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

Worldwide, 16 million people suffer a stroke each year Italy: 200.000 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

(Stroke.2006;37:263-266.)

stroke, just one disease?

Sopravvivenza dopo primo episodio di ictus in base al sottotipo Lac=339 At=435 Card=224 p=<0.0001 Giorni di follow up Giorni di follow up De Jong et al J Clin Epidemiol 2003 De Jong et al J Clin Epidemiol 2003

AF associated with increased risk of recurrent stroke Patients with AF Patients without AF Recurrent stroke after ischaemic stroke Months after first stroke Cumulative probability of recurrence (%) 10 12 8 6 4 2 P=0.0398 Marini C et al. Stroke 2005;36:1115–9

Paciaroni et al, Stroke 2008

age 65to 74, heart failure, hypertension diabetes, vascular disease. 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.

AF and cardioembolic stroke 1549 PATIENT WITH ISCHEMIC STROKE Age (yrs) 75.8±12.8 Known AF (%) 15.8 New diagnosis of AF (%) 4.9 52.1% no treatment 34.9% antiplatelet agents 13% anticoagulants Only 10.1% adequately treated Paciaroni & Agnelli, JTH 2005

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. 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. CHA2DS2-VASc counts 2 points each for previous stroke/transient ischemic attack and age ≥75 years, and one point each for age 65 to 74 years, heart failure, hypertension, diabetes, vascular disease and female sex. Leif Friberg et al. Stroke. 2014;45:2599-2605 Copyright © American Heart Association, Inc. All rights reserved.

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 2050 12 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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Increasing use of warfarin – increasing rates of anticoagulant-related ICH 1988 1993–1994 1999 All ischaemic stroke N/A 140.0 (133.2–146.8) 142.6 (135.8–149.3) Cardioembolic ischaemic stroke 31.1 (27.9–34.3) 30.4 (27.3–33.5) Cardioembolic ischaemic stroke due to AF 22.0 (19.3–24.7) 20.6 (18.1–23.2) All ICH 16.5 (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) Abbreviation N/A, not available Reference Flaherty et al. Neurology 2007;68:116-121. 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;68:116-121 13

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 dimissione2. Mesi (finestra temporale di 30 giorni) Tasso di incidenza di emorragie, % per persona/anno Figura tratta da rif. 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 CHADS2 all'inizio del trattamento 1 Eikelboom JW et al. J Thromb Haemost 2010;8:1438-9; 2. Gomes T et al. CMAJ. 2013;185:E121–E127

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 trattamento2 Incidenza di ictus ischemico tra i pazienti con fibrillazione atriale, naive al warfarin2 Tasso di incidenza, % per persona/anno Mesi (finestra temporale di 30 giorni) Figura tratta da rif. 2 1 Eikelboom JW et al. J Thromb Haemost 2010;8:1438-9;; 2. Tung Stroke. 2015;46:00-00

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

18.113 pazienti, durata media del follow up di 2 anni N Engl J Med 2009;361(12):1139-51

New Anticoagulant Therapies Compared to Warfarin: Stroke or Systemic Embolism Study Drug Better Warfarin Better 1. Connolly, 2010, p1876, Table 1 Dabigatran 150 mg BID1 HR 0.65 (95% CI, 0.52 to 0.81) 2. Patel, 2011, p883, c1, ¶3, p887, c1, ¶1 Dabigatran 110 mg BID1 HR 0.90 (95% CI, 0.74 to 1.10) 3. Granger, 2011, p981, ¶3, p986, c2, ¶4 Rivaroxaban 20 mg QD2 HR 0.88 (95% CI, 0.74 to 1.03) Apixaban 5 mg BID3 HR 0.79 (95% CI, 0.66 to 0.95) Edoxaban 60 mg QD4 HR 0.87 (95% CI, 0.73 to 1.04) HR 1.13 (95% CI, 0.96 to 1.34) Edoxaban 30 mg QD4 0.5 1 1.5 Hazard Ratio Connolly SJ et al. N Engl J Med. 2010;363:1875-1876. Patel MR et al. N Engl J Med. 2011;365:883-891. Granger CB et al. N Engl J Med. 2011;365:981-992. Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: 10.1056/NEJMoa1310907 Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363;1875-1876. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992. (Placeholder)

New Anticoagulant Therapies Compared to Warfarin: Intracranial Hemorrhage Study Drug Better Warfarin Better 1. Connolly, 2009, p1142, c2,¶2 HR 0.41 (95% CI, 0.28 to 0.60) Dabigatran 150 mg BID1 2. Mahaffey, 2010, Slide 14 HR 0.30 (95% CI, 0.19 to 0.45) Dabigatran 110 mg BID1 3. Granger, 2011, p981, ¶3, p985, Table 1 HR 0.67(95% CI, 0.47 to 0.93) Rivaroxaban 20 mg QD2 Apixaban 5 mg BID3 HR 0.42 (95% CI, 0.30 to 0.58) Edoxaban 60 mg QD4 HR 0.47 (95% CI, 0.34 to 0.63) Edoxaban 30 mg QD4 HR 0.30 (95% CI, 0.21 to 0.43) 0.5 1.0 1.5 2.0 Hazard Ratio Connolly SJ et al. N Engl J Med. 2010;363:1875-1876. Patel MR et al. N Engl J Med. 2011;365:883-891. Granger CB et al. N Engl J Med. 2011;365:981-992. Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: 10.1056/NEJMoa1310907 Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L, for the RE-LY Investigators. Newly identified events in the RE-LY trial [suppl app]. N Engl J Med. 2010;363(19);1875-1876 Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891 Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992. (Placeholder)

