Terapia e profilassi. Quali dati nella pratica clinica?

Transcript

1 Terapia e profilassi i antitrombotica nel DEA Quali dati nella pratica clinica? Dott. Rita Bonfini

2 Definizione AHA 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) 2) absence of distinct repeating P waves 3) irregular atrial activity. ESC AF is defined as a cardiac arrhythmia with the following characteristics: (1) The surface ECG shows absolutely l 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. (3) The atrial cycle length (when visible), i.e. the interval between two atrial activations, is usually variable and,200 ms (.300 bpm).

3 Classificazione 1 Valvolari: correlabili a malattia reumatica - impianto di valvole. ESC: valvular AF is used to imply that AF is related to rheumatic valvular disease (predominantly mitral stenosis) or prosthetic heart valves Non valvolari:

4 Classificazione 2 AIAC Di nuova insorgenza Ricorrente Parossistica Persistente Persistente di lunga durata Permanente Silente Secondaria Primitiva

5 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 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 bpm

6 Ripristino di ritmo sinusale Cardioversione Farmacologica Elettrica Studio elettrofisiologico ed ablazione

7

8 Ifarmaci Farmaco Dosaggio Raccomandazione Flecainide 2 mg/kg in min (max 150 mg) ev mg singola dose os Propafenone 2mg/kg in min (max 150 mg) ev mg singola dose os Classe I Livello A Classe I Livello A Ibutilide 1 mg in 10 min: dopo 10 min Classe I Livello A ripetere se necessario mg in 10 min ev Amiodarone 5 7 mg/kg in 60 min, seguiti da 15 mg/kg in 24 h ev 600 mg/d x 2 3 settimane (o 10 mg/kg x 10 gg) poi 200 mg die os Vernakalant 3 mg/kg in 10 min ripetibile 2 mg/kg dopo 15 min Classe IIb Livello A Classe I Livello A

9 Cardioversione elettrica 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 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 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

10 Complicanze AHA: AF, whether paroxysmal, persistent, or permanent, and whether symptomatic or silent, significantly ifi increases the risk of thromboembolic b ischemic i stroke. Nonvalvular l 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. 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 ( %) è paragonabile a quello dei pazienti con FA permanente

11 Risk stratification schemes CHA2DS2 - CHA2DS2-VASC - HAS-BLED

12 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 values and preference. (Level of Evidence: C) Selection of antithrombotic therapy should be based on the risk of thromboembolism irrespective of whether the AF pattern is paroxysmal, persistent, t or permanent. (Level of Evidence: B) In patients with nonvalvular AF, the CHA 2DS 2-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 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 CHA 2 DS 2 -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)

13 Casistica italiana - 295,906 pazienti hanno presentato FA (0,16% anni, 9,0% anni, 10,7% 85 anni ) - Incidenza di fibrillazione atriale è stata 2,04% : 20,2% parossistica 4,3% persistente 55,5% 5% permanente - 91,5% dei pazienti aveva una comorbilità cardiaca Il punteggio CHA2DS2: 0 per 12,1% 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. Studio ISAF (Italian Survey Atrial Fibrillation)

14 Casistica italiana pazienti con FA non valvolare Terapia antitrombotica: % 5% dei pazienti Terapia anticoagulante t Età avanzata abitudine alcoolica % dei pazienti Terapia antiaggregante procedure a rischio di sanguinamento, scarsa % dei pazienti - Nessuna terapia Età avanzata, abitudine alcoolica, compliance, rischio di 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)

15

16 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

17 Warfarin Agisce su diversi fattori della coagulazione. Se mantenuto nella finestra terapeutica (INR 2-3) 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.

18 Dabigatran etexilato 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 CHADS 2 score was 2.1 and the primary outcome was stroke (of any type) and systemic embolism, with any major hemorrhage being the primary safety outcome. Half of the patients were naïve to oral anticoagulants. The mean TTR for those randomized to Warfarin was 64%. The primary outcome 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.

