2 CLINICAL AND SYSTEMATIC REVIEWS

see related editorial on page x

Prevention of Gastrointestinal Bleeding in Patients

Receiving Direct Oral Anticoagulants
Neena S. Abraham, MD, MSCE, FACG, FASGE, AGAF1,2,3

The direct oral anticoagulants (DOACs) have quickly become popular choices for convenient stroke and
thromboembolism protection. Popularity of this new anticoagulant class is driven by their predictable fixed
dosing without the necessity for serum monitoring of anticoagulant effect. However, this convenience must be
balanced against the risk of gastrointestinal (GI) bleeding. Age > 65 years, hepatorenal dysfunction, low body
weight, concomitant prescription of antiplatelet agents, or non-steroidal anti-inflammatory drugs, and drugs that
interact with P-glycoprotein or the cytochrome P450 system, can influence therapeutic effectiveness of DOACs
and increase the risk of GI bleeding. In this state-of-the-science review, these aforementioned risks are explored,
as is DOAC pharmacology and the potential for drug, dietary, and herbal supplement interaction. Current best
practice recommendations for peri-endoscopic DOAC management and temporary interruption are reviewed. The
utility of existing risk-prediction scores and other practical risk-management strategies, based on specific patient
characteristics, are highlighted. Finally, pragmatic advice to enhance GI and cardiology dialogue, patient education,
and shared decision-making regarding DOAC prescription is provided.
Am J Gastroenterol Suppl 2016; 3:2–12; doi:10.1038/ajgsup.2016.2

INTRODUCTION interact with P-glycoprotein or the cytochrome P450 system, can

Direct oral anticoagulants (DOACs) have a single enzymatic target
for anticoagulation, thrombin (dabigatran), or factor Xa (rivaroxa-
ban, apixaban, edoxaban), permitting a predictable fixed dose to
be taken without plasma monitoring of coagulation factors (1–3).
This pharmacokinetic advantage has contributed to an unprec-
edented market shift as pharmaceutical companies introduce
new agents leading to a 78% increase in new patient visits (from
2009 to 2014) for the treatment of atrial fibrillation (4), especially
among those who seek a convenient alternative to warfarin for
lifelong stroke prevention. By 2013, DOACs represented 98% of
the total dollars spent on anticoagulants in the United States and
accounted for 62% of new anticoagulant prescriptions (5). DOACs
will further increase their market share with new indications for
treatment and prophylaxis of venous thromboembolism. By 2016,
it is anticipated that DOACs will dominate the anticoagulant mar-
ket generating sales of $10 billion annually (6).
The incidence of new atrial fibrillation patients has increased
12.6% over the last 20 years, and it is projected that 15.9 million
Americans will have atrial fibrillation by 2050 (7). However, these
drugs may not be the right choice for every patient. Identification
of patients at highest risk of DOAC-related bleeding is critical to a
risk prevention strategy. Age > 65 years, hepatorenal dysfunction,
low body weight, concomitant prescription of antiplatelet agents or
non-steroidal anti-inflammatory drugs (NSAIDs), and drugs that
influence therapeutic effectiveness of DOACs and increase the risk
of gastrointestinal (GI) bleeding (GIB).
How big is this risk? The prevalence of atrial fibrillation among
patients > 65 years is conservatively estimated at 3.4 million patients
in the United States (1.1% of the total US population in 2007) (8).
When compared with the general population, atrial fibrillation
patients have an increased risk of GI bleeding (0.3–0.5% per year
vs. 0.1% per year) related to the use of warfarin (5). Dabigatran
and rivaroxaban may be associated with up to a 30% increase in GI
bleeding when compared with warfarin (9–11); thus, 0.4–0.7% of
patients per year will experience a DOAC-related GI bleed, which
translates to 13,600–23,800 DOAC-related GI bleeds per year.
OVERVIEW OF PHARMACOLOGY AND EXCRETION
Factor Xa inhibitors
These molecules inhibit both free and thrombin-bound factor Xa
and clot-associated factor Xa at the point at which the intrinsic
and extrinsic pathways of the coagulation cascade meet. Factor Xa
normally binds to the factor Va to form prothrombinase, which
then cleaves prothrombin to thrombin, allowing clot formation.
All available factor Xa inhibitors, rivaroxaban, apixaban, and
edoxaban, achieve peak plasma levels between 1 h and 4 h follow-
ing ingestion with a trough plasma level occurring 12–24 h post

