Come gestire il sanguinamento acuto nel paziente in cura con NAO - Decision-making e problematiche aperte nella gestione della TAO nel paziente ...
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Decision-making e problematiche
aperte nella gestione della TAO
nel paziente complesso
Come gestire il sanguinamento
acuto nel paziente in cura con NAO
Ettore Porreca
Università G. D’Annunzio
Chieti-Pescara
My talk today • Safety of NAO • Laboratory NAO measurement • Reversal of NAO • Antithrombotic therapy after bleeding
Disclosures
Il sottoscritto dichiara di non aver avuto, negli
ultimi due anni, alcun rapporto, anche di
finanziamento con soggetti portatori di
interessi commerciali in campo sanitario
My talk today • Safety of NAO • Laboratory NAO measurement • Reversal of NAO • Antithrombotic therapy after bleeding
Bleeding profiles of NOACs compared with dose-
adjusted warfarin in phase III clinical trials for
stroke prevention in patients with NVAF
NAO WARFARIN
Re-LY (dabigratan 110
4
bid)
3,5 RE-LY 150 Bid
3
ROCKET AF ( rivaroxaban
%/Y 2,5
20 mg od)
2 ARISTOTLE ( apixaban
5mg bid)
1,5
ENGAGE-AF-TIMI 48 (
1 edoxaban 30 od)
0,5 ENGAGE-AF-TIMI 48 (
edoxaban 60 mgod)
0
major intracranial major intracranial
bleeding bleeding bleeding bleeding
Weitz J I & Pollack CV Throm Haemost 2015; 114:1113-26 (mod)
Bleeding profiles of NVKA compared with dose-
adjusted warfarin in phase III clinical trials for
stroke prevention in patients with NVAF
2,5
NAO WARFARIN Re-LY (dabigratan 110
2 bid)
RE-LY 150 Bid
1,5 ROCKET AF ( rivaroxaban
%/Y 20 mg od)
1 ARISTOTLE ( apixaban
5mg bid)
ENGAGE-AF-TIMI 48 (
0,5 edoxaban 30 od)
ENGAGE-AF-TIMI 48 (
0 edoxaban 60 mgod)
GI bleeding GI bleeding
Weitz J I & Pollack CV Throm Haemost 2015; 114:1113-26 (mod)
Most common types of major bleeds in
trials comparing VKAs with NAO
No. of Type of major
Indication VKA NAO
trials bleed
All major bleeds
1769 2091
Atrial 1005 (48%)
4
fibrillation Gastrointestinal 583 (33%) (dabigratan,
rivaroxaban,
edoxanan)
Intracranial 425 (24%) 272 (13%)
All major bleeds 263 161
VTE
7
treatment Gastrointestinal 83 (32%) 50 (31%)
Intracranial 45 (17%) 17 (11%)
Piran S & Schulman S Blood 2019; 133: 425-435
Net Clinical Benefit of Non-Vitamin K Antagonist vs Vitamin K
Antagonist Anticoagulants in Elderly Patients with Atrial Fibrillation
PREFER registry.
Incidence and related adjusted odds ratios (OR) for the net composite endpoint* and its individual
components in patients receiving NOACs or VKAs
Patti G et al Am J Med 2019; 132:749-757
My talk today • Safety of NAO • Laboratory measurement • Reversal of NAO • Antithrombotic therapy after bleeding
How: responsiveness of routine coagulation assays
Assays dabigatran rivaroxaban apixaban edoxaban
aPTT ++ + + +
PT + ++ + ++
TT +++ No effect No effect No effect
Note: + = poorly responsive, ++ = moderate responsive, +++ = highly
responsive. The responsiveness of the aPTT and PT are highly dependent
on the thromboplastin reagents used.
