New Oral Anticoagulants Increase Risk for … Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis Holster IL, Valkhoff VE, Kuipers

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)


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


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)


• Total 151578 patients were included in the 43 trials

• Rivaroxaban most frequently used anticoagulants


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




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)



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


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


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


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


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)


Recommendation British Societey of Gastroenterology

Documents

New Oral Anticoagulants Increase Risk for … Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis Holster IL, Valkhoff VE, Kuipers