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Scacco all’ictus! Dabigatran ed il ruolo del neurologo nelle strategie di cura e prevenzione dell’ictus cerebrale cardioembolico Francesca Romana Pezzella,

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Presentazione sul tema: "Scacco all’ictus! Dabigatran ed il ruolo del neurologo nelle strategie di cura e prevenzione dell’ictus cerebrale cardioembolico Francesca Romana Pezzella,"— Transcript della presentazione:

1 Scacco all’ictus! Dabigatran ed il ruolo del neurologo nelle strategie di cura e prevenzione dell’ictus cerebrale cardioembolico Francesca Romana Pezzella, MD, PhD, BSc Stroke Unit AO S Camillo Forlanini

2 Worldwide, 16 million people suffer a stroke each year Italy: stroke/year 0.27% of gross domestic product was spent on stroke by national health systems stroke care accounted for ∼ 3% of total health care expenditures 27 EU countries, total annual cost of stroke is estimated at €27 billion: – €18.5 billion (68.5%) for direct cost – €8.5 billion (31.5%) for indirect costs €11.1 billion is calculated for the value of informal care Indirect and informal care costs are related to mortality, morbidity and functional impairment

3 (Stroke.2006;37: )

4 stroke, just one disease?

5 Sopravvivenza dopo primo episodio di ictus in base al sottotipo Giorni di follow up Lac=339 At=435 Card=224 p=< De Jong et al J Clin Epidemiol 2003 Giorni di follow up

6 AF associated with increased risk of recurrent stroke 6 Marini C et al. Stroke 2005;36:1115–9 Patients with AF Patients without AF Recurrent stroke after ischaemic stroke Months after first stroke Cumulative probability of recurrence (%) P=0.0398

7 Paciaroni et al, Stroke 2008

8 prevalence of atrial fibrillation in relation to CHADS-VASC score BEFORE stroke onset; CHADS-VASC counts 2 points for prevoius stroke/TIA, age> 75 aa; 1 point for female sex, age 65to 74, heart failure, hypertension diabetes, vascular disease.

9 1549 PATIENT WITH ISCHEMIC STROKE Age (yrs)75.8±12.8 Known AF (%)15.8 New diagnosis of AF (%) % no treatment 34.9% antiplatelet agents 13% anticoagulants Paciaroni & Agnelli, JTH 2005 Only 10.1% adequately treated AF and cardioembolic stroke

10 Warfarin purchase within 3 months after ischemic stroke among patients with atrial fibrillation in relation to risk for new ischemic stroke expressed as CHA2DS2-VASc score at discharge. Leif Friberg et al. Stroke. 2014;45: Copyright © American Heart Association, Inc. All rights reserved.

11 the stroke “cold” case: atrial fibrillation and stroke victims ✎ Atrial fibrillation (AF) is the most common cardiac arrhythmia (1,5%-2%) ✎ Over 6 million Europeans are affected, by milions are expected to be AF victims as the population ages ✎ AF confers a 5-fold risk of stroke, and one in five of all strokes is attributed to AF ✎ Ischaemic strokes in association with AF are often fatal, survivors are left more disabled and more likely to suffer a recurrence than patients with other causes of stroke ✎ The risk of death from AF-related stroke is doubled and the cost of care is increased 1.5-fold ✎ PREFER (9/2014): 80% patients with OAC: 12,5 NOAC, 67% VKA 20% receive aspirin or no treatment at all!!! ✎ EORP-AF (7/2014): 7,7 NOAC; 72,2 5 VKA

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13 Increasing use of warfarin – increasing rates of anticoagulant-related ICH – All ischaemic stroke N/A140.0 (133.2–146.8) (135.8–149.3) Cardioembolic ischaemic stroke N/A31.1 (27.9–34.3) 30.4 (27.3–33.5) Cardioembolic ischaemic stroke due to AF N/A22.0 (19.3–24.7) 20.6 (18.1–23.2) All ICH16.5 (14.1–18.9) 22.1 (19.4–24.8) 24.6 (21.8–27.4) Anticoagulant- associated ICH 0.8 (0.3–1.3) 1.9 (1.1–2.7) 4.4 (3.2–5.5) Annual incidence rates for intracerebral haemorrhage (ICH) and ischaemic stroke in the Greater Cincinnati/Northern Kentucky area: age-, sex- and race-adjusted to the 2000 US population, expressed per 100,000 persons. Parentheses indicate 95% confidence intervals Flaherty et al. Neurology 2007;68:

