Il sanguinamento digestivo nel paziente in terapia con ...♂ 75 yr-old, AF on warfarin, haematemesis and hypovolemic shock, INR 3.9 Management of warfarin -associated coagulopathy

Il sanguinamento digestivo nel paziente in terapia con farmaci antitrombotici

Franco Radaelli UOC Gastroenterologia, Ospedale Valduce, Como

Cardiologists and Gastroenterologists

The burden of GI bleeding associated with antithrombotics

Patients on AC + APA

10-15% 1,2 15-30%3,4

1 Loperfido S et al. Changing trends in acute upper-GI bleeding: a population-based study. Gastrointest Endosc. 2009;70: 212-24

2 Hearnshaw S et al. Acute upper GI bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 UK audit. Gut 2011; 60: 1327-35 3 Hashash JG et al. Gross lower GI bleeding in patients on anticoagulant and/or antiplatelet therapy: endoscopic findings, management, and clinical

outcomes. J Clin Gastroenterol. 2009; 43:36-42 4 Aoki T et a. Recurrence and mortality among patients hospitalized for acute lower GI bleeding. Clin Gastroenterol Hepatol 2015; 13: 488-494

18-25% 1,2

12-30% 3,4

18-34%

Patients on APA

Chart1

AC

Others

63

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23

Foglio1

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Others23

63

Chart1

AC

Others

35

Vendite

LGIB

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40

Foglio1

Vendite

AC25

Others40

35

Antithrombotic therapy [AT] and GI bleeding: Clinical implications

AT interruption Diagnosis Treatment

AT resumption GI Bleeding

Correction of coagulopathy?

Timing endoscopy

Timing of resumption

VKAs NOACs APA DAPT

risk/benefit assessement

very-low quality of evidence !!

• In-hospital bleeding related mortality therapy is high (up to 8-12%), mainly related to comorbidity

Antithrombotic therapy [AT] and GI bleeding: General rules

1 Barkun AN et al, Ann Intern Med 2010;152:101-113

• Early intensive resuscitation of patients, including correction of coagulopathy, decreases bleeding-related mortality1

• Correction of coagulopathy should not delay therapeutic endoscopy2. Endoscopic haemostasis is safe and effective in anticoagulated patients

• Early resumption of AT following resolution of GI bleeding has a favourable risk/benefit in most patients2

2 Gralnek JM et al. Endoscopy 2015; 47: 1-46

0

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20

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nulla vit k per os vit k ev plasma cp plasma + vitk

cp + vit k altro

Case Scenario 1: life-threathening GI bleeding, supra-therapeutic INR

Radaelli F et al. Dig Liv Dis 2011; 43:444-7

Nihil os vit K i.v. vit K FFP PCC FFP+vitK PCC+vit K other

Cross sectional physician web-based survey amongst 105 gastroenterologists (62% on-call for emergency) in Lombardia

♂ 75 yr-old, AF on warfarin, haematemesis and hypovolemic shock, INR 3.9

Management of warfarin-associated coagulopathy in patients with acute GI bleeding. A cross-sectional survey of current practice

- Management largely varies among gastroenterologistists - Poor compliance to practice guidelines - Topic only marginally addressed by gastroenterological guidelines

Diagnosis and Management of Nonvariceal Gastrointestinal Bleeding

New Practice Guidelines

Management of Patients wiht Acute Lower GI Bleeding

Gralnek JM et al. Endoscopy 2015 ESGE 2015

ACG 2016 Strate L, Am J Gastroenterol 2015

Alghoritm: management strategies in patients on Anticoagulants

(1) Patients presenting overt GI bleeding, with shock or persistent or intermittent hemodynamic instability (2) Patients presenting overt GI bleeding, anemia or need for transfusion (3) Patients with scanty, self-limiting haematochezia with neither significant anemia or hemodynamic comprimise

