Dabigatran L anticoagulazione reversibile

Capri Conference 2.0-15/16 Aprile 2016 Presidente Prof. Massimo Volpe Hotel La Residenza - Via F. Serena, 22-80073 Capri Dabigatran L anticoagulazione reversibile Claudio Ferri Università dell Aquila Cattedra e Scuola di Medicina Interna Dipartimento MeSVA UOC di Medicina Interna e Nefrologia Ospedale San Salvatore

Connolly S et al. N Engl J Med 2009;361:1139-1151,* Connolly SJ., et al. N Engl J Med 2010; 363 (19):1875-7 RE-LY Study: Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group Percent Time in Therapeutic Range (TTR) 67% warfarinexperienced 61% warfarin-naïve relative risk with dabigatran 110 mg, 0.91; 95% CI, 0.74 to 1.11 P<0.001 for non inferiority relative risk with dabigatran 150 mg, 0.65; 95% CI, 0.52 to 0.81; p<0.001 for superiority *

0.0 0.02 0.04 0.06 0.08 Cumulative Hazard Rates RE-LY Study: Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group, in patients with prior stroke/tia : time to primary outcome # at Risk Year 0.5 1.0 1.5 2.0 2.5 D110 1195 1160 1132 908 573 289 D150 1233 1201 1164 938 617 321 W 1195 1160 1126 895 565 262 Warfarin Dabigatran 110 mg Dabigatran 150 mg RR dabigatran 150 mg versus warfarin 0 75 (0 52-1 08) Years of follow-up 0 0.5 1.0 1.5 2.0 2.5 Diener HC et al. Lancet Neurol. 2010;9(12):1157-63

1) Where are different forms of AF? Atrial fibrillation Valvular AF Yes Yes No (i.e. nonvalvular) <65 years and lone AF (including females) No Assess risk of stroke CHA 2 DS 2 -VASc score 0 1 2 No antithrombotic therapy Oral anticoagulant therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences NOAC VKA Eur Heart J 2012 2012 Focused update of the ESC Guidelines for the management of atrial fibrillation

Type of AF in the RE-LY study Connolly SJ., et al. N Engl J Med 2010; 363 (19):1875-7

Type of AF in the RE-LY study - Stroke/systemic embolism D110 Type of AF D150 D110 Annual rate (%) Warfari n D150 vs warfarin HR (95% CI) Paroxysmal 1.09 1.07 1.77 0.61 (0.42 0.90) D110 vs warfarin HR (95% CI) 0.60 (0.41 0.89) Paroxysmal D150 Persistent 1.14 1.72 1.80 0.64 (0.43 0.93) 0.96 (0.69 1.35) Persistent D150 Interaction P=0.8835 Permanent 1.11 1.78 1.58 0.70 (0.48 1.01) 1.13 (0.81 1.57) Permanent D110 Interaction P=0.0465 RE-LY total 1.11 1.54 1.71 0.65 (0.52 0.81) 0.90 (0.74 1.10) 0.1 BID = twice daily; D150 = dabigatran 150 mg BID; HR = hazard ratio 1 Hazard ratio 10 Flaker G et al. J Am Coll Cardiol. 2012;59:854 5

2) Choice of Anticoagulant:Where is ASA? Atrial fibrillation Valvular AF* Yes Yes No (i.e. nonvalvular) <65 years and lone AF (including females) No Assess risk of stroke CHA 2 DS 2 -VASc score 0 1 2 Oral anticoagulant therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences No antithrombotic therapy NOAC VKA Antiplatelet therapy with ASA plus clopidogrel or less effectively ASA only, should be considered in patients who refuse any OAC or cannot tolerate anticoagulation for reasons unrelated to bleeding. Eur Heart J 2012 2012 Focused update of the ESC Guidelines for the management of atrial fibrillation

Incidenza di ictus cerebri per 1000 pazienti per anno ACTIVE Study - Ictus cerebri in pazienti con FA Major bleedings Nessun trattamento antitrombotico Aspirina Warfarin Vazquez FJ et al Thromb Res. 2016;138:1-6.

