La presentazione è in caricamento. Aspetta per favore

La presentazione è in caricamento. Aspetta per favore

Paolo Verdecchia, F.A.C.C., F.E.S.C., F.A.H.A. Hospital of Assisi Department of Medicine Via Valentin Müller, 1 06081 - Assisi PG

Presentazioni simili


Presentazione sul tema: "Paolo Verdecchia, F.A.C.C., F.E.S.C., F.A.H.A. Hospital of Assisi Department of Medicine Via Valentin Müller, 1 06081 - Assisi PG"— Transcript della presentazione:

1 Paolo Verdecchia, F.A.C.C., F.E.S.C., F.A.H.A. Hospital of Assisi Department of Medicine Via Valentin Müller, Assisi PG Dabigatran Simposio: Nuovi anticoagulanti orali: dai criteri di scelta all’esperienza sul campo

2 Conflict of Interest Disclosure Travel grants/fee for membership on Advisory Committees and speaking at scientific meetings: Boehringer-Inghelheim Bayer Daiichi-Sankyo Stroder Travel grants/fee for membership on Advisory Committees and speaking at scientific meetings: Boehringer-Inghelheim Bayer Daiichi-Sankyo Stroder No honorarium for today’s talk

3 Dabigatran 1.Lo studio RE-LY 2.Le indagini della Food and Drug Administration (FDA) 3.L’esperienza di Assisi

4 Dabigatran 1.Lo studio RE-LY 2.Le indagini della Food and Drug Administration (FDA) 3.L’esperienza di Assisi

5 ParametroRELY N = ROCKET-AF N = ARISTOTLE N = ENGAGE-AF N = Disegno dello studio: Multicentrico (951 centri), randomizzato, warfarin in aperto, dabigatran in doppia cecità (PROBE) Multicentrico (1178 centri), randomizzato, doppia cecità, double dummy Multicentrico (1030 centri), randomizzato, doppia cecità, double dummy Multicentrico (1393 centri), randomizzato, doppia cecità, double dummy Dose Dabigatran: 110 mg b.i.d.; 150 mg b.i.d. Rivaroxaban: 20 mg o.d. (15 mg o.d. se VFG cc/min) Apixaban: 5 mg b.i.d. (2.5 mg o.d. se età > 80, peso <60 o creatininemia > 1.5 mg/dl) Edoxaban: 60 mg od; 30 mg od. Dosi dimezzate se: VFG 30-50; peso <60, verapamil e/o chinidina Endpoint primario Composito di ictus (ischemico / emorragico) ed embolia sistemica Composito di ictus (ischemico ed emorragico) ed embolia sistemica Durata follow-up 2.0 anni (mediana)1.8 anni (mediana)1.9 anni (mediana)2.8 anni (mediana) Endpoint primario di sicurezza Sanguinamenti maggiori (inclusi i sanguinamenti pericolosi per la vita e quelli fatali) Composito di sanguinamenti maggiori e non maggiori clinicamente rilevanti Sanguinamenti maggiori (criteri ISTH) Età (anni) 71.5 (media)73 (mediana)70 (mediana)72 (mediana) CHADS 2 Score TTR (medio%) Analisi statistica Intention to treatPer protocol Intention to treat Per protocol Intention to treat

6 BID = 1 somministrazione ogni 12 ore Connolly SJ et al. N Engl J Med 2010;363:1875–6 6 Anni di osservazione Rischio cumulativo 0.00 Warfari n Dabigatran 110 mg BID Dabigatran 150 mg BID Dabigatran 150 mg BID vs. warfarin: HR 0.65 (95% CI: 0.52–0.81) Non inferiorità: p<0.001 Superiorità: p<0.001 Dabigatran 150 mg BID vs warfarin: -35% RE-LY: stroke or systemic embolism Dabigatran 110 mg BID vs. warfarin: RR 0.90 (95% CI: 0.74–1.10) Non inferiorità: p<0.001 Superiorità: p=0.30 Dabigatran 110 mg BID vs warfarin: -10%

