Dagli studi clinici al real life

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1 UNIVERSITA DEGLI STUDI DEL PIEMONTE ORIENTALE A. AVOGADRO OSPEDALE MAGGIORE DELLA CARITA NOVARA Dagli studi clinici al real life Dott.G.Francalacci Divisione Clinicizzata di Cardiologia Novara, 15/01/2015

2 I VKA hanno un ristre0o range Ictus ischemico terapeu3co Emorragia intracranica Eventi / 1000 pazienti-anno Target INR ( ) L effetto anticoagulante dei VKA è ottimale quando le dosi terapeutiche vengono mantenute entro un range molto stretto 0 < >4.5 International Normalized Ratio (INR) Hylek EM, et al. N Eng J Med 2003;349:

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5 Solo la metà dei pazienti in TAO è in range terapeutico in Italia

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7 Lo sviluppo dei NAO negli studi clinici Dabigatran RE- LY Pubblicato 2009 Rivaroxaban Rivaroxaban ROCKET Pubblicato 2011 Edoxaban ENGAGE AF Risula3 pubblicato AVERROES Pubblicato 2011 ARISTOTLE Pubblicato 2011 PRATICA CLINICA Apixaban

8 In the USA, the licensed doses for Pradaxa are: Pradaxa 150 mg BID and Pradaxa 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF IN EUROPA I DOSAGGI REGISTRATI DI PRADAXA SONO 110 E 150 MG

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11 RE-LY Sicurezza

12 Dabigatran: esperienza nella pratica clinica Food and Drug Administration 2 Novembre 2012 FDA Drug Safety Communica4on: Safety review of post- market reports of serious bleeding events with the an4coagulant Pradaxa (dabigatran etexilate mesylate) I risulta3 della valutazione post marke3ng svolta indicano che i tassi di sanguinamento rileva3 nei pazien3 che hanno iniziato l assunzione di Pradaxa non risultano superiori a quelli di warfarin. Ques3 da3 sono coeren3 con le osservazioni dello studio clinico di grandi dimensioni RE- LY u3lizzato per l approvazione di Pradaxa SouthWorth et al., 2013 NEJM.org. March 13 12

13 Esperienza di Pratica CLINICA da 6 anni di utilizzo in oltre pz. Registri osservazionali americani e danesi > patients from independent FDA Medicare study 1 > patients from two large US health insurance databases 2 > patients from US Department of Defense (DoD) database 33 > patients from independent Danish observational studies 4, /CIRCULATIONAHA ; 2. Seeger JD et al. Presented at AHA 2014; 3. Villines TC et al. Presented at AHA 2014; 4. Larsen TB et al. Am J Med 2014;127:650 6.e5; 5. Larsen TB et al. Am J Med 2014;127: e4 13

14 > patients (new users dabigatran or warfarin -OAC treatment-naïve) from independent FDA Medicare study Observational cohort study Comparison of ischaemic stroke, ICH, major GI bleeding, acute MI, and mortality rates using insurance-claim and administrative data All recently diagnosed with AF All aged 65 years person-years of follow-up 2010 Study period 2012

15 * Incidence rate per 1000 person-years Adjusted HR (95% CI) Dabigatran Warfarin Ischaemic stroke ( ) Intracranial haemorrhage ( ) Major GI bleeding ( ) Acute MI ( ) Mortality ( ) In the USA, the licensed doses for Pradaxa are: Pradaxa 150 mg BID and Pradaxa 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by 15 dose HR = hazard ratio Available at accessed September 2014

16 Independent FDA Medicare analysis findings are consistent with findings from RE-LY 0.86 Medicare 1 > patients RE-LY 2 4 > patients Independent FDA analysis confirmed the favourable benefit risk profile of dabigatran in clinical practice In the USA, the licensed doses for Pradaxa are: Pradaxa 150 mg BID and Pradaxa 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF Numbers on bars denote HRs vs warfarin. D75 = dabigatran 75 mg; D150 = dabigatran 150 mg 1. Available at accessed September 2014; 2. Connolly SJ et al. N Engl J Med 2009;361: ; 3. Connolly SJ et al. N Engl J Med 2010;363:1875 6; 4. Pradaxa : EU SPC,

17 > patients from two large US health insurance databases (MarketScan and UnitedHealth) 2 Observational cohort study new users of dabigatran or warfarin CHA2DS2-VASc score 1 Comparison of stroke (effectiveness), major bleeding (safety) and secondary outcomes 2010 Study period 2012 Mean follow-up 5 months (dabigatran); 4 months (warfarin)

