ADVANCES IN CARDIAC ARRHYTHMIAS and GREAT INNOVATIONS IN CARDIOLOGY XXVI Giornate Cardiologiche Torinesi

Torino, 23 – 25 ottobre2014 THE ITALIAN EXPERIENCE WITH DABIGATRAN Pasquale Perrone Filardi Università Federico II di Napoli

Suddivisione dei pazienti in base al tipo di fibrillazione atriale (FA) nei singoli paesi europei

G Ital Cardiol 2014;15(2):99-109

Distribuzione dei pazienti in base al punteggio CHA2DS2- VASc: raffronto tra dati italiani ed europei (EU)

G Ital Cardiol 2014;15(2):99-109

Distribuzione delle classi di trattamento nei pazienti italiani G Ital Cardiol 2014;15(2):99-109

Percentuale di pazienti con valori di INR adeguati, subottimali o instabili/alti G Ital Cardiol 2014;15(2):99-109

Numero medio di monitoraggi dell’INR nell’ultimo mese nei paesi europei (EU) partecipanti allo studio

G Ital Cardiol 2014;15(2):99-109

Main Outcome Measures

Larsen et al. JACC 2013;61:2264–73

Bleeding events among new starters and switchers to dabigatran compared with warfarin: an observational study among patients with atrial fibrillation

Larsen TB et al. Am J Med 2014;127:650–6.e5 doi: 10.1016/j.amjmed.2014.01.031

Observational study of bleeding risk in patients with AF

2011

Study period

2012

• • Observational cohort study Nationwide Danish registries

2013

• • • • Patients with AF, stratified by prior VKA use 11 315 first-time dabigatran users (7063 VKA-naïve) 22 630 matched warfarin users VKA-naïve = ≥2 years since last warfarin purchase 13 months of follow-up (mean) Larsen TB et al. Am J Med 2014;127:650–6.e5. doi: 10.1016/j.amjmed.2014.01.031

D110 users were older, more often female, and at higher bleeding and stroke risk than D150 users (VKA-naïve stratum: applying new-user design [see slide 2])

Characteristic

Patients, n Median age (IQR), yrs Age ≥65 yrs, % Age ≥75 yrs, % Female, % HAS-BLED score, mean (SD) CHADS 2 score, mean (SD) CHA 2 DS 2 VASc score, mean (SD)

D110

3045 82 (77–86) 95.3 80.1 55.1 2.32 (1.04) 1.91 (1.21) 3.70 (1.47)

VKA-naïve stratum D150

4018 67 (62–72) 63.6 13.7 36.6 1.70 (1.11) 0.94 (1.05) 2.12 (1.41) D110 = dabigatran etexilate 110 mg BID; D150 = dabigatran etexilate 150 mg BID; IQR = interquartile range; SD = standard deviation Larsen TB et al. Am J Med 2014;127:650–6.e5. doi: 10.1016/j.amjmed.2014.01.031

Warfarin

14 126 73 (66–80) 76.8 42.5 41.3 1.97 (1.18) 1.33 (1.21) 2.80 (1.67)

Both dabigatran doses showed significant reductions in risk of any bleeding vs warfarin* (VKA-naïve stratum) 0.10

VKA-naïve stratum

Hazard ratio (95% CI) 0.50 1.00 2.00 5.00 Adjusted HR †

Dabigatran 110 mg

vs warfarin Any Major Fatal GI ICH 0.72 (0.59–0.88) 0.93 (0.74–1.16) 0.52 (0.28–0.95) 0.50 (0.27–0.94) 0.30 (0.17–0.54)

Dabigatran 150 mg

vs warfarin Any Major Fatal GI ICH 0.68 (0.55–0.84) 0.67 (0.53–0.85) 0.70 (0.33–1.52) 1.45 (0.84–2.50) 0.33 (0.17–0.66)

Dabigatran better Dabigatran worse

*Adjusted HR; † A ge, 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: 10.1016/j.amjmed.2014.01.031

Both dabigatran doses showed significant reductions in risk of any bleeding vs warfarin* (VKA-naïve stratum) 0.10