New Anticoagulant Therapies Compared to Warfarin: Major Bleeding Study Drug Better Warfarin Better 1. Connolly, 2010, p1876, Table 1 Dabigatran 150 mg BID1 HR 0.93 (95% CI, 0.81 to 1.07) 2. Patel, 2011, p890, Table 3 3. Granger, 2011, p981, ¶3, p987, c2, ¶2 Dabigatran 110 mg BID1 HR 0.80 (95% CI, 0.70 to 0.93) HR 1.04 (95% CI, 0.90 to 1.20) Rivaroxaban 20 mg QD2 Apixaban 5 mg BID3 HR 0.69 (95% CI, 0.60 to 0.80) Edoxaban 60 mg QD4 HR 0.80 (95% CI, 0.71 to 0.91) Edoxaban 30 mg QD4 HR 0.47 (95% CI, 0.41 to 0.55) 0.5 1 1.5 Hazard Ratio Connolly SJ et al. N Engl J Med. 2010;363:1875-1876. Patel MR et al. N Engl J Med. 2011;365:883-891. Granger CB et al. N Engl J Med. 2011;365:981-992. Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: 10.1056/NEJMoa1310907 Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363;1875-1876. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992. (Placeholder)

Circulation 2013;128:237-43

Stroke and ischaemic events: RELY-ABLE® D 150 mg (%/yr) D110 mg HR 95% CI Stroke or SEE 1.46 1.60 0.91 0.69–1.20 All stroke 1.24 1.38 0.89 0.66–1.21 Ischaemic 1.15 0.92 0.67–1.27 Haemorrhagic 0.13 0.14 0.34–2.30 Myocardial infarction 0.69 0.72 0.96 0.63–1.45 Pulmonary embolism 0.11 1.14 0.41–3.15 During 2.3 years of additional treatment after RE-LY® (total mean follow-up 4.3 years), rates of stroke and major bleeding remain low on dabigatran and are consistent with those seen during RE-LY® 5851 patients followed for mean of 2.3 years D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio 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.

Bleeding events: RELY-ABLE® RELY-ABLE® only D150 mg (%/yr) D110 mg (%/yr) HR 95% CI Major bleeding 3.74 2.99 1.26 1.04–1.53 Life-threatening 1.79 1.57 1.14 0.87–1.49 GI 1.54 1.56 0.99 0.75–1.31 Intra-cranial 0.33 0.25 1.31 0.68–2.51 Extra-cranial 3.43 2.82 1.23 1.01–1.49 Fatal 0.24 0.94 0.46–1.89 Minor bleeding 9.70 8.19 1.21 1.07–1.36 During 2.3 years of additional treatment after RE-LY® (total mean follow-up 4.3 years), rates of stroke and major bleeding remain low on dabigatran and are consistent with those seen during RE-LY® 5851 patients followed for mean of 2.3 years D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio 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.

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

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).

aggiungere foto di persone di varie età

“… 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 …” 2013, 100 pazienti nel trial re-cover aderenza a dabigatran 98% recover: trial per dabigatran come terpia del tromboembolismo venoso acuto

Gorst-Rasmussen A et al. J Thromb Haemost 2015 dati registro danese, 3000 pazienti seguiti per un anno, 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.

63% 39% Maggior frequenza di interruzioni nei pazienti con basso rischio tromboembolico Circ Cardiovasc Qual Outcomes 2013;6(5):567-74

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

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

Baseline Characteristics J Am Coll Cardiol 2013;61:2264-73

Primary Outcome Measures: Efficacy «…We found no evidence of an excess of bleeding events or MI among dabigatran-treated patients in this propensity-matched comparison against warfarin, even in the subgroup with 1-year follow-up». Favors Dabi 110 mg Favors Dabi 150 mg J Am Coll Cardiol 2013;61:2264-73

Primary Outcome Measures: Safety «…We found no evidence of an excess of bleeding events or MI among dabigatran-treated patients in this propensity-matched comparison against warfarin, even in the subgroup with 1-year follow-up». Favors Dabi 110 mg Favors Dabi 150 mg J Am Coll Cardiol 2013;61:2264-73

(Circulation.2015;131:157-164.)

Independent FDA Medicare analysis findings are consistent with findings from RE-LY® Medicare1 >134 000 patients 0.86 1.28 0.92 0.80 0.34 RE-LY®2–4 >18 000 patients 0.88 1.48 0.75 1.27 0.41 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 http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm; 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

<< >> Ann Emerg Med 2013;61(4):475-79 Pazienti con emorragia in corso di dabigatran hanno un decorso clinico più favorevole, con ospedalizzazione più breve rispetto ai pazienti con emorragia in corso di warfarin. Una patologia renale predispone i pazienti che assumono dabigatran a possibili sanguinamenti. Ann Emerg Med 2013;61(4):475-79

Circulation 2013;128:2325-32

ESC 2012 : Insufficienza Renale

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.

il neurologo è presente in ogni fase della cura dell’ictus cerebrale, il neurologo dovrebbe orientare la terapia e la gestione dei pazienti con ictus cerebrale World Stroke Organization Global Stroke Services Guidelines and Action Plan Lindsay P et al, IJS 2014

il neurologo deve essere leader nella gestione del paziente con ictus, ogni giorno, in qualsiasi contesto