7 Ischaemic Stroke -24% vs warfarin P= Warfarin Dabigatran 150 mg Dabigatran 110 mg p = p = N Engl J Med 2010;363:1875–6 N Engl J Med 2011;365: N Engl J Med 2011;365: Warfarin Edoxaban 30 mg Edoxaban 60 mg N Engl J Med 2013;369: % vs warfarin P<0.001

8 Warfarin Dabigatran 150 mg Dabigatran 110 mgApixabanRivaroxabanEdoxaban 30 mg Edoxaban 60 mg Haemorragic Stroke in RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF Rate (x 100 patients per year) HR 0.26 p<0.001 HR 0.51 p<0.001 HR 0.33 p<0.001 HR 0.54 p< HR 0.59 p=0.024 HR 0.31 p<0.001

9 Intracranial bleeding is less with dabigatran than with warfarin at any level of cTTR < 57.1% % %> 72.6% cTTR: Rate of intracranial bleeding (per 100 patients per year) cTTR < 57.1% D 110 mg vs warfarin: HR 0.43 ( ) D 150 mg vs warfarin: HR 0.53 ( ) cTTR % D 110 mg vs warfarin: HR 0.31 ( ) D 150 mg vs warfarin: HR 0.45 ( ) cTTR % D 110 mg vs warfarin: HR 0.20 ( ) D 150 mg vs warfarin: HR 0.35 ( ) cTTR > 72.6% D 110 mg vs warfarin: HR 0.27 ( ) D 150 mg vs warfarin: HR 0.39 ( ) Wallentin L et al. Lancet 2010;376:975–83

10 Warfarin Dabigatran 150 mg Dabigatran 110 mgApixabanRivaroxabanEdoxaban 30 mg Edoxaban 60 mg Major Bleedings in RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF Rate (x 100 patients per year) HR 0.81 p=0.002 HR 0.71 p<0.001 HR 0.53 p<0.001 HR 0.80 p<0.001 Lower with dabigatran 110 mg, apixaban and both doses of edoxaban versus warfarin

11 Warfarin Dabigatran 150 mg Dabigatran 110 mgApixabanRivaroxabanEdoxaban 30 mg Edoxaban 60 mg Gastrointestinal Bleedings in RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF Rate (x 100 patients per year) HR 1.49 p<0.001 HR 0.89 P=0.37 HR 0.67 p<0.001 HR 1.23 P= HR 1.45 P<0.05 HR 1.09 P=0.44 Lower only with edoxaban 30 mg versus warfarin Higher with dabigatran 150 mg, rivaroxaban and edoxaban 60 mg versus warfarin

12 Quindi, rispetto al warfarin, il dabigatran: Riduce significativamente l’end-point primario e l’ictus ischemico (150 mg), o è equivalente al warfarin (110 mg) Riduce drasticamente le emorragie endocraniche e l’ictus emorragico (110 mg e 150 mg) Riduce significativamente le emorragie maggiori (110 mg), o è equivalente al warfarin (150 mg) Aumenta le emorragie gastrointestinali (150 mg), o è equivalente al warfarin (110 mg)

13 Apix D150 Riva ED60 Warf ED30 D110 D150 ED60 Apix Riva D110 Warf ED30 Stroke/Systemic Embolism Stroke Ischaemic Stroke Death D150 ED60 Apix Riva D110 Warf ED30 D150 ED60 Apix Riva D110 Warf ED30 Apixaban (Apix)Dabigatran (D) 110 mg 150 mg Edoxaban (ED) 30 mg 60 mg Rivaroxaban (Riva)Warfarin (Warf) Probability of each rank Verdecchia P, Lip GYH, et al. Expert Opin Drug Saf Oct 14:1-14. [Epub ahead of print]