18 Incidence rate per 100 person-years HR (95% CI) Dabigatran (pooled) Warfarin (pooled) Stroke ( ) Major bleeding ( ) Intracranial bleeding ( ) Extracranial bleeding ( ) GI bleeding ( ) MI ( ) * Significant reduction in stroke risk in larger MarketScan database: * MarketScan: HR 0.64 (95% CI ) * UnitedHealth: HR 1.62 (95% CI ) Significant reduction in major bleeding in both databases * MarketScan: HR 0.78 (95% CI ) * United Health: HR 0.56 (95% CI ) A selected subset of secondary outcomes are shown; In the USA, the licensed doses for Pradaxa are: Pradaxa 150 mg BID and Pradaxa 75 mg BID for the prevention of stroke 18and systemic embolism in adult patients with nonvalvular AF; Pooled data from MarketScan and Optum US health insurance databases Seeger JD et al. Presented at AHA 2014

19 > patients from US Department of Defense (DoD) database 3 Observational study Comparison of stroke (effectiveness), major bleeding (safety) and secondary outcomes > new users (OAC treatment-naïve) of dabigatran or warfarin AF diagnosis within 12 months prior to first OAC treatment Aged years at index date Study period Mean follow-up 9.9 months (dabigatran); 7.2 months (warfarin)

20 * Dabigatran vs warfarin Adjusted HR and 95% CI HR (95% CI) P value Stroke Ischaemic stroke Haemorrhagic stroke TIA VTE DVT PE 0.73 ( ) ( ) ( ) ( ) ( ) ( ) ( ) Favours dabigatran Favours warfarin In the USA, the licensed doses for Pradaxa are: Pradaxa mg BID and Pradaxa 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF Villines TC et al. Presented at AHA 2014

21 * Dabigatran vs warfarin Adjusted HR and 95% CI HR (95% CI) P value Major bleeding Major intracranial bleeding Major extracranial bleeding Major GI bleeding Major upper GI bleeding Major lower GI bleeding Major urogenital bleeding Major other bleeding MI Death 0.87 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) < Favours dabigatran Favours warfarin In the USA, the licensed doses for Pradaxa are: Pradaxa mg BID and Pradaxa 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF Villines TC et al. Presented at AHA 2014

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23 Dabigatran nel real life: il Danish Registry

24 Patients with AF, stratified by prior VKA use first-time dabigatran users (7063 VKA-naïve) matched warfarin users Dabigatran 110 and 150mg analyzed separately 2011 Study period months of follow-up (mean) 24 Larsen TB et al. Am J Med 2014;127:650 6.e5. doi: /j.amjmed

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26 * VKA-naïve stratum Hazard ratio (95% CI) Adjusted HR Dabigatran 110 mg vs warfarin Any Major Fatal GI ICH 0.72 ( ) 0.93 ( ) 0.52 ( ) 0.50 ( ) 0.30 ( ) Dabigatran 150 mg vs warfarin Any Major Fatal GI 0.68 ( ) 0.67 ( ) 0.70 ( ) 1.45 ( ) ICH 0.33 ( ) Conclusion: Except for GI bleeding among D150 users, rates of fatal, GI, and intracranial bleeding were decreased Dabigatran relative Dabigatran to warfarin worse among both groups of dabigatran users in the VKA-naïve stratum. better These findings are consistent with RE-LY *Adjusted HR; Age, components of CHA 2 DS 2 -VASc, HAS-BLED, months since August 2011, time since initiation of VKA therapy VKA = Vitamin K antagonist; Larsen TB et al. Am J Med 2014;127:650 6.e5. doi: /j.amjmed

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28 * Dabigatran vs warfarin MI D110 MI D150 VKA-naïve stratum HR (95% CI) Dabigatran better Dabigatran worse Adjusted HR 0.71 ( ) 0.93 ( ) *Adjusted HR; Age, components of CHA 2 DS 2 -VASc, HAS-BLED, history of any MI event, months since August 2011, time since initiation of VKA therapy Larsen TB et al. Am J Med 2014;127: e4. doi: /j.amjmed

29 Conclusion: Except for GI bleeding among D150 users, rates of fatal, GI, and intracranial bleeding were decreased relative to warfarin among both groups of dabigatran users in the VKA-naïve stratum. These findings are consistent with RE-LY

30 Registri in corso sulla ges3one della FA 55,000 Pazienti in 34 paesi Pazienti consecutivi indipendentemente dalle caratteristiche 2 anni follow-up Sponsor: Bayer 56,000 pazienti in 50 paesi Pazienti ad alto rischio di stroke con FA nv < 3 mesi Follow-up: 2017 Sponsor: Boehringer

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32 1888 pz arruolati in italia

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36 Il GIGANTE WARFARIN RIDIMENSIONATO DAI NAO. TAO NAO

37 Grazie per l attenzione