De Caterina R et al. Thromb Haemost 2019; 119:14-38How: quantitative assays for NAO
Anticoagulants Assay methods Principle Assays/Calibrators
Direct thrombin Chromogenic Thrombin-based Hyphen Biomed,
inhibitor: Biophen DTI
Dabigatran Diluted thrombin
time (d-TT)
Ecarin-based Stago ECA-II
Ecarin clotting time
Clot-based Thrombin-based Hyphen Biomed
HTI, HemosIL DTI,
Technoclot DTI,
Roche Dilute
Thrombin Time,
Siemens,
INNOVANCE DTI
Direct factor Xa Chromogenic Factor Xa based Hyphen, Stago,
inhibitors: Technoclone, STA-
Rivaroxaban, liquid Xa
apixaban and Anti-FXa assays
edoxaban
De Caterina R et al. Thromb Haemost 2019; 119:14-38Range of NAO levels observed in clinical trials
of atrial fibrillation
NOACs Dabigatran Rivaroxaban Apixaban Edoxaban
Dose 150 mg bid 20 mg daily 5 mg bid 60 mg daily
Cpeak levels 184 290 171 170
Median; [10th–90th] [5th–95th] [5th–95th] N/A
ng/mL 74.3–383 177–409 91–321
[range of levels
between
quoted
centiles][a]
Ctrough levels 93 32 103 36.1
Median; [10th–90th] [5th–95th] [5th–95th] [25th–75th]
ng/mL 39.8–215 5–155 41–230 19.4–62.0
[range of levels
between
quoted
centiles][a]
De Caterina R et al. Throb Haemost 2019; 119:14-38Laboratory testing in patients treated with direct oral anticoagulants:
plasma concentration at peak and through vs ranges of applicability of
tests
ISTH: In patients with serious bleeding, antidote administration should be
considered if the drugs concentration exceeds 50 ng ml-1
Douxfils J et al JTH 2018: 16: 209-219My talk today • Safety of NAO • Laboratory measurement • Reversal of NAO • Antithrombotic therapy after bleeding
Management of bleeding in patients taking non-vitamin K antagonist oral
anticoagulants.
When
How
European Heart Journal, Volume 39, Issue 16, 21 April 2018, Pages 1330–1393,
.Gli antidoti
Humanized
monoclonal
antibody fragment
Recombinant modified factor Xa molecule
lacking catalytic and membrane binding
activity
Ruff CT et al Circulation 2016; 134: 248-261Idarucizumab for
Dabigatran Reversal —
Full Cohort Analysis
Pollak CV et al N Engl J Med 2017; 377:431-441
RE-VERSE ADPollak CV et al N Engl J Med 2017; 377:431-441
Application and effect of idarucizumab
European Heart Journal, Volume 39, Issue 16, 21 April 2018, Pages 1330–1393,Key Measurements before and after the Administration of Idarucizumab
Pollack CV et al N Engl J Med 2017; 377:431-441CLINICAL OUTCOME
Efficacy 24 h
Time of the 67% (median
cessation of 2.4 h)
bleeding (n
134/203) group a
Safety 30-days 90-days
Mortality 13.5% 18.8%
Thromboembolic 4.8% 6.8%
complication
(IMA, Stroke,
PE)
Pollack CV et al N Engl J Med 2017; 377:431-441Full Study Report of
Andexanet Alfa for Bleeding
Associated with Factor Xa
Inhibitors
Connolly SJ et al N Egl J Med 2019
ANNEXA-4Characteristics of the patients at baseline
Safety Efficacy
Population Population
(N = 352) (N = 254) (bleeding severity + antiXa
Characteristic activity ≥ 75 ng/ml)
Age — yr 77.4±10.8 77.1±11.1
Primary indication for anticoagulation — no. (%)¶
Atrial fibrillation 280 (80) 201 (79)
Venous thromboembolism║ 61 (17) 46 (18)
Other 11 (3) 7 (3)
Factor Xa inhibitor — no. (%)**
Rivaroxaban 128 (36) 100 (39)
Apixaban†† 194 (55) 134 (53)
Enoxaparin 20 (6) 16 (6)
Edoxaban 10 (3) 4 (2)
Site of bleeding — no. (%)‡‡
Gastrointestinal 90 (26) 62 (24)
Intracranial 227 (64) 171 (67)
Other 35 (10) 21 (8)
Connolly SJ et al N Egl J Med 2019; 380: 1326-1335Characteristics of the patients at baseline
Safety Efficacy
Population Population
Characteristic (N = 352) (N = 254)
Male sex — no. (%) 187 (53) 129 (51)
White race — no. (%)† 307 (87) 222 (87)
Body-mass index‡ 27.0±5.9 27.0±6.2
Medical history — no. (%)
Myocardial infarction 48 (14) 36 (14)
Stroke 69 (20) 57 (22)
Deep-vein thrombosis 67 (19) 53 (21)
Pulmonary embolism 41 (12) 28 (11)
Atrial fibrillation 286 (81) 204 (80)
Heart failure 71 (20) 56 (22)
Diabetes mellitus 107 (30) 80 (31)
Estimated creatinine clearance — no. (%)§Application and effect andexanet alpha.
