La gestione del paziente con FA: ruolo dei
NAO
21-22 Novembre 2014
Fossano
La gestione del paziente con
FA: nuovi trattamenti
Dott. Sergio Agosti
Cardiologo,
Ospedale Novi Ligure (AL)
www.docvadis.it/agostisergio
[email protected]
Dabigatran in numeri….
• 60000 pz nei trials
•2170 articoli - studi clinici (PUBMED)
•Almeno 260000 pz nei registri
(Minisentinel, Medicare, registro AHA)
•50000 pz in GLORIA
•Oltre 3 milioni di pz trattati nel mondo
Lancet, published online December 4, 2013
STROKE OR SYSTEMIC EMBOLISM
NNT 173
Ruff CT,Lancet, December 4, 2013
MAJOR BLEEDING
Ruff CT,Lancet, December 4, 2013
EFFICACY AD SAFETY
SECONDARY ENDPOINTS
ICH NNT 141
Ruff CT, Lancet, December 4, 2013
ESC 2012 Guideline recommendations1
CHA2DS2-VASc
Recommendation
0
No antithrombotic therapy
1
OAC therapy with
• Adjusted-dose VKA (INR 2–3); or
• A direct thrombin inhibitor (dabigatran); or
• An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)
…should be considered
≥2
OAC therapy with
• Adjusted-dose VKA (INR 2–3); or
• A direct thrombin inhibitor (dabigatran); or
• An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)
…is recommended
Class*
Level†
I
B
IIa
A
I
A
*Class of recommendation; †Level of evidence; OAC, oral anticoagulant
1. Camm et al. Eur Heart J 2012;33:2719–2747.
ESC 2012 Guideline recommendations1
Recommendations for prevention of thromboembolism
in NVAF—NOACs
Class*
Level†
IIa
A
Where OAC is recommended, one of the NOACs, either:
• A direct thrombin inhibitor (dabigatran); or
• An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)
…should be considered rather than adjusted-dose VKA
(INR 2–3) for most patients with NVAF, based on their net clinical benefit
*Class of recommendation; †Level of evidence; OAC, oral anticoagulant
1. Camm et al. Eur Heart J 2012;33:2719–2747.
ESC 2012 Guideline recommendations1
*Class of recommendation; †Level of evidence; OAC, oral anticoagulant
1. Camm et al. Eur Heart J 2012;33:2719–2747.
RE-LY, ROCKET-AF, ARISTOTLE
Popolazioni studiate
6076
6015
6022
150mg BID
110mg BID
W
20mg OD
15mg OD
5619
1462
7081
W
8692
5mg BID
2.5mg BID
W
428
9081
Connolly et al. NEJM 2009; 361:1139-51; Patel et al. NEJM 2011; 365:883-91; Granger et al. NEJM 2011; 365:981-92; Fox et al. European Heart Journal
2011; 32:2387-2394
Lip, Thromb Haemost 2014; 111
Lip, Thromb Haemost 2014; 111
Lip, Thromb Haemost 2014; 111
Condizioni di
ingresso
Eliquis
Pradaxa
Xarelto
Paziente con fibrillazione
atriale non valvolare
(FAVN) cronica o
parossistica (>65 anni)
Paziente con fibrillazione
atriale non valvolare
(FAVN)
Paziente con fibrillazione
atriale non valvolare
(FAVN)
Ai fini dell’eleggibilità bisogna rientrare in una delle seguenti condizioni (1 o 2 o 3)
Gruppo 1
CHA2DS2-VASC ≥1
e
HAS-BLED >3
CHA2DS2-VASC ≥1
e
HAS-BLED >3
CHA2DS2-VASC >3
e
HAS-BLED >3
Gruppo 2
TTR negli ultimi 6
mesi <70%
TTR negli ultimi 6
mesi <70%
TTR negli ultimi 6
mesi <60%
Gruppo 3
Il trattamento
anticoagulante non è
attuabile per difficoltà
oggettive ad eseguire i
controlli INR
Il trattamento
anticoagulante non è
attuabile per difficoltà
oggettive ad eseguire i
controlli INR
Il trattamento
anticoagulante non è
attuabile per difficoltà
oggettive ad eseguire i
controlli INR
TTR: ANALISI DI SOTTOGRUPPO
TIME TO PRIMARY OUTCOME
Cumulative hazard ratio
Dabigatran 150 mg
0.06
Cumulative hazard ratio
0.06
cTTR <57.1%
0.05
0.04
0.04
0.03
0.03
0.02
0.02
0.01
0.01
0
0.5
1.0
1.5
2.0
2.5
1497
1509
1504
1450
1469
1445
1411
1427
1395
1144
1164
1094
649
699
640
274
283
242
0.06
0
0.5
1.0
1.5
2.0
2.5
1524
1526
1514
1477
1493
1476
1440
1453
1438
1169
1192
1175
783
801
752
379
394
351
2.0
2.5
730
750
737
347
367
366
0.06
cTTR 65.5–72.6%
0.05
0.04
0.04
0.03
0.03
0.02
0.02
0.01
0.01
0
0.5
1474
1484
1487
1456
1419
1458
1.0
1.5
Follow-up (yrs)
1420
1419
1436
cTTR 57.1–65.5%
0
0.05
0
Number at risk
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Warfarin
0.05
0
Number at risk
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Dabigatran 110 mg
1142
1153
1150
2.0
2.5
760
761
755
370
369
359
0
cTTR >72.6%
0
0.5
1482
1514
1509
1444
1487
1476
1.0
1.5
Follow-up (yrs)
1405
1437
1440
1108
1135
1166
TTR = time in therapeutic range; cTTR = centre mean TTR.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Wallentin L, et al. Lancet 2010;376:975-983.