Acute GI bleeding

Active bleeding/Shock1 Significant bleeding2 Without haemodynamic compromise

Minor rectal bleeding3 Life-threatening bleeding

Major bleeding Non-major bleeding

Alghoritm: management strategies in patients on VKAs

Acute GI bleeding

Active bleeding/Shock1 Significant bleeding Without o haemodynamic compromise

Minor rectal bleeding

Urgent clinical assessment and resuscitation - Stop Warfarin - Vitamin K 5-10 i.v. over 30 minutes - PCC 25-50 IU/Kg according to baseline INR [FFP 15ml/Kg if PCC unavailable]

Check clotting screen 20-30 min. after PCC infusion

emergent endoscopy vs. radiology preferably when INR < 2.5

Prothrombin Complex Concentrates (PCCs) promote hameostasis (therapeutic role) and fast correct INR, thus allowing emergent endoscopy even if INR is supratherapeutic: INR 2-4= 25 IU/Kg INR 4-6= 35 IU/Kg INR > 6= 50 IU/Kg


Acute GI bleeding






Urgent clinical assessment and resuscitation - Stop Warfarin - Vitamin K 5-10 i.v. over 30 minutes

urgent endoscopy

Consider PCC only if INR is supra-therapeutic and endoscopy is planned within 6-12 hours


Acute GI bleeding






Urgent clinical assessment and resuscitation - Stop Warfarin - Vitamin K 5-10 i.v. over 30 minutes

urgent endoscopy

Potential outpatient management Hold one dose warfarin - INR < 5: no further action - INR > 5: oral vit.

Consider elective endoscopy

Consider PCC only if INR is supra-therapeutic and endoscopy is planned within 6-12 hours

Alghoritm: management strategies in patients on DOACs

Acute GI bleeding



Specific issues related to DOAC: •Routine coagulation tests (PT, aPTT) not sensitive for the quantitative assessement of DOAC activity[diluite TT/ anti-Xa assay not routinely available in emergency setting]

•Specific antidote currently available for dabigatran only (idarucizumab) •Short half-lives: loss of anticoagulation is rapid and predictable, occurring gradually over 12–24 h with a near complete recovery after five half-lives [time is the best antidote!]

•All DOACs have significant renal clerance, and dabigatran is 85% renally excreted

– a normal aPTT may exclude the anticoagulation effect due to dabigatran – a normal prothrombin time ratio usually excludes an anticoagulation effect due to rivaroxaban

• Specific ‘reversal agents’ are largely expected by physicans, but not used in the vast majority of bleed events.

• There is no evidence of worse outcomes following major bleeding events in patients treated with rivaroxaban.

• In 15.690 patients treated with rivaroxaban in ROCKET AF trial, Dresden registry and XANTUS study, only 13 cases were treated with coagulation factor administration

Study and registry Patients MB Pro-coagulants ROCKET AF1 7.131 395 5 DRESDEN REGISTRY2 1.775 66 6 XANTUS3 6.784 128 2

1 C Patel MR et al. N Engl J Med. 2011;365(10):883–891; 2 Beyer-Westendorf J et al. Blood. 2014;124(6):955–962; 3 Camm AJ et al, Eur Heart J 2015

In the Majority of Events, Standard Clinical Measures are Sufficient to Manage Bleeding

Anticoagulant Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin: ROCKET AF Trial. Sherwood MW et al. J Am Coll Cardiol 2015; 66: 2271-91

Fatality rate: 1/221 vs. 5/140 (0.4% vs. 3.5%)

Alghoritm: management strategies in patients on DOACs

Acute GI bleeding



To do ever: 1. Resuscitation with aggressive fluid

replacement (cristalloids) 2. CrCl estimation 3. DOAC level dosage, if available 4. Inquire last dose of DOAC intake

Not to do: 1. Consider PT or aPTT to assess DOAC

activity 2. Vit K, FFP 3. Haemodyalis ([DABIGATRAN]

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Consider emergent endoscopy/radiology Defer endoscopy 6-12 after last dose intake

Potential outpatient management: 1. Hold last dose of DOAC 2. Observation

Consider elective endoscopy if appropriate

Consider acute reversal (selected cases)