1
Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA; 2Division of Health Care Policy and Research,
Department of Health Services Research, Rochester, Minnesota, USA; 3Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery,
USA. Correspondence: Neena S. Abraham, MD, MSCE, FACG, FASGE, AGAF, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic,
13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA. E-mail: abraham.neena@mayo.edu

The American Journal of GASTROENTEROLOGY Supplements VOLUME 3 | JULY 2016 www.nature.com/ajgsup


ingestion. Bioavailability of rivaroxaban is dose-dependent and
improved with food intake, thus a fasting condition may result in
risk of inadequate anticoagulation effect. However, a fasting state
does not influence the fixed 50% bioavailability of apixaban.
Rivaroxaban elimination depends on both renal excretion (35–
50%) and the hepatobiliary tract (50%). It is susceptible to hepatic
cytochrome P450 (CYP) interactions with enzymes 3A4 and 2J2.
It is also subject to interaction of the P-glycoprotein (P-gp) efflux
transporter located in the gut, liver, and kidney. The function of
this transporter is to excrete xenobiotics, such as drugs and toxins
out of the body by transporting these substances through the bile
duct, kidney, and the GI tract epithelia into the lumens of these
organs. P-gp has an important role in drug transport, influences
bioavailability and clinical effect. Apixaban elimination is 35–50%
renal and the remainder is fecal following hepatic metabolism and
biliary excretion. Elimination is subject to drug interactions with
the CYP enzymes 3A4-5 and interaction with P-gp. Edoxaban
elimination includes 40% excretion by urine and the rest by feces.
It too, is subject to interaction with P-gp but has a modest interac-
tion with CYP enzymes (12). A dose modification is required in
patients with impaired renal function and low body weight.
Direct thrombin inhibitors
The direct thrombin inhibitor, dabigatran, binds to and inhibits
the free and clot-bound thrombin and thrombin-induced platelet
aggregation. Dabigatran is administered as a prodrug (dabigatran
etexilate) to facilitate drug absorption. Once absorbed, it under-
goes conversion to its active form by hepatic and serum esterases.
Non-absorbed prodrug can be cleaved by enterocytes (or possibly,
gut bacteria) to produce intra-luminal active drug. The balance
between absorbed and non-absorbed drug is modulated by the
P-gp efflux transporter of the enterocyte. Clearance of the drug
is 80% renal and 20% fecal. In Europe, dose adjustment is rec-
ommended for the elderly ( > 80 years), for those with moderate
renal impairment (creatinine clearance [CrCl] of 30–50 ml/min)
or previous GI bleeding. In these vulnerable populations a lower
dose of 110 mg twice daily may be considered. In the United
States, a reduced dose of 75 mg twice daily is recommended for
non-valvular atrial fibrillation patients with CrCl of < 30 ml/min
instead of the standard dose of 150 mg twice daily. US package
labeling does not require age-related dose adjustment, despite
growing evidence of increased GI bleeding risk associated with
advanced age. Dabigatran is not recommended for use in patients
with severe renal impairment (CrCl of < 15 ml/min).
POTENTIAL FOR DRUG, DIETARY, AND HERBAL
SUPPLEMENT INTERACTIONS
Harmful interactions are possible with concomitant use of cer-
tain drugs and dietary supplements, and occur at multiple lev-
els—absorption, prodrug transformation (dabigatran etexilate),
metabolism, or elimination. Mechanisms of action include inter-
action with P-gp and the CYP3A4 isoform of the cytochrome
P450. When compared with the body of literature regarding
harmful interactions with warfarin, there is a paucity of literature
© 2016 by the American College of Gastroenterology
Prevention of GI Bleeding in Patients Receiving DOACs 3
to inform our knowledge regarding the magnitude of risk of these
potential interactions with DOACs. Most interactions have been
demonstrated in vitro and in vivo, and regulatory agencies have
cautioned against concomitant prescription of certain DOACs
with specific drugs and dietary agents.
Once the DOAC has been absorbed in the gut, P-gp is involved
in re-secretion, gut absorption, and renal clearance (13). Increased
DOAC plasma levels are seen with competitive inhibition of the
P-gp, whereas inducers of P-gp decrease plasma concentration of
DOAC (see Table 1). CYP3A4 is involved in hepatic clearance of
rivaroxaban and to a lesser degree, apixaban. Concomitant prescrip-
tion of drugs metabolized by CYP3A4 can influence rivaroxaban