TTR: ANALISI DI SOTTOGRUPPO
TIME TO MAJOR BLEEDING
Cumulative hazard ratio
Dabigatran 150 mg
Dabigatran 110 mg
0.12
0.12
cTTR <57.1%
cTTR 57.1–65.5%
0.10
0.10
0.08
0.08
0.06
0.06
0.04
0.04
0.02
0.02
0
Number at risk
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
0
0
0.5
1.0
1.5
2.0
2.5
0
0.5
1.0
1.5
2.0
2.5
1497
1509
1504
1443
1448
1430
1398
1399
1371
1135
1135
1065
647
680
614
274
276
231
1524
1526
1514
1465
1467
1460
1416
1416
1403
1139
1160
1140
753
774
729
362
377
333
2.0
2.5
706
716
714
336
350
354
Cumulative hazard ratio
0.12
0.12
cTTR 65.5–72.6%
0.10
cTTR >72.6%
0.10
0.08
0.08
0.06
0.06
0.04
0.04
0.02
0.02
0
Number at risk
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Warfarin
0
0
0.5
1474
1484
1487
1445
1415
1445
1.0
1.5
Follow-up (yrs)
1392
1372
1398
1108
1105
1121
2.0
2.5
0
0.5
736
715
725
364
343
344
1482
1514
1509
1438
1455
1452
1.0
1.5
Follow-up (yrs)
1385
1399
1411
1087
1109
1129
TTR = time in therapeutic range; cTTR = centre mean TTR; HR = hazard ratio; CI = confidence interval.
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
Wallentin L, et al. Lancet 2010;376:975-983.
TTR subgroup analysis: intracranial bleeding
Reduced risk of intracranial bleeding with both doses vs warfarin, irrespective of
centre-based INR control
Dabigatran
110 mg
Dabigatran
150 mg
Warfarin
Rate per
100
person-yrs
Rate per
100
person-yrs
Rate per
100
person-yrs
<57.1%
0.28
0.34
0.64
0.43
(0.19–1.00)
0.53
(0.25–1.15)
57.1–
65.5%
0.30
0.42
0.93
0.31
(0.15–0.66)
0.45
(0.24–0.88)
65.5–
72.6%
0.13
0.24
0.67
0.20
(0.07–0.58)
0.35
(0.15–0.82)
>72.6%
0.21
0.30
0.77
0.27
(0.11–0.66)
cTTR
Dabigatran 110 mg
vs warfarin
HR
(95% CI)
P value*
(interaction)
0.71
Dabigatran 150 mg
vs warfarin
HR
(95% CI)
0.39
(0.18–0.84)
*Interaction P value evaluated by a multivariate approach with centre-based TTR as a continuous variable
cTTR = centre mean TTR; HR = hazard ratio; INR = international normalized ratio; TTR = time in therapeutic range
Wallentin L et al. Lancet 2010;376:975–83
P value*
(interaction)
0.89
Ictus emorragico
RR 0,26 (IC al 95%: 0,14–0,49)
p<0,001 (superiorità)
RRR
74%
50
Numero di eventi
RR 0,31 (IC al 95%: 0,17–0,56)
p<0,001 (superiorità)
RRR
69%
40
45
0,38%
30
20
10
12
14
0,10%
0,12%
D150 mg BID
6.015
D110 mg BID
6.076
0
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151.