Agent IDARUCIZUMAB (Boehringer Ingelheim)

ANDEXANET Alpha (Portola Pharmaceuticals)

ARIPAZINE (PER977) (Perosphere)

Target - selective: Dabigatran

- selective: FXa-Inhibitors Rivaroxaban, Apixaban, Edoxaban

- non selective: Dabigatran Fxa-Inhibitors Fondaparinux Heparin

Structure Humanized antibody fragment

Recombinant FXa, inactive Syntetic small molecule (512Da)

Mechanism Binding to Dabigatran with 350 times greater affinity than thrombin

Targeting and sequestering with high competitivey FXA-Inhibithors

Reversal effect through direct binding to anticoagulants

Phase III clinical trials

Ongoing RE-VERSE AD

Ongoing ANNEXA-A (apixaban) ANNEXA-R (rivaroxaban) ANNEXA-E (edoxaban, planned)

Enriquez A, Europace 2015

DOAC specific antidotes:

FDA-EMEA approved Praxbind® ($ 3.500)

FDA-EMEA approved Ondexxya®

– Off-label use of procoagulants (4F-PCC, aPCC) based on experimental data in animal model/

volunteers and anedoctal clinical experience (ICH>> GI bleeding!)

Reversal Agents for DOACS

Dabigatran F-Xa Inhibitors

First Line Idarucizumab [5g] 4F-PCC [50 IU/kg] aPCC [50 IU/Kg]

Second Line 4F-PCC [50 IU/kg] aPCC [50 IU/Kg]

Reversal Agents for DOACS

Idarucizumab Andexanet Alpha DOAC Dabigatran Rivaroxaban, Apixaban Indication

U

Dosage 2 vials (2.5g/50mL) rapid infusion

Apix, Riva (last intake >7h): 400mg bolus 4mg/min for 120 min. (Total 880mg) Riva (last intake

Anticoagulant therapy and GI bleeding: Clinical implications



Correction of coagulopathy?

Timing endoscopy

Resumption (timing)

VKAs NOACs

Study Design AC Indication Resumed [#pts] Did not resume [#pts]

Qureshi 2014 Retrospective, cohort Warfarin AF 653 676

Witt 2012 Retrospective, cohort Warfarin AF, MHV, VTE 260 182

Nieto 2008 Prospective registry Warfarin VTE 39 15

Risk of Thromboembolism: -32% HR 0.68 [95% CI 0.52-0.88] Risk of Mortality: -24% HR 0.76 [95% CI 0.66-0.88] Risk of Recurrent GI Bleeeding: NS HR 1.20 [95% CI 0.97-1.48]

Chai-Adisaksopha C et al. Thromb Haemost 2015; 114: 819-825

Resuming warfarin should be strongly considered in most patients following resolution of GI bleeding

Thromboembolic events, recurrent bleeding and mortality after resuming anticoagulant following GI bleeding – A Meta-analysis

When?

Qureshi W et al. Am J Cardiol 2014; 113: 662-8

< 7

7-15

15-21

21-30

>30

No. Patients n=62 n=51

n=58

n=53

n=429

Thromboembolism (100 person-years)

11.6 (8.3-16.2)

12.0 (8.2-17.5)

18.1 (13.4-24.5)

20.7 (15.5-27.7)

20.4 (17.8-23.5)

Recurrent GI bleeding (100 person-years)

19.3 (14.6-25.5)

10.8 (7.2-16.3)

10.9 (7.2-16.4)

9.9 (6.3-15.5)

9.9 (8.0-12.3)

Duration of suspension (days)

Incidence of adverse outcomes per 100 person-years in the warfarin group, stratified by the time of duration of warfarin interruption:

There is a trend toward reduced incidence of thromboemboic events the earlier warfarin is introduced; this trend is more evident within 15 days

Resuming warfarin within 7 days is associated with a 2-fold increased risk of rebleeding

Decision to restrat warfarin after 7 days of interruption is associated with decreased thromboembolism, imporved survival without increased risk of recurrent GI bleeding

Best trade-off?