VKA-naïve stratum

Hazard ratio (95% CI) 0.50 1.00 2.00 5.00 Adjusted HR †

Dabigatran 110 mg

vs warfarin Any Major Fatal GI ICH 0.72 (0.59–0.88) 0.93 (0.74–1.16) 0.52 (0.28–0.95) 0.50 (0.27–0.94) 0.30 (0.17–0.54)

Dabigatran 150 mg

vs warfarin Any Major Fatal GI ICH 0.68 (0.55–0.84) 0.67 (0.53–0.85) 0.70 (0.33–1.52) 1.45 (0.84–2.50) 0.33 (0.17–0.66)

Dabigatran better Dabigatran worse

*Adjusted HR; † A ge, 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: 10.1016/j.amjmed.2014.01.031

Both dabigatran doses showed significant reductions in risk of any bleeding vs warfarin* (VKA-naïve stratum) 0.10

VKA-naïve stratum

Hazard ratio (95% CI) 0.50 1.00 2.00 5.00 Adjusted HR †

Dabigatran 110 mg

vs warfarin Any Major Fatal GI ICH 0.72 (0.59–0.88) 0.93 (0.74–1.16) 0.52 (0.28–0.95) 0.50 (0.27–0.94) 0.30 (0.17–0.54)

Dabigatran 150 mg

vs warfarin Any Major Fatal GI ICH 0.68 (0.55–0.84) 0.67 (0.53–0.85) 0.70 (0.33–1.52) 1.45 (0.84–2.50) 0.33 (0.17–0.66)

Dabigatran better Dabigatran worse

*Adjusted HR; † A ge, 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: 10.1016/j.amjmed.2014.01.031

Myocardial ischemic events in ‘real world’ patients with atrial fibrillation treated with dabigatran or warfarin: a nationwide cohort study

Larsen TB et al. Am J Med 2014;127:329–36.e4 doi: 10.1016/j.amjmed.2013.12.005

Both dabigatran doses showed a non-significant trend to lower MI rates vs warfarin* (VKA-naïve stratum) MI D110 MI D150 0.10

VKA-naïve stratum

HR (95% CI) 0.50 1.00 2.00 5.00 Adjusted HR † 0.71 (0.47–1.07) 0.93 (0.62–1.41) Dabigatran better Dabigatran worse *Adjusted HR; † A ge, 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;127:329–36.e4. doi: 10.1016/j.amjmed.2013.12.005

Patologie concomitanti e fattori di rischio nei pazienti con fibrillazione atriale nei diversi paesi europei

G Ital Cardiol 2014;15(2):99-109

Caratteristiche generali dei pazienti (n=204) in terapia con Dabigatran etexilato (Pradaxa)

Eta' (anni; media±DS);

72 ±8

>80 anni Sesso (maschi)

109

CHA 2 DS 2 VASc (media±DS)

4,3±1,6

numero pazienti per classe di rischio

1 2 3 4 5 6 7 8 9

7 19 48 40 43 27 15 3 2

HAS-BLED (media±DS)

2,9±0,9

Scompenso cardiaco Diabete mellito II Pregresso Ictus cerebrale/TIA/ Episodio trombo-embolico Ipertensione arteriosa IM, malattia arteriosa periferica o placca aortica Insufficienza renale cronica Insufficienza epatica Storia di sanguinamento o diatesi emorragica o anemia Terapia concomitante con antiaggreganti piastrinici con ASA o clopidogrel con ASA e clopidogrel Pazienti Naive Pazienti già in TAO

numero pazienti per classe di rischio

1 2 3 4

16 46 83 51

INR instabile con tempo in range terapeutico < 60% TTR (%; media±DS) Pazienti in terapia con 220 mg/die Pazienti in terapia con 300 mg/die

85 55 54 189 74 35 2 33 51 19 12 75 129 118 48±14 119 85

Caratteristiche generali dei pazienti (n=119) in terapia con Dabigatran etexilato 220 mg/die (Pradaxa)

Eta' (anni; media±DS) Sesso (maschi) CHA 2 DS 2 VASc (media±DS)

