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
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) New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 2
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 3
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 4
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 5
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 6
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
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) New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 9
New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 10
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 New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 11
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 New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 12
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 13
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 New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 14
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) New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 15
Recommendation British Societey of Gastroenterology New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis 16