14 DATI DI REAL LIFE ONTARIO – CANADA: In questo ampio studio su pazienti anziani con fibrillazione atriale si osserva una più alta incidenza di emorragie nei primi 30 giorni di terapia con Warfarin e che circa 1 paziente su 5, ospedalizzato per emorragia, è morto in ospedale o poco dopo la dimissione 2. Nei pazienti anziani ( ≥ 66 anni), con fibrillazione atriale, il tasso di incidenza delle visite in ospedale per emorragia incrementa nell’arco dei 30 giorni dopo l'inizio della terapia con warfarin. I tassi sono stratificati in base al punteggio CHADS 2 all'inizio del trattamento Figura tratta da rif. 2 Mesi (finestra temporale di 30 giorni) Tasso di incidenza di emorragie, % per persona/anno 1 Eikelboom JW et al. J Thromb Haemost 2010;8:1438-9; 2. Gomes T et al. CMAJ. 2013;185:E121–E127

15 Figura tratta da rif. 2 Tasso di incidenza, % per persona/anno Mesi (finestra temporale di 30 giorni) Incidenza di ictus ischemico tra i pazienti con fibrillazione atriale, naive al warfarin 2 DATI DI REAL LIFE ONTARIO – CANADA: in pazienti anziani con fibrillazione atriale che iniziavano il trattamento con warfarin, il tasso di ictus ischemico era significativamente più elevato durante il primo mese di trattamento 2 1 Eikelboom JW et al. J Thromb Haemost 2010;8:1438-9;; 2. Tung Stroke. 2015;46:00-00

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17 anticoagulante più efficace nel ridurre il rischio di ictus cerebrale anticoagulante più sicuro più “facile” per i pazienti risultati dei trial= risultati del mondo reale

18 N Engl J Med 2009;361(12):

19 New Anticoagulant Therapies Compared to Warfarin: Stroke or Systemic Embolism 0.51 HR 0.65 (95% CI, 0.52 to 0.81) HR 0.90 (95% CI, 0.74 to 1.10) HR 0.88 (95% CI, 0.74 to 1.03) HR 0.79 (95% CI, 0.66 to 0.95) Hazard Ratio Study Drug BetterWarfarin Better 1.Connolly SJ et al. N Engl J Med. 2010;363: Patel MR et al. N Engl J Med. 2011;365: Granger CB et al. N Engl J Med. 2011;365: Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: /NEJMoa Dabigatran 150 mg BID 1 Dabigatran 110 mg BID 1 Rivaroxaban 20 mg QD 2 Apixaban 5 mg BID 3 Edoxaban 60 mg QD 4 Edoxaban 30 mg QD HR 1.13 (95% CI, 0.96 to 1.34) HR 0.87 (95% CI, 0.73 to 1.04)

20 New Anticoagulant Therapies Compared to Warfarin: Intracranial Hemorrhage HR 0.41 (95% CI, 0.28 to 0.60) HR 0.30 (95% CI, 0.19 to 0.45) HR 0.67(95% CI, 0.47 to 0.93) HR 0.42 (95% CI, 0.30 to 0.58) Warfarin Better 1.Connolly SJ et al. N Engl J Med. 2010;363: Patel MR et al. N Engl J Med. 2011;365: Granger CB et al. N Engl J Med. 2011;365: Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: /NEJMoa Dabigatran 150 mg BID 1 Dabigatran 110 mg BID 1 Rivaroxaban 20 mg QD 2 Apixaban 5 mg BID 3 Edoxaban 60 mg QD 4 Edoxaban 30 mg QD 4 Study Drug Better Hazard Ratio HR 0.47 (95% CI, 0.34 to 0.63) HR 0.30 (95% CI, 0.21 to 0.43)