14 Apix D150 Riva ED60 Warf ED30 D110 D150 ED60 Apix Riva D110 Warf ED30 Major Bleeding Intracranial Bleeding Gastrointestinal Bleeding Myocardial Infarction D150 ED60 ApixRiva D110 Warf ED30 D150 ED60 Apix Riva D110 Warf ED30 Apixaban (Apix)Dabigatran (D) 110 mg 150 mg Edoxaban (ED) 30 mg 60 mg Rivaroxaban (Riva)Warfarin (Warf) Probability of each rank Verdecchia P, Lip GYH, et al. Expert Opin Drug Saf Oct 14:1-14. [Epub ahead of print]

15 Dabigatran 1.Lo studio RE-LY 2.Le indagini della Food and Drug Administration (FDA) 3.L’esperienza di Assisi

16

17 Event (x 100 patient-years) Dabigatran (N=67 207) Warfarin (reference) (N=67207) Adjusted HR (95% CI) Ischemic stroke ( ) Intracranial hemorrhage ( ) Major Gastrointestinal bleeding 3,422, ( ) Acute Myocardial Infarction 1,571, ( ) Death 3,263, ( ) Event Rates with Dabigatran (75 mg or 150 mg bid) vs Warfarin in patients with AF aged ≥ 65 years Graham DJ et asl. Circulation 2014; October 30

18 -20% Adjusted HR: 0.80 ( ); p= % Adjusted HR: 0.34 ( ); p< % Adjusted HR 0.86 ( ); p= % Adjusted HR: 1.28 ( ); p=0.006

19 Dabigatran 1.Lo studio RE-LY 2.Le indagini della Food and Drug Administration (FDA) 3.L’esperienza di Assisi

20 L’esperienza di Assisi Maria Gabriella MoliniFrancesca ValecchiPaolo Verdecchia Claudia BartoliniAdolfo Aita Letizia Di Giacomo Stefania Martone

21

22 Number115 Age (years)78.3 (  8) Weight (Kg)75.6 (  13) Height (cm)166.3 (  10) Sex (% women)53 Classification of AF (N, %) - New-onset24 (21%) - Paroxysmal12 (10%) - Persistent30 (26%) - Permanent49 (43%) Main Characteristics of Patients (1) Verdecchia P et al. Curr Op Drug Saf 2014 (in press)

23 CHA 2 DS 2 VASc Group Per cent of Patients Distribution of CHA 2 DS 2 VASc Verdecchia P et al. Curr Op Drug Saf 2014 (in press)

24 21% 18% 9% 52% Terapie antitrombotiche/antiaggreganti assunte in precedenza Warfarin Nulla Eparina Aspirina Verdecchia P et al. Curr Op Drug Saf 2014 (in press)

25 Sospensione Definitiva Trattamento N = 97 (84%) N = 18 (16%) Sospensione definitiva by Dabigatran dose: 11 su 76 pazienti (14%) con Dabigatran 110 mg 7 su 39 pazienti (18%) con Dabigatran 150 mg Sospensione definitiva: In media, 76 giorni dopo l’inizio del trattamento Cause sospensione definitiva: Distress epigastrico: 10 pazienti Sanguinamento GI: 1 paziente VFG < 30 ml/min: 3 pazienti Prurito intenso: 1 paziente By pass aorto-coronarico: 2 pazienti Polmonite: 1 paziente Totale18 pazienti Totale: 115 pazienti Dopo la sospensione: Warfarin:7 pazienti; Altro NAO: 7 pazienti Né anticoagulanti né ASA: 4 pazienti Verdecchia P et al. Curr Op Drug Saf 2014 (in press)

26 Tollerabilità Distress epigastrico Diarrea Sanguinamenti Minori Sanguinamenti Maggiori Assente (N=90) Presente (N=25 21,7%) Assente (N=106) Presenti (N=9; 7,8%) Assente (N=112) Presente (N=3 2,6%) Assenti (N=113) Presenti (N=2; 1,7%) Verdecchia P et al. Curr Op Drug Saf 2014 (in press)