and apixaban concentration (14). CYP3A4 has no impact on hepatic
clearance of dabigatran and modest impact on edoxaban clearance.
Potent inhibitors of P-gp and/or CYP3A4 include antifungals
(ketoconazole, itraconazole) and protease inhibitors (ritonavir,
indinavir, atazanavir, nelfinavir). These drugs should be avoided
with prescription of apixaban, rivaroxaban, or dabigatran (15) to
prevent a clinically relevant increase in DOAC plasma concentra-
tion due to the inhibition of both CYP3A4 and/or P-gp (16).
Potent inducers of P-gp and CYP3A4 include rifampicin,
St John’s Wort (Hypericum perforatum), carbamazepine, and
phenytoin. These drugs can reduce the bioavailability and plasma
level of rivaroxaban, dabigatran, and apixaban (by up to 50% for
rivaroxaban and apixaban, and possibly more for dabigatran),
thus, the dose must be adjusted to ensure clinical efficacy (16,17).
The CYP3A4 inhibitor fluconazole can be used with caution with
rivaroxaban if the dose of rivaroxaban is adjusted.
Drugs to be used with caution with rivaroxaban include the
P-gp inhibitors diltiazem, verapamil, amiodarone, quinidine, and
clarithromycin. P-gp inhibitors should be used with caution with
dabigatran, especially in patients with moderate renal impairment
(CrCl of 30–50 ml/min). In the US, dose adjustment to 75 mg twice
daily is recommended in patients with moderate renal impairment
when concomitantly prescribed with dronedarone and ketocona-
zole. The use of P-gp inhibitors verapamil, amiodarone, quinidine,
clarithromycin, and ticagrelor does not require dabigatran dose
adjustment based on updated US package labeling. In Europe,
dose adjustment of dabigatran is required when co-prescribed
with verapamil. Dose modification of edoxaban is required when
concomitantly prescribed with verapamil and quinidine.
Compared with warfarin, there has been little investigation
regarding adverse effects associated with DOAC use and dietary or
herbal supplements. Decreased rivaroxaban concentration has
been shown with St John’s Wort (H. perforatum), a known potent
inducer of CYP3A4 and P-gp, and co-administration is not recom-
mended. Potential exists for other known herbal and dietary
inhibitors of CYP3A4 (echinacea, grapefruit juice, milk thistle,
peppermint, Bishop’s weed, Cat’s claw, eucalyptus, goldenseal,
licorice, resveratrol, valerian, and wild cherry) to increase DOAC
plasma concentration and influence bleeding risk, similar to that
observed with warfarin (18). At this time, there are insufficient
data to definitively advise physicians regarding the risk of con-
comitant prescription of DOACs with herbal or dietary supple-
ments. Prescribing physicians should be aware of the potential for
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4 Abraham
Table 1. Inhibitors and inducers of CYP3A4 and P-gp
Inhibitorsa Inducersb
Amiodarone Ketoconazole Carbamazepine St John’s Wort
Cimetidine Itraconazole Phenobarbital Rifampicin
Clarithromycin Nifedipine
Erythromycin Nelfinavir
Fluconazole Ritonavir
Itraconazole Saquinavir
Verapamil Voriconazole
Prescribing physicians should be aware of the potential for pharmacodynamic
interactions that may alter DOAC plasma level and bioavailability. Future
research in this area is required to better inform clinical decision-making.
a
Concomitant prescription increases DOAC plasma level and/or bioavailability.
b
Concomitant prescription decreases DOAC plasma level and/or bioavailability.
pharmacodynamic interactions that may alter DOAC plasma level
and bioavailability, as highlighted in Table 1. Future research in
this area is required to better inform clinical decision-making.
CLINICAL CHARACTERISTICS THAT INCREASE DOAC
BLEEDING RISK
Age
In 2011, dabigatran was flagged by the FDA MedWatch adverse
reporting program as one of the most common prescription drugs
associated with serious, disabling, or fatal injury. Of the 3,781 seri-
ous adverse events reported, 2,367 cases of hemorrhage and 542
deaths were reported. The unexpectedly large number of bleed-
ing events was observed in the elderly, many of whom had con-
comitant renal disease (19). Greater than 50% of atrial fibrillation
patients > 80 years of age have concomitant moderate renal fail-
ure (20), and creatinine-based dose reduction has not completely
eliminated the bleeding risk associated with dabigatran (21). Some
have reported elderly age reduces renal clearance of dabigatran by
0.41% per year from the age of 72 years onward (22).
Meta-analyses of trial data had previously identified increased