21 New Anticoagulant Therapies Compared to Warfarin: Major Bleeding Dabigatran 150 mg BID 1 Dabigatran 110 mg BID 1 Rivaroxaban 20 mg QD 2 Apixaban 5 mg BID 3 HR 0.80 (95% CI, 0.70 to 0.93) HR 1.04 (95% CI, 0.90 to 1.20) HR 0.69 (95% CI, 0.60 to 0.80) Edoxaban 60 mg QD 4 Edoxaban 30 mg QD 4 Hazard Ratio HR 0.93 (95% CI, 0.81 to 1.07) Study Drug BetterWarfarin Better 21 1.Connolly SJ et al. N Engl J Med. 2010;363: Patel MR et al. N Engl J Med. 2011;365: Granger CB et al. N Engl J Med. 2011;365: Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: /NEJMoa HR 0.80 (95% CI, 0.71 to 0.91) HR 0.47 (95% CI, 0.41 to 0.55)

22 Circulation 2013;128:237-43

23 Stroke and ischaemic events: RELY-ABLE ® 5851 patients followed for mean of 2.3 years D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio Event D 150 mg (%/yr) D110 mg (%/yr) HR95% CI Stroke or SEE –1.20 All stroke –1.21 Ischaemic –1.27 Haemorrhagic –2.30 Myocardial infarction –1.45 Pulmonary embolism –3.15 Connolly SJ, et al. Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the RELY-ABLE Double- blind Randomized Trial. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives. Presented on 7 November 2012 at the American Heart Association Scientific Sessions 2012.

24 Bleeding events: RELY-ABLE ® 5851 patients followed for mean of 2.3 years D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio Event RELY-ABLE ® only D150 mg (%/yr) D110 mg (%/yr) HR95% CI Major bleeding – 1.53 Life-threatening – 1.49 GI – 1.31 Intra-cranial – 2.51 Extra-cranial – 1.49 Fatal – 1.89 Minor bleeding – 1.36 Connolly SJ, et al. Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the RELY-ABLE Double- blind Randomized Trial. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives. Presented on 7 November 2012 at the American Heart Association Scientific Sessions 2012.

25 Pengo et al. New oral anticoagulants Thrombosis and Haemostasis 106.5/2011 NOACs Drug Interaction according to Type of Metabolism

26 VKA therapy, apixaban, and dabigatran (1 B) are all indicated for the prevention of recurrent stroke in patients with nonvalvular AF, whether paroxysmal or permanent. (Class I; Level of Evidence A) Rivaroxaban is reasonable for the prevention of recurrent stroke in patients with nonvalvular AF (Class IIa; Level of Evidence B).

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28 “… we found a surprisingly good adherence; overall 88% of the patients had adequate adherence, without any difference by sex, age or previous participation in the clinical trials …”

29 Gorst-Rasmussen A et al. J Thromb Haemost 2015 Conclusions More than 75% of patients were showed > 80% adherence to medication regimens during the first year. Patients with higher morbidity, including patients with a higher risk of stroke or bleeding, exhibited better adherence.

30 Circ Cardiovasc Qual Outcomes 2013;6(5): Maggior frequenza di interruzioni nei pazienti con basso rischio tromboembolico 39% 63%

31 Real World Data Mini Sentinel Registry (FDA) Ampio registro del mondo reale Danese Medicare (FDA)

32 La FDA ha richiesto il “Mini Sentinel”: studio di sicurezza, focalizzato sulla reale incidenza di sanguinamenti GI ed intracranici in nuovi pazienti in terapia con Pradaxa rispetto a Warfarin

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35 J Am Coll Cardiol 2013;61: Baseline Characteristics

36 Primary Outcome Measures: Efficacy J Am Coll Cardiol 2013;61: Favors Dabi 110 mg Favors Dabi 150 mg

37 Primary Outcome Measures: Safety Favors Dabi 110 mg Favors Dabi 150 mg J Am Coll Cardiol 2013;61:

38 (Circulation.2015;131: )

39 RE-LY ®2–4 > patients Medicare 1 > patients Independent FDA Medicare analysis findings are consistent with findings from RE-LY ® 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;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–6; 4. Pradaxa ® : EU SPC, 2014 Independent FDA analysis confirmed the favourable benefit–risk profile of dabigatran in clinical practice 39

40 >> >> << Ann Emerg Med 2013;61(4):475-79

41 Circulation 2013;128:

42 ESC 2012 : Insufficienza Renale

43 Real World Data confirm the results of Dabigatran RCTs :  reduced risk of ischemic stroke  reduced risk of intracranial hemorrhage  reduced risk of death compared with Warfarin.

44 World Stroke Organization Global Stroke Services Guidelines and Action Plan Lindsay P et al, IJS 2014

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