Lip GY et al Stroke. 2014;45(7):2127-30. AVERROES Study - Ictus cerebri e sanguinamenti maggiori in pazienti con FA

3) What is Nonvalvular? Atrial fibrillation Valvular AF * Yes Yes No (i.e. nonvalvular) <65 years and lone AF (including females) No Assess risk of stroke CHA 2 DS 2 -VASc score 0 1 2 * No antithrombotic therapy Oral anticoagulant therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences NOAC VKA EHRA practical guide 2015 Eur Heart J 2012 2012 Focused update of the ESC Guidelines for the management of atrial fibrillation

Definitions of Nonvalvular AF? * Study SPORTIF III SPORTIF V PETRO RE-LY ROCKET AF J-ROCKET AF Dabigatran Study AVERROES ARISTOTLE ARISTOTLE-J EDOXABAN PHASE II STUDY ENGAGE AF-TIMI 48 EXPLORE Xa History of heart valve disorder including haemodinamically relevant mitral valve disease and prostethic valve Modified from: De Caterina R, Camm J. European Heart Journal (2014) 35, 3328 3335 * MARM-AF = mechanical and rheumatic mitral valvular AF

Valvular Heart Disease associated with AF in the RE-LY study Ferreira J et al. European Journal of Heart Failure doi:10.1093/eurjhf/hft111

Stroke/SE and major bleedings in valvular AF Stroke/SEE Rivaroxaban Interaction p value n.s. Apixaban Dabigatran 150 mg Dabigatran 110 mg Major Bleedings Rivaroxaban Apixaban Dabigatran 150 mg Dabigatran 110 mg Valvular 0.5. 1.0. 2.0 Nonvalvular Hohnloser SH and Lopes RD. European Heart Journal (2014) 35, 3323 3325 n.s. n.s. n.s. p=0.034 n.s. n.s. n.s.

Rischio Tromboembolico ed Emorragico versus Warfarin Dabigatran 150 mg RE-LY Dabigatran 110 mg Stroke/SE: Non inferiorità HR 0.90 (0.74-1.10) Stroke/SE: Superiorità Riduzione ictus emorragico HR 0.66 (0.53-0.82) HR 0.26 (0.14-0.49) HR 0.31 (0.17-0.56) Riduzione emorragie cerebrali HR 0.41 (0.28-0.60) HR 0.30 (0.19-0.45) Riduzione ictus ischemico Riduzione mortalità totale HR 0.76 (0.59-0.97) Riduz. mortalità vascolare Riduz. emorragie maggiori Riduz. emorragie fatali Riduz. emorragie intestinali HR 0.85 (0.72-0.99) HR 0.80 (0.70-0.93) HR 0.58 (0.35-0.97)

Rate of intracranial bleeding (per 100 patient per year) Wallentin L et al. Lancet 2010;376:975 83 Intracranial bleeding is less with dabigatran than with warfarin at any level of cttr cttr: < 57.1% 57.1-65.5% 65.5-72.6% > 72.6% cttr < 57.1% D 110 mg vs warfarin: HR 0.43 (0.19-1.00) D 150 mg vs warfarin: HR 0.53 (0.25-1.15) cttr 57.1-65.5% D 110 mg vs warfarin: HR 0.31 (0.15-0.66) D 150 mg vs warfarin: HR 0.45 (0.24-0.88) cttr 65.5-72.5% D 110 mg vs warfarin: HR 0.20 (0.07-0.58) D 150 mg vs warfarin: HR 0.35 (0.15-0.82) cttr > 72.6% D 110 mg vs warfarin: HR 0.27 (0.11-0.66) D 150 mg vs warfarin: HR 0.39 (0.18-0.84)

Modified from: Lopalco PL and DeStefano F Vaccine 2015;33(13):1541-8. NAO: i dati post-marketing After marketing authorisation has been granted, Phase 4 trials and other post-licensure surveillance activities can be carried out. Their scope is primarily to assess - Long-term effectiveness - Safety (than can be not statistically significant in Phase 3 trials) Phase 4 studies can be an integral part of the authorisation process in terms of post-marketing action required by the regulatory agencies Phase 4 studies are complemented by other post-licensure surveillance activities that are carried out by different agents (public health institutions, universities, research groups) as part of their public health mission

