Post on 06-May-2018
New Oral Anticoagulants Increase Risk for
Gastrointestinal Bleeding - A Systematic
Review and Meta-Analysis
Holster IL, Valkhoff VE, Kuipers EJ, Tjwa ET Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, Netherlands
Gastroenterology, accepted for publication 27.02.2013
New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 2
Background
• Antithrombotic medication associated with higher risk for
gastrointestinal bleeding (aspirin, clopidogrel, VKA, heparin)
• Limitations for anticoagulants: need for INR-monitoring (VKA) or
subcutaneous administration (LMWH)
• Novel oral anticoagulants (dabigatran [Pradaxa®], rivaroxaban
[Xarelto®], apixaban [Eliquis®], edoxaban) lack these limitations
• No clinically tested antidot currently available for nOAC (factor
IIa- or Xa-inhibitors)
• RCT reported an isolated higher gastrointestinal bleeding risk
Systematic review focusing on the risk of GIB of all nOAC
compared to standard care (LMWH,VKA, antiplatelet therapy or
therapy depending on national guidelines)
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Methods
• Meta-analysis and systematic review
• Literature search til 07/2012: Pubmed, EMbase and the Cochrane Central register of controlled Trials; Keywords: rivaroxaban, Dabigatran, apixiban, edoxaban, betrixaban, humans, RCT
• Meeting following criteria:
1. Study compared nOAC with current standard care in a randomized setting
2. Results included bleeding events as safety outcome
3. Study conducted in target population (not in healthy volunteers)
4. Study published as full-text article
• Primary outcome: risk of gastrointestinal bleeding
• Secondary outcome: risk of clinically relevant bleeding
New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 4
Subgroups
• Included studies divided bei clinical indication:
1. Atrial fibrillation (AF)
2. Thromboprophylaxis after orthopedic surgery (OS)
3. Thromboprophylaxis in medical ill patients
4. Deep venous thrombosis & pulmonary embolism
(DVT/PE)
5. acute coronary syndrome (ACS)
New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 5
• Total 151578 patients were included in the 43 trials
• Rivaroxaban most frequently used anticoagulants
New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 6
Results: gastrointestinal bleeding outcome
• 19 trials reported separate data on GIB (44%), 2 trials
excluded (no event in both arms)
• 1101 GIB in 75081 patients reported (1.4%), 89% major
bleeds
• Bleedings: – OS (nOAC 0.1%vs control 0.2%) < AF (2.1%vs1.6%) < DVT/PE
(3.0%vs1.9%)< ACS (5.3%vs 1.0%)
• nOAC had higher risk of GIB compared to standard care
(OR 1.45, 95% CI. 1.07-1.97)
• NNH 500
• Substantial heterogeneity
New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 7
New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 8
New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 9
Results: clinically relevant bleeding outcome
• Overall risk of clinically relevant bleeding was significantly
higher with the use of nOAC compared to standard care
(OR 1.16, 95% CI 1.0-1.34)
• Considerabel heterogeneity
• Subgroup analysis: patient treated for ACS showed
increased risk of GIB (OR 2.06) and patient treated with
rivaroxaban (OR 1.31, 95 CI 1.04-1.64)
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New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 11
Discussion
• nOAC associated with a higher risk of GIB compared to current
standard care
• Risk is highest in patients treated for thrombosis (ACS,
DVT/PE).
• ACS-patients had additional antithrombotic treatment which
explains higher bleeding risk
• Bleeding risk lower for patients receiving nOAC for
thromboprophylaxis suggesting dose- and/or duration-effect
Pro:
• Meta-analysis focus on GIB
• Take into account currently all available nOAC
• All present indication were included the GI physicians have to
deal with
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Discussion
Cons/Limitation:
• Studies were non-inferior or superior efficacy design; most studies reported on bleeding outcomes in general
• Heterogenity between studies
• Most trials use extensive exclusion criteria -> risk for bleeding complication underestimated
• No data on concomitant PPI use
Conclusion: GIB risk on nOAC higher than standard care; current data based on highly selected patient group with low bleeding risk which doesn‘t reflect future daily clinical practice
Future studies specifically report on GIB risk, evaluate gastroprotective agents in nOAC
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Dabigatran Pradaxa®
• Factor IIa-Inhibitor (direct thrombin inhibitor, free & bound)
• Indication: stroke prevention, AF with one or more risk
factor (DM, heart failure, TIA, EF <40%, CHD); DVT/PE
• Standard regime 150mg 2x/d, patients at higher risk or age
>80 110mg 2x/d
• Half-life 14-17h, eliminated by kidney -> dose reduction in
CKF, should be avoided Cl <30ml/min
• Can not be monitored; aPTT, diluted TT or ecarin clotting
time can be used to measure anticoagulant effect
• no antidote
New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 14
Rivaroxaban Xarelto®
• Direct factor Xa-inhibitor
• Indication: DVT/PE, thromboprophylaxis, stroke prevention
(AF)
• Standard regime: 20mg 1x/d (AF); 15mg 2x/d (VTE)
• Half-life 4-9h, eliminated renally, should be avoided Cl
<30ml/min
• No routine monitoring, PT or modified anti-Xa-assay
provide measure of drug effect
• no antidote
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Dabigatran &
Rivaroxaban
Emergency endoscopy:
- if PT, APTT & TT normal,
procedure can be performend
safely;
- if abnormal (even slightly) there
may be significant drug effect ->
postpone procedure
No evidence for tranexamic acid,
but clealrly useful agent in
management of massive
hemorrhage
No place for Vit.K or FFP for
reversal of these agents
Prothrombin factor concentrate &
recombinant factor VIIa partial
effective (animal models)