19 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 Interazioni con IPP Rapida fase di distribuzione Escrezione renale 80% (riduzione dose nell Insufficienza renale)

20 Dabigatran etexilato Ottobre 2015: FDA approva Idarucizumab antagonista specifico di Dabigatran che mostra 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 terapie chirurgiche urgenti in paz trattati con Dabigatran -Effetto terapeutico massimo entro 4 h

21 Rivaroxaban 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 on the ROCKET AF (Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation) trial, which was an RCT comparing rivaroxaban (20 mg once daily, 15 mg once daily if CC CrCl was30ml/min to49ml/min) with warfarin among 14,264 patients. ROCKET AF differed from RE-LY in that it selected higher-risk patients with AF ( 2 riskfactorsforstroke compared with 1 risk factor) the primary hypothesis was noninferiority The trial 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 more strokes with rivaroxaban than with warfarin. The risk of stroke wassimilar il for patients t assigned to rivaroxaban and warfarin

22 Rivaroxaban Inibitore diretto selettivo del fattore Xa 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

23 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 blind RCT of 18,201 patients with AF and a mean CHADS 2 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 benefit was independent of type of AF, risk profile, CHADS 2 or CHA 2 DS 2 -VASc score, and whether there was a prior stroke. Apixaban was compared with aspirin in the AVERROES study. The mean CHADS 2 scorewas2and 36% of the subjects had a CHADS 2 score of 0 to 1. After ameanfollow-up of 1.11 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 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 endstage 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 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.

24 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)

25 Casistica italiana - 295,906 pazienti hanno presentato FA (0,16% anni, 9,0% anni, 10,7% 85 anni ) - Incidenza di fibrillazione atriale è stata 2,04% : 20,2% parossistica 4,3% persistente 55,5% 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 g piastrinico 16,5% non ha ricevuto alcuna terapia antitrombotica. Studio ISAF (Italian Survey Atrial Fibrillation)

26 16,5% non assunto alcuna terapia antitrombotica In patients with nonvalvular AF, the CHA 2 DS 2 -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 CHA 2DS 2-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) Il punteggio CHA2DS2 era: 0 per 12,1% 1 per 25,3% 2 per 62,6%

27 37,5% ha assunto farmaco antiaggregante piastrinico Aspirin i 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 CHADS 2 score of 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 dampenedd by the significant ifi increase in major bleeding events.

28 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 CHA 2 DS 2 -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 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 CHA 2 DS 2 - 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)

29 Xantus European Heart Journal Advance Access published September 1, 2015 Primo studio osservazionale internazionale, (approvato EMA), prevenzione dello stroke in pazienti del mondo reale con FANV. prospettico di un NAO per la 6784 pazienti arruolati (78.7%) 20 mg Rivaroxaban (20.8%) 15 mg - 35 (0.5%) Altre dosi 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)

30 - 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); - 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. 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 CHADS 2 (fermo restando che il farmaco rimane approvato per la prevenzione dello stroke in pazienti con FANV e uno o più fattori di rischio).

31 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; Italia suddivisa in macroaree (Nord-Centro-Sud); Terapia anticoagulante Nord 61% - Centro 60% - Sud 53% 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

32 Quote di mercato AC Lazio agosto % 30% Coumadin NAO 32% Altri AC Sintrom 25%

33 25% 20% 18,3% 19,9% 15,9% Quota di mercato 15% 10% 5% 0% 5,4% 3,7% 3,2% 27% 2,7% 1,6% 0,4% 0,0% 0,1% 8,0% 4,6% 27% 2,7% 0,7% 12,3% 10,6% 5,2% 5,4% 3,9% 4,9% 2,1% 1,4% 14,1% 5,6% 5,6% 29% 2,9% 6,5% 5,8% 3,5% 7,6% 6,2% 4,5% 8,3% 6,6% 5,1% NOA Xarelto Pradaxa Eliquis

34

35 Grazie per l attenzione!