NAO: i dati post-marketing FDA may require postmarketing studies and clinical trials To assess a known serious risk related to the use of the drug To assess signals of a serious risk related to the use of the drug To identify an unexpected serious risk when available data indicate the potential for serious risk http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/ucm292758.htm

NAO: i dati post-marketing Unitamente alla normativa vigente sulla farmacovigilanza post-marketing, il MINSAL ha (30.4.2015, GU 23.6.2015, n.143) decretato: Art. 6 - Studi dopo l autorizzazione 1. Dopo aver rilasciato un autorizzazione all immissione in commercio, l AIFA può imporre al titolare della stessa l obbligo: a) di effettuare uno studio sulla sicurezza dopo l autorizzazione se esistono problematiche quanto ai rischi per un medicinale autorizzato. Se sussistono le stesse pro-blematiche di sicurezza in merito a più di un medicinale, l AIFA, previa consultazione del comitato di valutazione dei rischi per la farmacovigilanza, invita i titolari delle autorizzazioni all immissione in commercio interessati a effettuare uno studio congiunto sulla sicurezza dopo l autorizzazione; b) di effettuare uno studio sull efficacia dopo l autorizzazione qualora le conoscenze della malattia o la metodologia clinica indichino che le precedenti valutazioni dell efficacia potrebbero essere riviste in misura significativa. L obbligo di effettuare lo studio sull efficacia dopo l autorizzazione è basato sugli atti delegati adottati a norma del comma 5, tenendo conto degli orientamenti scientifici di cui all art. 41

Statistiche del Registro Danese Dabigatran Larsen TB et al J Am Coll Cardiol. 2013;61(22):2264-2273.

Idarucizumab was designed as a specific reversal agent for anticoagulant activity of dabigatran Humanized Fab fragment Binding affinity ~350 higher than dabigatran to thrombin Dabigatran No intrinsic procoagulant or anticoagulant activity IV dosing by bolus or rapid infusion, immediate onset of action Idarucizumab Short half-life Schiele et al. Blood 2013; Stangier et al. OR 320; presented at ISTH 2015

Changes in the distribution of dabigatran after idarucizumab administration Eikelboom JW et al. Circulation. 2015;132:2412-2422

dtt (s) Idarucizumab provided immediate, complete, and sustained reversal of dabigatran anticoagulation in human volunteers End of idaarucizumab (5-min infusion) 70 65 60 55 50 45 40 Dabigatran + placebo (n=9) Dabigatran + 4 g idarucizumab (day 4) (n=8) Immediate, complete, and sustained reversal 1 Consistent pattern in elderly patients and patients with moderate renal impairment 2 No serious adverse events reported 2 35 30 2 0 2 4 6 8 10 12 24 36 48 60 72 Time after end of infusion (hours) 1. Glund S et al. Lancet 2015 june 15; 2. Glund et al et al. Blood 2014, 124: abstr. 344

Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) Clinical Characteristics of the Patients Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) Time Course of the Dilute Thrombin Time and Ecarin Clotting Time Pollack CV Jr et al. N Engl J Med 2015;373:511-520.

Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) Plasma Concentrations of Unbound Dabigatran and Idarucizumab Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) Serious Adverse Events Leading to Death Pollack CV Jr et al. N Engl J Med 2015;373:511-520.

Sommario e Conclusioni Il NOAC dabigatran è più efficace (150 mg) o egualmente (110 mg) efficace rispetto a warfarin Il NOAC dabigatran riduce le emorragie intracraniche e quelle fatali rispetto a warfarin L uso di Idarucizumab ripristina la coagulazione nel paziente in terapia con il NOAC dabigatran nel periodo immediatamente seguente la sua somministrazione e.v. L uso di Idarucizumab non è caratterizzato da eventi avversi e non è soggetto a titolazione L uso di Idarucizumab non è seguito da immunizzazione