75 ±6 60(51%) 4,64±1,43

Scompenso cardiaco Diabete mellito II Pregresso Ictus cerebrale/TIA/ Episodio trombo-embolico

numero pazienti per classe di rischio

1 2 3 4 5 6 7 8 9 HAS-BLED (media±DS)

3,1±0,91 0 4 30 23 28 20 12 2 0

numero pazienti per classe di rischio

1 2 3 4

6 20 50 38

Ipertensione arteriosa IM, malattia arteriosa periferica o placca aortica Insufficienza renale cronica Insufficienza epatica Storia di sanguinamento o diatesi emorragica o anemia Terapia concomitante con antiaggreganti piastrinici con ASA o clopidogrel con ASA e clopidogrel Pazienti Naive Pazienti già in TAO INR instabile con tempo in range terapeutico < 60% TTR (%; media±DS) Effetti collaterali Epigastralgia

48 (41%) 31 (26%) 39 (33%) 111 (93%) 44(37%) 32(27%) 1 (0,1%) 22 (19%) 35 (29%) 14 11 51(43%) 67 (56%) 68 (57%) 50±12 1(0,1%) 1

Caratteristiche generali dei pazienti (n=85) in terapia con Dabigatran etexilato 300 mg/die (Pradaxa)

Eta' (anni; media±DS) Sesso (maschi) CHA 2 DS 2 VASc (media±DS)

69 ±8 49 (57%) 3,8±1,80

numero pazienti per classe di rischio

1 2 3 4 5 6 7 8 9

HAS-BLED (media±DS)

2,62±0,99

numero pazienti per classe di rischio

1 2 3 4 10 26 33 13 7 15 18 17 15 7 3 1 2

Scompenso cardiaco Diabete mellito II Pregresso Ictus cerebrale/TIA/ Episodio trombo-embolico Ipertensione arteriosa IM, malattia arteriosa periferica o placca aortica Insufficienza renale cronica Insufficienza epatica Storia di sanguinamento o diatesi emorragica o anemia Terapia concomitante con antiaggreganti piastrinici con ASA o clopidogrel con ASA e clopidogrel Pazienti Naive Pazienti già in TAO INR instabile con tempo in range terapeutico < 60% TTR (%; media±DS) Effetti collaterali Epigastralgia

37 (43%) 23 (27%) 16(13%) 78(66%) 30(25%) 3(0,3%) 1(0,1%) 11 (13%) 16(14%) 13 3 23(27%) 62(72%) 50(60%) 46±15 1(0,1%) 1

Time to discontinuation by treatment group in matched patients

B

1.00 0.75 0.50 0.25 Dabigatran Warfarin

A

1.00 0.75 0.50 0.25 0 0 90 180 270 360 Time to discontinuation (days) 450 0 0 90 180 270 360 Time to discontinuation (days) 450 A) 30-day medication gap B) 60-day medication gap dabigatran (389 days) than warfarin (135 days) (P<0.001) Median persistence was longer for Kaplan–Meier survival curves for propensity score-matched patients by treatment group Zalesak M et al. Circ Cardiovasc Qual Outcomes 2013;6:567–74 Median persistence was longer for dabigatran (>400 days) than warfarin (222 days) (P<0.001)

Association between adherence (PDC) and outcomes

Am Heart J 2014 Jun;167(6):810-7

Mortality in relation to atrial fibrillation subtype Eur Heart J 2014 Aug 31 doi:10.1093/eurheartj/ehu374

Risk of stroke, HF, AMI and GI bleeding in pts with AF

Piccini JP, Duke University, Eur Heart J 2014, 35: 250-6

• • • • • •

REMARKS The vast majority of real world atrial fibrillation patients should be anticoagulated according to Guidelines VKA therapy remains problematic in many patients Use of new oral anticoagulants is increasing but still suboptimal in Italy A substantial number of perceived contraindications to anticoagulation therapy appear not justified Data from registries of NOA indicate and efficacy and safety profile even more favorable than that observed in clinical trials However, despite stroke risk reduction, prognosis of AF is influenced by comorbidities, mainly heart failure and CAD