greater, oral anticoagulants are recommended. Options

2 2

g , g p include: Warfarin (INR 2.0 to 3.0) (Level of Evidence: A), Dabigatran (Level of Evidence: B), Rivaroxaban (Level of Evidence: B), or Apixaban. (Level of Evidence: B) Il punteggio CHA2DS2 era: 0 per 12,1% 1 per 25,3% 2 per 62,6%

37,5% ha assunto farmaco antiaggregante piastrinico A i i i ff ti i ti t k i th >75 f d Aspirin was ineffective in preventing strokes in those >75 years of age and did not prevent severe strokes

Clopidogrel plus aspirin was evaluated for stroke prevention in the ACTIVE-W trial…. proved inferior to Warfarin (target INR 2.0 to 3.0) in patients with a mean CHADS2 score

• f 2. ACTIVE-A compared clopidogrel combined with aspirin versus aspirin alone in

patients with AF The results of ACTIVE-W and ACTIVE-A demonstrate that adjusted-dose warfarin for stroke prevention is significantly better than clopidogrel plus aspirin, and clopidogrel plus aspirin is superior to aspirin alone. The latter benefits are d d b th i ifi t i i j bl di t dampened by the significant increase in major bleeding events.

46% ha assunto un anticoagulante

In patients with AF, antithrombotic therapy should be individualized based on shared decision-making after discussion of the absolute and RRs of stroke and bleeding, and the patient’s values and preferences. (Level of Evidence: C) In patients with nonvalvular AF, the CHA2DS2-VASc score is recommended for assessment of stroke risk. (Level of Evidence: B) For patients with AF who have mechanical heart valves warfarin is recommended and the target For patients with nonvalvular AF with prior stroke transient ischemic attack (TIA) or a CHA DS For patients with AF who have mechanical heart valves, warfarin is recommended and the target international normalized ratio (INR) intensity (2.0 to 3.0 or 2.5 to 3.5) should be based on the type and location of the prosthesis. (Level of Evidence: B) For patients with nonvalvular AF with prior stroke, transient ischemic attack (TIA), or a CHA2DS2- VASc score of 2 or greater, oral anticoagulants are recommended. Options include: warfarin (INR 2.0 to 3.0) (Level of Evidence: A), dabigatran (Level of Evidence: B), rivaroxaban (Level of Evidence: B), or apixaban. (Level of Evidence: B) For patients with nonvalvular AF unable to maintain a therapeutic INR level with warfarin, use of a direct thrombin or factor Xa inhibitor (dabigatran, rivaroxaban, or apixaban) is recommended. (Level of Evidence: C) Renal function should be evaluated prior to initiation of direct thrombin or factor Xa inhibitors and should be re-evaluated when clinically indicated and at least annually. (Level of Evidence: B)

Xantus Xantus

Primo studio osservazionale internazionale (approvato EMA) prospettico di un NAO per la

European Heart Journal Advance Access published September 1, 2015

Primo studio osservazionale internazionale, (approvato EMA), prospettico di un NAO per la prevenzione dello stroke in pazienti del mondo reale con FANV. 6784 pazienti arruolati - 5336 (78.7%) 20 mg Rivaroxaban ( %)

• 1410 (20.8%) 15 mg
• 35

(0.5%) Altre dosi Età media 71 5 anni Età media 71.5 anni CHA2DS2 2.0 <ROCKET-AF 3.5 CHA2DS2VASc 3.4 ±RE-LY / ARISTOTLE Stroke 0.7 paz/100/anno inferiore a ROCKET-AF, RE-LY, ARISTOTLE (1.7) Emorragie maggiori 2.1 paz/100/anno inferiore a ROCHET-AF, RE-LY, ARISTOTLE (3.6) Per emostasi in corso di terapia: sospensione del farmaco, Concentrato di Complessi Protrombinici, Ac Tranexemico, Etamsilato Maggiore aderenza terapeutica (monosomministrazione)

• Conferma i dati di sicurezza ed efficacia di Rivaroxaban in ROCKET AF nel mondo reale

con tassi di sanguinamenti maggiori pari al 2,1%/anno e tassi di stroke/embolia sistemica al 0.8%/anno e riduzione delle emorragie digestive (0.9%/anno); al 0.8%/anno e riduzione delle emorragie digestive (0.9%/anno);

• 96% dei pazienti non ha sperimentato alcun outcome tra stroke ed embolia sistemica,

sanguinamento maggiore o mortalità per tutte le cause mentre ricevevano Rivaroxaban;

• Mono-somministrazione Rivaroxaban ha portato ad un tasso di aderenza alla terapia, nel

mondo reale, pari all’80% nel periodo di un anno di osservazione e più del 75% dei pazienti si sono detti “molto soddisfatti” o “soddisfatti” dal loro trattamento. pazienti si sono detti molto soddisfatti o soddisfatti dal loro trattamento. ROCKET-AF CHA2DS2 medio 3,5 (range 2-6) XANTUS CHA2DS2 medio 2,0 (range 0-6) Rivaroxaban ha dati a supporto in tutto lo spettro di valori di CHADS2 (fermo restando che il farmaco rimane approvato per la prevenzione dello stroke in pazienti con FANV e uno o più fattori di rischio). uno o più fattori di rischio).

ARAPACIS ARAPACIS

Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assesment Collaborative Italian Study Intern Emerg Med (2014)

• Ritratto italiano sull’aderenza prescrittiva nella NVAF ;
• Arruolati 1366 pazienti con FA non Valvolare CHA2DS2-VASC > 2;

Intern Emerg Med (2014)

• Italia suddivisa in macroaree (Nord-Centro-Sud);
• Terapia anticoagulante

Nord 61% - Centro 60% - Sud 53%

• Terapia antiaggregante

Nord 18% - Centro 24% - Sud 35% Terapia antiaggregante Nord 18% Centro 24% Sud 35%

• Aderenza terapeutica

Nord 79% - Centro 64% - Sud 59% Soltanto il 60% dei pazienti ha ricevuto terapia antitrombotica adeguata (dati congruenti con altri studi clinici) Considerare l’uso dei NOAC come alternativa applicabile per la prevenzione del rischio tromboembolico Aumentare l’aderenza? Educazione del paziente Livello socioeconomico

Quote di mercato AC Lazio – agosto 2015

13% 30% 13% 32%

Coumadin NAO Altri AC

25% 32%

Sintrom

25%

25% 15 9% 18,3% 19,9% 20% 12,3% 14,1% 15,9% 15% mercato NOA 8,0% 10,6% 7,6% 8,3% 10% Quota di Xarelto Pradaxa Eliquis 3,2% 5,4% 2 7% 3,9% 4,9% 5,6% 6,5% 2 7% 3,7% 4,6% 5,2% 5,4% 5,6% 5,8% 6,2% 6,6% 2 9% 3,5% 4,5% 5,1% 5% 0,4% 1,6% 2,7% 2,7% 0,0% 0,1% 0,7% 1,4% 2,1% 2,9% 0%

Grazie per l’attenzione!