Nuovi Anticoagulanti- Aspetti pratici - eoc.ch fileIndicazioni NOAC in CH • Profilassi TVP in...
Transcript of Nuovi Anticoagulanti- Aspetti pratici - eoc.ch fileIndicazioni NOAC in CH • Profilassi TVP in...
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