27 A che punto siamo con l’antidoto ?

28 Sept 2014 Idarucizumab An Antidote Specific to Dabigatran Restoration of coagulation Potent binding affinity ~350 times higher than the binding of dabigatran to thrombin No procoagulant or anticoagulant effects Short half-life Easy and rapid administration IV administration, immediate onset of action Low risk of adverse reactions –No Fc receptor binding –No endogenous targets Idarucizumab is currently in development and is not approved for use in any country. The information presented here is intended for medical education purposes only Glund S et al. AHA 2013; abstract 17765; van Ryn J. AHA 2012; Presentation 9928; van Ryn J et al. Circulation 2012;126:A9928 Fully humanized antibody fragment (Fab)

29 Sept 2014 Healthy volunteer study: immediate, complete, and sustained reversal of dabigatran anticoagulation Idarucizumab is currently in development and is not approved for use in any country. The information presented here is intended for medical education purposes only ‘Normal upper reference limit’ refers to (mean+2SD) of 86 predose measurements from a total of 51 subjects Glund S et al. AHA 2013; abstract Dabigatran plus: Placebo (n=9) 1 g idarucizumab (day 4) (n=9) 2 g idarucizumab (day 4) (n=9) 4 g idarucizumab (day 4) (n=8) Normal upper reference limit (n=86) Mean baseline (n=86) 29 End of idarucizumab injection (5 min infusion) Dabigatran + placebo –2 Time after end of infusion (hours) dTT (s) Dabigatran Antidote

30 Sept 2014 First patient trial of a NOAC-specific antidote Study to evaluate reversal of the anticoagulant effects of dabigatran with idarucizumab in: Bleeding patients – overt bleeding judged by the physician to require a reversal agent Surgical patients – require an emergency surgery or procedure for a condition other than bleeding Idarucizumab is currently in development and is not approved for use in any country. The information presented here is intended for medical education purposes only NCT : Available at Accessed August 2014http://www.clinicaltrials.gov/ct2/show/NCT Started in April 2014, currently recruiting in >35 countries worldwide

31 Grazie per la vostra attenzione Grazie per la vostra attenzione

32 Rate of Major Bleeding (% per year) Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin Dans M et al. Circulation 2013;127: Of patients, 6952 (38.4%) received concomitant aspirin or clopidogrel, or both, at some time during the study (in 1 out of 5 for the total study duration).

33 Graham DJ et asl. Circulation 2014; October 30 La dose 150 mg bid (pazienti con VFG > 30 ml/min) è migliore del warfarin per ictus ischemico, emorragie endocraniche e mortalità, e peggiore del warfarin per emorragie gastrointestinali La dose 75 mg bid (pazienti con VFG < 30 ml/min) è equivalente al warfarin per ictus ischemico, sanguinamenti GI e mortalità, ma pur sempre migliore del warfarin per emorragie endocraniche

34 Drug-safety investigation, focused on the occurrence of bleeding, promoted by Food and Drug Administration (FDA) over the period October 19, 2010 to December 31, Limitations 1.Lack of adjustment for confounders 2.Lack of detailed medical records review Southworth MR et al. N Engl J Med 2013

35 Effect of Dabigatran Plasma Concentrations and Patient Characteristics on Ischemic Stroke and Major Bleeding in AF Patients Reilly PA et al. J Am Coll Cardiol 2014;63:321–8

36 Italia: individui Umbria: individui (1,5% della popolazione Italiana) 2.730/ piani terapeutici = 2.0% (rispetto ad 1,5% atteso)


Scaricare ppt "Paolo Verdecchia, F.A.C.C., F.E.S.C., F.A.H.A. Hospital of Assisi Department of Medicine Via Valentin Müller, 1 06081 - Assisi PG"

Presentazioni simili


Annunci Google