Nuovi Anticoagulanti- Aspetti pratici

Hans Stricker

Ospedale La Carità

Angiologia

Introduzione

• Basics

• Scelta del NOAC

• Compliance/Adherence

• Gestione periintervenzionale

• Quando determinare il tasso

• Conclusione

Basics

Indicazioni per NOAC in CH

Indicazione Dabigatran

(Pradaxa)

Rivaroxaban

(Xarelto)

Apixaban

(Eliquis)

Edoxaban

(Lixiana)

Profilassi

Ortopedia - + + -

Terapia TVP + + + +

Terapia EP + + + +

Profilassi

post-TVP/EP + + + +

Fibr. atriale + + + +

Indicazioni NOAC in CH

• Profilassi TVP in ortopedia: Rivaroxaban Apixaban

• Terapia TVP; profilassi post TVP/EP: Rivaroxaban Apixaban Dabigatran Edoxaban

• Profilassi cardioembolia in FA: Rivaroxaban Apixaban Dabigatran Edoxaban

• Rivaroxaban (1x10 mg), • Apixaban (2x2.5 mg)

• Rivaroxaban (2x15 mg per 3 settimane, poi 1x20 mg)

• Apixaban (2x10 mg per 1 settimana, poi 2x5 mg- 3 mesi, in seguito 2x2.5 mg)

• Dabigatran (Eparina per 5 dì, poi 2x150/110 mg)

• Edoxaban (Eparina per 5 dì, poi 1x60/30 mg)

• Dabigatran (2x110 o 2x150 mg) • Rivaroxaban (1x20 mg o 1x15 mg) • Apixaban (2x5 mg o 2x2.5 mg) • Edoxaban (1x60 o 30 mg)

• Pazienti (n=3365) con MTEV dopo 6-12 mesi di terapia anticoagulante

• 3 gruppi: aspirina 100 mg, vs Rivaroxaban 20 mg vs. Rivaroxaban 10 mg

• Durata dello studio -12 mesi

• Endpoints: recidiva di MTEV e sanguinamento

Risultati Einstein Choice

Risultati Apixaban extension

Major bleeding: 0.2 risp. 0.1% per Apixaban

Are all NOAC’s the same?

RE-COVER I1

RE-COVER II2

EINSTEIN-DVT3

EINSTEIN-PE4

AMPLIFY5 Hokusai-VTE6

Study drug Dabigatran Rivaroxaban Apixaban Edoxaban

Study design* Double-blind Open-label Double-blind Double-blind

Pre-randomization

heparin

NR <48 hrs <36 hrs <48 hrs

Heparin lead-in At least 5 days None None At least 5 days

Dose 150 mg BID 15 mg BID x 3 wk

then 20 mg QD

10 mg BID x 7 d

then 5 mg BID

60 mg QD

30 mg QD†

Dose reduction NONE NONE NONE 18%

Randomized

population

2,5641

2,5682

3,4493

4,8334

5,400 8,292

Treatment

duration

6 months Pre-specified

3, 6, 12 months

6 months Flexible

3 to 12 months

1. Schulman et al. N Engl J Med 2009;361:2342–2352; 2. Schulman et al. Blood 2011;118:Abstract 205 3. EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 4. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297

5. Agnelli et al. N Engl J Med 2013. doi:10.1056/NEJMoa.1302507; 6. The Hokusai-VTE Investigators. N Engl J Med 2013

NOAC VTE: study designs

*Comparator was warfarin in each case †Dose was halved to 30 mg in patients perceived to be at higher risk for bleeding by predefined criteria NR=not reported

RE-COVER1# (Dabigatran)

EINSTEIN DVT2

(Rivaroxaban) EINSTEIN PE3 (Rivaroxaban)

AMPLIFY4 (Apixaban)

Hokusai-VTE5 (Edoxaban)