Warfarin
6.022
Ictus emorragico
Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A
Systematic Review and Meta-Analysis of Subgroups. Thrombosis, Sept 2013; antonio Gomez Outes
Ictus emorragico (TF receptor)
Mackmann, Anesth Analg. 2009 May; 108(5):1447-52
The role of tissue factor and factor VIIa in hemostasis.
J Thromb Thrombolysis, 2013
Thrombin generation profiles: Plasma samples from patients on warfarin were pooled to yield an
INR value of 2.6. the pooled plasma was then diluited with PNP to create plasma pools with a range
of INR values.
Dabigatran was added to PNP. The thrombin generation profile for PNP is shown on each plot for
comparison.
NAO: aspetti gestionali
•Modalità di accesso ai centri prescrittori
•Valutazione iniziale pazienti
•Informazione/educazione pazienti
•Modalità del follow up
•Coinvolgimento del MMG nel follow up del paziente
•Protocolli condivisi con il Pronto Soccorso
•Interazione con il Laboratorio Analisi
NAO: aspetti gestionali
•Modalità di accesso ai centri prescrittori
•Valutazione iniziale pazienti
•Informazione/educazione pazienti
•Modalità del follow up
•Coinvolgimento del MMG nel follow up del paziente
•Protocolli condivisi con il Pronto Soccorso
•Interazione con il Laboratorio Analisi
BioMed Research International, 20 Jul 2014
BioMed Research International, 20 Jul 2014
BioMed Research International, 20 Jul 2014
Esiste un antidoto?
Antidoto Fattore X
• Andexanet alfa
• Fase II (volontari sani), su inibitori Fattore X
• Bolo e infusione ev per 2 h
• Inibizione rapida e quasi completa dell’effeto anicoagulante
• Nessun effetto procoagulante
•Anticorpo monoclonale contro il Dabigatran (DABI-FAB)
AHA Congress
•Ha conformazione simile alla trombina
19/11/2013
•Elevatissima
affinità (350 vv vs trombina)
• Idarucizumab
• Fase II (145 volontari sani)
•Non interagisce
con l’attività coagulativa spontanea
• ben tollerato
• immediato,
e mantenuto
blocco
dell’anticoagulazione
•Ha dimostrato
unacompleto
reversibilità
potente ed
immediata
(1 minuto)
• nessun effetto procoagulante
dell’anticoagulazione da Dabigatran, in vivo sui ratti
Blood. 2013 May 2;121(18):3554-62.
Idarucizumab
• Studio di Fase III
• aprile 2014-aprile 2017
• 5 gr ev
• end point primario: ripristino assetto coagulativo
• arruolamento previsto 250 pz
• circa 30 pz già arruolati
Real world data
2 aa
2,3 aa
RELY-ABLE®: Risultati di efficacia
5851 pazienti sono stati seguiti mediamente per 2,3 anni
D 150 mg BID
D110 mg BID
(%/yr)
(%/yr)
Ictus o SEE
1.46
Tutti i casi di ictus
Evento
HR
IC al 95%
1.60
0.91
0.69–1.20
1.24
1.38
0.89
0.66–1.21
ischemici
1.15
1.24
0.92
0.67–1.27
emorragici
0.13
0.14
0.89
0.34–2.30
Infarto del miocardio
0.69
0.72
0.96
0.63–1.45
Embolia polmonare
0.13
0.11
1.14
0.41–3.15
D150 e D110 = rispettivamente dabigatran 150 e 110 mg due volte al giorno; HR = hazard ratio
SEE = systemic embolic event = evento embolico sistemico
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.&nbsp; Presented on 7 November 2012 at the American Heart Association Scientific Sessions 2012.
RELY-ABLE®: risultati di sicurezza
5851 pazienti sono stati seguiti mediamente per 2,3 anni
Solo RELY-ABLE®
Evento
Sanguinamento maggiore
D150 mg BID D110 mg BID
(%/yr)
(%/yr)
HR
IC al 95%
3.74
2.99
1.26
1.04–1.53
pericolo di vita
1.79
1.57
1.14
0.87–1.49
GI
1.54
1.56
0.99
0.75–1.31
Intra-cranico
0.33
0.25
1.31
0.68–2.51
Extra-cranico
3.43
2.82
1.23
1.01–1.49
Fatale
0.24
0.25
0.94
0.46–1.89
9.70
8.19
1.21
1.07–1.36
Sanguinamento minore
D150 e D110 = rispettivamente dabigatran 150 e 110 mg due volte al dì; 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.&nbsp; Presented on 7 November 2012 at the American Heart Association Scientific Sessions 2012.
