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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Come gestire il sanguinamento acuto nel paziente in cura con NAO - Decision-making e problematiche aperte nella gestione della TAO nel paziente ...
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
Come gestire il sanguinamento acuto nel paziente in cura con NAO - Decision-making e problematiche aperte nella gestione della TAO nel paziente ...
My talk today

• Safety of NAO
• Laboratory NAO measurement
• Reversal of NAO
• Antithrombotic therapy after
  bleeding
Come gestire il sanguinamento acuto nel paziente in cura con NAO - Decision-making e problematiche aperte nella gestione della TAO nel paziente ...
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
Come gestire il sanguinamento acuto nel paziente in cura con NAO - Decision-making e problematiche aperte nella gestione della TAO nel paziente ...
My talk today

• Safety of NAO
• Laboratory NAO measurement
• Reversal of NAO
• Antithrombotic therapy after
  bleeding
Come gestire il sanguinamento acuto nel paziente in cura con NAO - Decision-making e problematiche aperte nella gestione della TAO nel paziente ...
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)
Come gestire il sanguinamento acuto nel paziente in cura con NAO - Decision-making e problematiche aperte nella gestione della TAO nel paziente ...
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)
Come gestire il sanguinamento acuto nel paziente in cura con NAO - Decision-making e problematiche aperte nella gestione della TAO nel paziente ...
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
Come gestire il sanguinamento acuto nel paziente in cura con NAO - Decision-making e problematiche aperte nella gestione della TAO nel paziente ...
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
Come gestire il sanguinamento acuto nel paziente in cura con NAO - Decision-making e problematiche aperte nella gestione della TAO nel paziente ...
My talk today

• Safety of NAO
• Laboratory measurement
• Reversal of NAO
• Antithrombotic therapy after
  bleeding
Come gestire il sanguinamento acuto nel paziente in cura con NAO - Decision-making e problematiche aperte nella gestione della TAO nel paziente ...
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; 119:14-38
How: 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; 119:14-38
Range 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; 119:14-38
Laboratory 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: 209-219
My 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: 248-261
Idarucizumab for
Dabigatran Reversal —
 Full Cohort Analysis
  Pollak CV et al N Engl J Med 2017; 377:431-441
                RE-VERSE AD
Pollak 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; 377:431-441
CLINICAL 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; 377:431-441
Full Study Report of
Andexanet Alfa for Bleeding
 Associated with Factor Xa
         Inhibitors
  Connolly SJ et al N Egl J Med 2019
             ANNEXA-4
Characteristics 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: 1326-1335
Characteristics 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: 1326-1335
CLINICAL 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: 1326-1335
Non-specific reversal
      agents
Prothrombin Complex Concentrate
  for Major Bleeding on Factor
         Xa Inhibitors
DOAC-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; 11:55
Comparison 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; 118:842-851
My 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)
                                    Total
Resuming anticoagulants after anticoagulant-associated intracranial
                          haemorrhage

                                              Zien Zhou et al. BMJ Open 2018;8:e019672
Resuming 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 1330–1393
Conclusioni
• 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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