Patients, N 2539 3449 4832 5395 8292

Age (yrs) 55 56 58 57 56

Female (%) 42 43 47 41 43

Creatinine clearance <50 mL/min (%)

NR 7 8 6 7

DVT (%) 69 99 - 65 59

PE±DVT (%) 31 0.6 100 35 40

Unprovoked (%) NR 62 65 90 65

Cancer (%) 5 6 5 3 9†

Previous VTE 26 19 19 16 18

NOAC VTE trials: Baseline characteristics

NR=not reported; #RECOVER II is still only available as an abstract and therefore is not included in the table †Data from Hokusai-VTE are for history of cancer; active cancer was observed in 2.4% of patients overall

1. Schulman et al. N Engl J Med 2009;361:2342–2352 2. EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 3. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297

4. Agnelli et al. N Engl J Med 2013. doi:10.1056/NEJMoa.1302507; 5. The Hokusai-VTE Investigators. N Engl J Med 2013

RE-COVER I1 EINSTEIN-DVT2 EINSTEIN-PE3 AMPLIFY4 Hokusai-VTE5-7

Drug Dabigatran Rivaroxaban Rivaroxaban Apixaban Edoxaban

Treatment duration (%) 3 months 6 months*

6-12 months 12 months

-

100 - -

12 63 -

25

5

58 -

37

-

100 - -

12 26 61 40†

Mean treatment duration, days

<180 NR 215 <180 249

≥1 dose heparin prior to randomization (%)

100 72 92 86 100

Adherence to therapy >80% (%)

98 NR 94 96 99

NOAC VTE trials: Baseline characteristics

*For Hokusai-VTE duration was 3 to 6 months †40% of patients in Hokusai-VTE reaching 12 months is included within 61% of patients reaching 6-12 months NR= Not Reported

1. Schulman et al. N Engl J Med 2009;361:2342–2352; 2. EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510 3. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297; 4. Agnelli et al. N Engl J Med 2013. doi:10.1056/NEJMoa.1302507

5. The Hokusai-VTE Investigators. N Engl J Med 2013; 6. Raskob et al. J Thromb Haemost 2013;11:1287-1294; 7. Daiichi Sankyo, data on file.

RE-COVER I1 EINSTEIN-DVT2 EINSTEIN-PE3 AMPLIFY4 Hokusai-VTE5

Drug Dabigatran Rivaroxaban Rivaroxaban Apixaban Edoxaban

Randomized patients, N 2564 3449 4833 5400 8292

Did not receive study drug, n (%) 25 (1) 20 (<1) 16 (<1) 30 (<1) 52 (<1)

Study discontinuations, n (%)

Overall

Adverse events

Non-adherence

Withdrew consent

Lost to follow-up

Other

387 (15)

228 (9)

56 (2)

75 (3)

15 (<1)

13 (<1)

440 (13)

141 (4)

NR

101 (3)

33 (1)

167 (5)

555 (11)

203 (4)

NR

184 (4)

18 (<1)

150 (3)

790 (15)

332 (6)

NR

98 (2)

28 (<1)

286 (5)

348 (4)

NR

NR

70 (<1)

11 (<1)

9 (<1)

Time in therapeutic range (%)

<2.0

2.0-3.0

>3.0

21

60

19

24

58

16

22

63

15

23

61

16

18.9

63.5

17.6

1. Schulman et al. N Engl J Med 2009; 361: 2342–2352 2. EINSTEIN Investigators. N Engl J Med 2010; 363: 2499–2510; 3. EINSTEIN–PE Investigators. N Engl J Med 2012; 366: 1287–1297