Restarting anticoagulation and outcomes after major GI bleeding in atrial fibrillation

Resumption of anticoagulant after GI bleeding

1 bridging therapy with UFH (LMWH?)

2 high thrombotic risk patients: - mechanical (mitralic) heart valve

- AF with CHADS2 score 5-6, previous embolic event - recent (< 1 month) DVT or pulmonary thromboembolism

1 2

ESGE: VKAs resumption between 7-15 days (within the first 7 days for patients at high TE risk)

ESC: VKAs resumption within 1 week in most cases

No evidences for DOACs (= VKAs ?)



Reversal?

Timing endoscopy

Yes/ No? Timing of resuption

– ♂ 75 yr-old, ischemic stroke 5 months before admission – Secondary porphylaxis with aspirin 100mg – Haemorragic shock, Hb 7.6g/dL –

Case scenario 2- APA:



PLT Transfusion?

Timing endoscopy

Yes/ No? Timing of resuption

– No benefit of PLT transfusion in patients with ICH

There are no data supporting routine use of platelet transfusion in GI bleeding

– In patients presenting with gastrointestinal bleeding after PCI, a few observations warn against platelet transfusion early after stent insertion, as it may precipitate in-stent occlusion

Creutzfeldt CJ et al. J Stroke Cerebrovasc Dis 2009 Downey DM et al. Am Surg 2009

Cornet AD et al. J Invasive Cardiol 2007 Schulz C et al. Thromb Haemost 2006

Simon BC et al. Cardiovasc Intervent 2000

When to restart anti-platelet therapy?

- In patients with cardiovascular comorbidities , discontinuation of aspirin after peptic GI bleeding associated with a 4-fold increased risk of death for CV events [70% within 10 days]

Derogar, Clin Gaastroentero Hepatol 2013; 11: 38-42

Sung JJ, Ann Intern Med 2010; 152: 1e-9

- In a RCT, bleeding patients continuing aspirin for secondary prevention have a 30-day non-significant increased risk of GI bleeding but a significant higher mortality

# Patients

Treatment

30-day bleeding

8-weeks mortality for GI bleeding/ CV events

78 PPI + ASA 80mg 10.3% 1.3%

78 PPI + Placebo 5.4% 10.3%

Absolute difference 4.9% [95% CI -3.6 - 13.4]

Absolute difference 9% [95% CI 1.7- 16.3]

- DAPT interruption is the major cause of stent thrombosis after PCI

Early upper GI endoscopy (within 24 hours) + haemostasis

No bleeding sources identified at upper GI endoscopy

How to manage APA (secondary prophylaxis)?

Single APA

DAPT

Treat AP therapy as high-risk endoscopic stigmata

Clinically unstable

Urgent colonoscopy versus CT mdc +/- angiography

Continue ASA Colonoscopy within 24-48h

Clinical assessment

Cllinically stable

Diapositiva numero 1Diapositiva numero 2Diapositiva numero 3Diapositiva numero 5Antithrombotic therapy [AT] and GI bleeding: �General rulesDiapositiva numero 7Diapositiva numero 8Diapositiva numero 9Diapositiva numero 10Diapositiva numero 11Diapositiva numero 12Diapositiva numero 13In the Majority of Events, Standard Clinical Measures are Sufficient to Manage BleedingDiapositiva numero 15Diapositiva numero 16Diapositiva numero 17Diapositiva numero 18Diapositiva numero 19Diapositiva numero 20Diapositiva numero 21Diapositiva numero 22Diapositiva numero 23Diapositiva numero 24Diapositiva numero 25Diapositiva numero 26Diapositiva numero 27Diapositiva numero 28

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Il sanguinamento digestivo nel paziente in terapia con ...♂ 75 yr-old, AF on warfarin, haematemesis and hypovolemic shock, INR 3.9 Management of warfarin -associated coagulopathy