Medicare analysis: results
Incidence rate per 1000 personyears
Adjusted HR
(95% CI)
Dabigatran
Warfarin
Ischaemic stroke
11.3
13.9
0.80 (0.67-0.96)
Intracranial haemorrhage
3.3
9.6
0.34 (0.26-0.46)
Major gastrointestinal
bleeding
34.2
26.5
1.28 (1.14-1.44)
Acute myocardial infarction
15.7
16.9
0.92 (0.78-1.08)
Mortality
32.6
37.8
0.86 (0.77-0.96)
Dabigatran was associated with a lower risk of ischaemic stroke, intracranial
haemorrhage and death than warfarin.
Risk of MI was similar for dabigatran and warfarin.
Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg
together without stratification by dose. Warfarin is the reference group. CI = confidence
interval; HR = hazard ratio; MI = myocardial infarction;
Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)
Medicare analysis: results
Incidence rate per 1000 personyears
Adjusted HR
(95% CI)
Dabigatran
Warfarin
Ischaemic stroke
11.3
13.9
0.80 (0.67-0.96)
Intracranial haemorrhage
3.3
9.6
0.34 (0.26-0.46)
Major gastrointestinal
bleeding
34.2
26.5
1.28 (1.14-1.44)
Acute myocardial infarction
15.7
16.9
0.92 (0.78-1.08)
Mortality
32.6
37.8
0.86 (0.77-0.96)
Dabigatran was associated with a lower risk of ischaemic stroke, intracranial
haemorrhage and death than warfarin.
Risk of MI was similar for dabigatran and warfarin.
Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg
together without stratification by dose. Warfarin is the reference group. CI = confidence
interval; HR = hazard ratio; MI = myocardial infarction;
Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)
Medicare analysis: results
Incidence rate per 1000 personyears
Adjusted HR
(95% CI)
Dabigatran
Warfarin
Ischaemic stroke
11.3
13.9
0.80 (0.67-0.96)
Intracranial haemorrhage
3.3
9.6
0.34 (0.26-0.46)
Major gastrointestinal
bleeding
34.2
26.5
1.28 (1.14-1.44)
Acute myocardial infarction
15.7
16.9
0.92 (0.78-1.08)
Mortality
32.6
37.8
0.86 (0.77-0.96)
Dabigatran was associated with a lower risk of ischaemic stroke, intracranial
haemorrhage and death than warfarin.
Risk of MI was similar for dabigatran and warfarin.
Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg
together without stratification by dose. Warfarin is the reference group. CI = confidence
interval; HR = hazard ratio; MI = myocardial infarction;
Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)
Medicare analysis: results
Incidence rate per 1000 personyears
Adjusted HR
(95% CI)
Dabigatran
Warfarin
Ischaemic stroke
11.3
13.9
0.80 (0.67-0.96)
Intracranial haemorrhage
3.3
9.6
0.34 (0.26-0.46)
Major gastrointestinal
bleeding
34.2
26.5
1.28 (1.14-1.44)
Acute myocardial infarction
15.7
16.9
0.92 (0.78-1.08)
Mortality
32.6
37.8
0.86 (0.77-0.96)
Dabigatran was associated with a lower risk of ischaemic stroke, intracranial
haemorrhage and death than warfarin.
Risk of MI was similar for dabigatran and warfarin.
Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg
together without stratification by dose. Warfarin is the reference group. CI = confidence
interval; HR = hazard ratio; MI = myocardial infarction;
Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)
Global Registry on Long-Term Oral
Antithrombotic Treatment in AF Patients
• Collection of data on dabigatran in countries/regions and globally
• Increase knowledge on AF patients, treatment patterns, and outcome events
in a real-world setting
• Involvement of up to 2200 physicians worldwide: GPs, cardiologists,
neurologists, internists, geriatricians, etc – hospital based or private practice
up to
56 000
patients
2200
sites
up to
50 countries
Piani terapeutici AIFA compilati al 12 luglio 2014
72000 Pradaxa®
Numero PT
46000 Xarelto®
17000 Eliquis®
http://www.agenziafarmaco.gov.it/sites/default/files/EurDURG_28082014_Xoxi.pdf
Analisi NAO Regione Piemonte
2013
ASL RES
2014 (gennaio - agosto)
Warfarin
B01AA03
Warfarin
B01AA03
di cui Soggetti che
Soggetti Warfarin
Soggetti che
consumano
nel 2013 e che nel
hanno iniziato a
entrambi
2014 sono passati
consumare solo
(Warfarin e NAO)
ai NAO
NAO nel 2014
nel 2014
Soggetti che
hanno assunto
Warfarin 2013 x Warfarin 2014 x
almeno una volta i 1.000 abitanti
1.000 abitanti
NAO nel 2014
NAO 2014 x
1.000 abitanti
201
9.202
7.955
442
204
717
1.159
19,2
16,6
2,4
202
8.654
7.605
251
121
376
627
20,5
18,0
1,5
203
11.412
9.984
566
260
723
1.289
19,4
17,0
2,2
204
9.986
8.628
401
194
469
870
19,2
16,6
1,7
205
5.525
4.907
205
114
358
563
17,8
15,8
1,8
206
2.294
1.871
176
89
288
464
13,1
10,7
2,7
207
2.996
2.592
108
53
168
276
17,2
14,9
1,6
208
4.910
4.140
268
162
379
647
14,0
11,8
1,8
209
1.917
1.609
68
29
155
223
11,1
9,4
1,3
210
7.518
6.454
413
145
573
986
17,9
15,3
2,3
211
2.700
2.136
382
135
367
749
15,7
12,4
4,4
212
3.363
2.874
164
67
291
455
16,2
13,8
2,2
213
7.333
6.070
522
197
753
1.275
16,4
13,6
2,9
Totale
77.810
66.825
3.966
1.770
5.617
9.583
17,5
15,1
2,2
COSTO-EFFICACIA DABIGATRAN
Mennini F. et al., Farmeconomia e percorsi 2011; 12(1): 63-69
ESPERIENZA DELL’OSPEDALE
DI NOVI LIGURE
NAO
TOTALE 392 pz
ESPERIENZA DELL’OSPEDALE
DI NOVI LIGURE
DABIGATRAN
•252 pazienti in Dabigatran
•60% uomini - 40% donne
•Età media 77 anni (range 42-93)
•Primo paziente trattato il 1 luglio 2013
•79% Piemonte - 21% Liguria
•CHADSVASC medio 3.9 (range 1-8)
•HASBLED medio 2 (range 0-5)
Event rate(95%CI) of
hospital admission
and death due to
thromboembolism
per
100 person year
ESPERIENZA DELL’OSPEDALE
DI NOVI LIGURE
•Scompenso cardiaco 27% (68 pt)
•Ipertensione arteriosa 88% (223 pt)
•Diabete 17% (43 pt)
•Pregresso ictus 18% (45 pt)
•Pregressa CAD 18% (44 pt)
•Pregresso sanguinamento significativo 7% (18 pt)
•Labile INR 20% (52 pt)
•Terapia concomitante 4% (11 pt)
•TAO experience 43% (108 pt) RELY 50%
•TTR medio 66% TTR medio RELY 64%, ROCKET 55%
CHADSVASC
MEDIO 3,9
CHADSVASC
Come abbiamo somministrato il
Dabigatran?
110 MG BID 69% (174 PZ)
Età media 80 anni (range 60-93)
Cl creat media 44 ml/min (range 33-77)
150 MG BID 31% (77 PZ)
Età media 70 anni (range 42-85)
Cl creat media 84 ml/min (range 58-109)
STADIO CHADSVASC CON LE DUE DOSI DI DABIGATRAN
% PAZIENTI
CHADSVASC
CONTINUAZIONE O SOSPENSIONE DAL
TRATTAMENTO
FOLLOW UP medio 8 mesi
Sospensione 5% (13 pazienti)
•Dispepsia 7% (17 pz)
•Sospensioni per dispepsia (2,5% - 7 pz)
•Ischemie cerebrali (0,8% - 2 pz)
•Emorragie maggiori (0,4% - 1 pz)
•Emorragie minori (3% - 8 pz)
•Emorragie cerebrali (0%)
•Orticaria (1,5% - 4 pz)
•CVE (3% - 8 pz) senza complicanze
Assume that NAOs have been on the market for 5 year
➢A new drug comes to the market. Compared to NAOs, the new drug
has:
- cheaper
- antidote
- requirement for monthly monitoring to adjust dose
- many food and drug interactions
- 25% increased relative risk of stroke/systemic embolism
- nearly 50% increased relative risk of major bleeding
- approx. 2.5 times the rate of ICH
- 10% increased relative risk of mortality
➢Would Warfarin be approved by regulatory authorities now?
GRAZIE PER L’ATTENZIONE
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