4. Agnelli et al. N Engl J Med 2013. doi:10.1056/NEJMoa.1302507; 5. The Hokusai-VTE Investigators. N Engl J Med 2013

NOAC VTE study quality parameters

RE-COVER I1 EINSTEIN DVT2 EINSTEIN PE3 AMPLIFY4 Hokusai-VTE5

Drug Dabigatran Rivaroxaban Rivaroxaban Apixaban Edoxaban

Primary efficacy outcome versus warfarin

Efficacy non-inferior non-inferior non-inferior non-inferior non-inferior

Safety outcomes versus warfarin

Major+CRNM bleeding

significantly lower

NS NS significantly

lower significantly

lower

Major bleeding NS NS significantly

lower significantly

lower NS

CRNM bleeding NR NS NS significantly

lower significantly

lower

Any bleeding significantly

lower NR NR NR

significantly lower

Phase III VTE trials – results

NR=not reported; NS=not statistically significant

1. Schulman et al. N Engl J Med 2009;361:2342–2352 2. EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 3. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297

4. Agnelli et al. N Engl J Med 2013. doi:10.1056/NEJMoa.1302507; 5. The Hokusai-VTE Investigators. N Engl J Med 2013

VTE Trial: Anticoagulant Effect

Relative Hazard Ratio (95% CI)

RE-COVER I

Favors NOAC Favors other treatment

0.25 0.5 1.0 2.0 4.0

EINSTEIN DVT

Hokusai-VTE

EINSTEIN PE

Relative Hazard Ratio (95% CI)

RE-COVER I

Favors NOAC Favors other treatment

0.25 0.5 1.0 2.0 4.0

EINSTEIN DVT

Hokusai-VTE

EINSTEIN PE

Recurrent VTE MCRNM Bleeding

AMPLIFY AMPLIFY

DVT PE

DVT PE

Practical consideration for NOAC selection

P. P. Dobesh

Indications for traditonal anticoagulants

Renal failure (GFR < 30 ml/’)

Mechanical heart valves

pregnancy

Formally where NOAC’s have not been tested (cf. in- and exclusion criteria)

NOAC’s Compliance

• Eine kürzlich veröffentlichte Studie zu Patienten, die Dabigatran für ein Vhfli einnehmen, ermittelte, dass die C. zwischen 41 und 96% liegt

• Kurze Halbwertszeit der NOAC’s im Vgl. zu Marcoumar: eine vergessene Dosis kann bereits Auswirkungen haben

• Eine schlechte Compliance korreliert mit kardiovaskulären Ereignissen

(Shore S, Carey EP, TurakhiaMP, et al. Adherence to dabigatran therapy and longitudinal patient outcomes:

insights from the veterans health administration. Am Heart J. 2014;167(6):810-817)

• Keine Kontrollen wie bei INR • Eine «Begleitung» des Patienten z.B. durch den

Apotheker verbessert die C.

Compliance bei Patienten mit Vhfli

Verbesserung der Compliance durch Monitoring

Early non-persistence with dabigatran and rivaroxaban in patients

with atrial fibrillation Cynthia A Jackevicius et al, Heart 2017; 1: 1-8

NOAC

• Dabigatran (n>15’000)

• Rivaroxaban (n>10’000)

• Stroke/TIA/Decesso (Dabi)

• Stroke/TIA/Decesso (Riva)

• Stroke/TIA (Dabi)

• Stroke/TIA (Riva)

Non-Compliance* dopo 6 mesi

• 36.4%

• 31.9%

• HR 1.76 (95% CI 1.60 to 1.94)

• HR 1.89 (95% CI 1.64 to 2.19)

• HR 3.75 (95% CI 2.59 to 5.43)

• HR 6.25 (95% CI 3.37 to 11.58

*Non compliance ≥ 14 giorni

Gestione dei NOAC in periintervenzionale

*Bridging may be considered in patients with a history of systemic embolus in the last 6 weeks

Situazioni a rischio

• Pazienti con FA sottoposti a PTCA • Posa PM

• Chirurgia non-cardiovascolare

• Chirurgia vascolare

• Anestesia neurassiale

• Fibrinolisi in pazienti anticoagulati con ictus

• V. sotto (PIONEER) • Stop 24 ore prima (R,A,E), o 24/36/48 ore (D)

(GFR >80/50-79/30-50 ml/’) • Di regola nessun bridging (bridging con più

emorragie). Cambierà con introduzione di antidoti

• Dati scarsi; piccolo studio con pazienti sotto R. sanguinavano più che sotto warfarina

• Ematoma spinale raro in 2 studi con R terapeutico (1/2550 risp 1/4086)

• Anestesia: stop D 4-5 giorni prima, R/A 3-5 giorni prima, ma rischio tromboembolico?