European Heart Journal, Volume 39, Issue 16, 21 April 2018, Pages 1330–1393,Anti-Factor Xa activity
Connolly SJ et al N Egl J Med 2019; 380: 1326-1335CLINICAL OUTCOME
Haemostatic Efficacy (N 254) 12 h
Exellent or good (≥ 75 ng/ml anti- 82%
factor Xa activity) 85% GI
80% ICH
Safety 30-days
(N 352)
Mortality 14%
Thromboembolic complication (IMA, 10%
Stroke, PE)
Connolly SJ et al N Egl J Med 2019; 380: 1326-1335Non-specific reversal
agents
Prothrombin Complex Concentrate
for Major Bleeding on Factor
Xa InhibitorsDOAC-induced anticoagulation and the proposed effect of PCCs
I concentrati di complesso protrombinico mitigano l’effetto
anticoagulante degli inibitori del Xa e del FIIa aumentando I
livelli di fattori della coagulazione non attivati
Hoffman M et al Inter J Emerg Med 2018; 11:55Comparison on management of anticoagulant-associated bleeds
Study Sarode Sarode et al Connoly et al Majeed t al Schulman et al TH
Circulation 2013 Circulation ANNEXA-4 Blood 2017 2018
N 103 N 9 8 N Engl J Med 2019 N N 84 N 66
67
Anticoagulant warfarin warfarin Xa inhibitors Xa inhibitors Xa inhibitors
Reverseal agent plasma PCC Andexanet alfa PCC (2000 U) PCC (2000U)
Age, mean (SD) 69,8 (13.9) 69,8 (12.8) 77.1 (10) 75 (10.9) 76.9 (10.4)
ICH n (%) 12 (12) 12(12) 28(42) 59(70) 36(55)
GI bleed (%) 64(62) 63(64) 33(49) 13(16) 16(24)
Time last dose Xa NA NA R:12.8±4.2 12.5 (9-16) 16.9 (12-21)
inhibitor to PCC, A 12.1±4.7
median (IQR)
Effectivenes
(Sarode) for SNC
Excellent or good 7(58) 5(42) 16(80) No done 25 (76)
n (%)
Effectiveness
ISTH for SNC
Effective 43 (73) 25 (69)
Safety outcome
during 30d
Thromboembolism 7(6) 8(8) 12(18) 3(4) 5(8)
Death 5(5) 6(6) 10(15) 27(32) 9(14)
Schulman S et al Thromb Haemost 2018; 118:842-851My talk today • Safety of NAO • Laboratory measurement • Reversal of NAO • Antithrombotic therapy after bleeding
Adjudicated Thrombotic Events within 30 Days after the Administration of
Idarucizumab.
The light gray portion of the bar indicates the time before the event, and the dark gray portion
the time after the event. Red
diamonds indicate the initiation of
parenteral or oral anticoagulant therapy, and blue circles the initiation of
antiplatelet therapy
Pollak CV et val N Engl J Med 2017;Safety (Andexanet Alfa)
Variable Safety Population (N = 352)
TotalResuming anticoagulants after anticoagulant-associated intracranial
haemorrhage
Zien Zhou et al. BMJ Open 2018;8:e019672Resuming anticoagulants after anticoagulant-associated GI haemorrhage
((B) Time-to-event analysis showing 90-day cumulative incidence of recurrent GIB stratified by
duration of interruption of warfarin.
Qureshi WT et al Am J Cardiol 2014; 113:662-668(Re-) initiation of anticoagulation post-gastrointestinal bleeding.
European Heart Journal, Volume 39, Issue 16, 21 April 2018, Pages 1330–1393,(Re-) initiation of anticoagulation post intracranial bleeding
European Heart Journal, Volume 39, Issue 16, 21 April 2018, Pages 1330–1393Conclusioni • il sanguinamento acuto (in particolare nei sanguinamenti maggiori) in pazienti in trattamento con NAO, può essere gestito in maniera efficace • abbiamo a disposizione antidoti o alternative come i concentrati protrombinici rapidamente efficaci. • una valutazione quantitativa dell’attività anticoagulante può essere utile nel valutare l’importanza dello specifico NAO e decidere l’uso di antidoti. • ogni paziente va considerato per la ripresa della terapia anticoagulante anche dopo un sanguinamento e possibilmente con NAO a minor rischio emorragico (GI)
Grazie per l’attenzione
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