• Non vi sono differenze c/o rischio emorragico tra {R, A, D}, Warf con INR<1.7, e nessuna anticoagulazione

Circulation. 2017;135:1024–1035

Design dello studio PIONEER

• Pazienti con FA sottoposti a PTCA

• 3 gruppi:

– Rivaroxaban 15 mg plus P2Y12-inibitore per 12 mesi (gruppo 1)

– Rivaroxaban 2x2.5 mg plus DAPT per 1, 6 o 12 mesi (gruppo 2)

– Warfarina (INR 2-3) plus DAPT (gruppo 3)

Cumulative Incidence of the Primary Safety End Point and a Secondary Efficacy End Point.

Gibson CM et al. N Engl J Med 2016;375:2423-2434

Quando determinare il tasso dei NOAC

• Compliance non chiara

• Evento tromboembolico sotto terapia

• Sangiunamento sotto terapia

• Sovvradosaggio

• Insufficienza renale/estremi di peso corporeo

• Pre-op (?)

Alterazioni dei test di coagulazione

Differentialdiagnose aufgrund der Globaltest und des spezifischen Rivaroxaban Messwertes

PT

aPTT Rivaroxaban

Konzentration

(chrom. AntiXa Test)

Beeinflussung der

Hämostase Massnahme

< 50 ng/ml > 50 ng/ml

reduziert wenn möglich warten mit Eingriff

↔ ↔ reduziert wenn möglich warten mit Eingriff

↔ gering reduziert Eingriff möglich

↔ ↔ gering reduziert Eingriff möglich

↔ reduziert, aber nicht wegen

Rivaroxaban Grund der aPTT Verlängerung abklären

↔ reduziert, aber nicht wegen

Rivaroxaban Grund der PT Reduktion abklären

Messwert reduziert > 20% unter Normbereich Messwert erhöht > 20% über Normbereich

↔ Messwert im Normbereich

û nicht nachweisbar ügemessen mit chromogenem Anti Xa Test und Rivaroxaban Kalibratoren

Interpretation der Rivaroxaban-Spiegel

Table 2

Rivaroxaban plasma concentrations after therapeutic doses based on phase II data and simulated virtual data

Dose Clinical setting Ctrough (μg/l)Cmax (μg/l)

2.5 mg bid Acute coronary syndrome 16 (6–34)*44 (28–66)*

10 mg od VTE prevention after total hip replacement 9 (1–38)# 125 (91–196)#

15 mg odStroke prevention in patients with AF (CrCl

≤50 ml/min)57 (18–136)‡ 229 (178–313)‡

20 mg od DVT treatment (continued treatment) 26 (6–87)§ 270 (189–419)§

20 mg odStroke prevention in patients with AF (CrCl

>50 ml/min)44 (12–137)‡ 249 (184–343)‡

Samama et al. Thrombosis Journal 2013 11:11 doi:10.1186/1477-9560-11-11

Conclusioni

• I NOAC sono sempre più presenti nella realtà terapeutica

• È essenziale conoscere le proprietà dei farmaci che si usano

• Come per tutti i medicamenti nuovi, le raccomandazioni per la gestione delle situazioni non contemplate nei grandi studi vanno seguiti

• Non è un errore usare un AVK • L’introduzione di antidoti cambierà ulteriormente

l’approccio farmacologico dei NOAC