risk of GI bleeding with dabigatran, rivaroxaban, and apixaban
(23,24). However, questions remained regarding the generalizabil-
ity of these data due to differences between the patients enrolled
in the clinical trial setting and those who might be receiving the
drugs in the community setting. Observational studies using real-
world national data have confirmed elderly age as an important
independent risk factor for DOAC-related bleeding complica-
tions. Initial data was focused on the Medicare population using
dabigatran (25). GI bleeding data have now been published from a
national sample of non-Medicare patients with and without atrial
fibrillation, who were less than or greater than age 65 years, pre-
scribed dabigatran or rivaroxaban. Bleeding outcomes in subsets of
patients (stratified by age, DOAC, and presence or absence of atrial
fibrillation) were compared with a propensity-matched warfarin
cohort and confirmed increased risk of DOAC-related GI bleeding
after age 65 years that exceeded the risk associated with warfarin
The American Journal of GASTROENTEROLOGY Supplements
by age 76 years and greater (26). Age > 65 years as an important
risk factor for DOAC-related bleeding has also been demonstrated
by others (27–29).
It remains unclear if increased DOAC risk in the elderly is a
class-effect or specific to individual agents. There is only one large
meta-analysis, which defined a priori subgroup analyses by age
(65–74) vs. ≥75 years, and rigorously rated included studies (N = 10
randomized controlled trials [RCTs]; 17 non-randomized studies)
as judged by the Cochrane Risk of Bias Tool for RCTs and ACRO-
BAT-NRSI (A Cochrane risk of bias assessment tool for non-ran-
domized studies of intervention) (30,31). In the Lin meta-analysis,
dabigatran 110 and 150 mg, and rivaroxaban showed a higher risk
of major bleeding than warfarin in patients ≥75 years (i.e., the
older elderly) when compared with those aged 65–74 years (i.e.,
the younger elderly). In addition, dabigatran 150 mg was associ-
ated with a 1.5-fold higher risk (relative risk 1.51; 95% confidence
interval [CI]: 1.61–1.96) of GI bleeding in the older elderly when
compared with the younger elderly (30).
A similar increase in GI bleeding among patients ≥75 years was
seen in the meta-analysis and systematic review of Romanelli et al.
(32). In this study, the likelihood of GI bleeding was ~50% higher
in patients ≥75 vs. patients < 75 years prescribed dabigatran 150 mg
twice daily, when compared with warfarin (β = 1.53; 95% CI: 1.10–
2.14; P = 0.020). A sub-study of the RE-LY trial also found a trend
for the effect of age on GI bleeding at this higher dose of dabigat-
ran, yet the interaction was not statistically significant (P = 0.06)
(23). These two aforementioned meta-analyses help corroborate
the importance of elderly age as a risk factor for GI bleeding with
dabigatran 150 mg twice daily; data that were first observed in the
large observational studies of Abraham et al. (33), Graham et al.
(27), and Tsadok et al. (34). As more studies emerge examining the
impact of DOACs in the elderly, there will be future data points,
which can be pooled to better inform knowledge regarding intra-
class risk differences in GI bleeding and major bleeding.
Renal disease
Impaired glomerular filtration rate is associated with an increased
risk of ischemic stroke and systemic embolism in atrial fibrilla-
tion, and is known to increase anticoagulant-related bleeding
(35). All DOACs have some degree of renal excretion. One can
expect > 80–85% renal clearance for dabigatran, 35–50% for
rivaroxaban, 40–50% for edoxaban, and 27–40% for apixaban
(36–39).
The degree of renal impairment is determined using the
Cockroft–Gault equation to calculate the patient’s glomerular filtra-
tion rate or the estimated CrCl. The latter is reported routinely by
most clinical laboratories. It can also be rapidly estimated using
reliable internet-based calculators. The observable impact of renal
dysfunction on the risk of GI bleeding will be greatest among agents
mainly cleared by a renal route (i.e., dabigatran, rivaroxaban) than
with edoxaban or apixaban. The variation in renal excretion of the
drug is important to consider when choosing a DOAC for patients
with renal impairment. As CrCl decreases (i.e., the renal function
deteriorates), the half-life of DOAC increases, its plasma level rises
as does the risk of bleeding complications.
VOLUME 3 | JULY 2016 www.nature.com/ajgsup

Table 2. Dosing modification of DOAC based on renal impairmenta
Subgroup Dabigatran
Moderate renal impairment FDA: 150 mg twice daily
CrCl: 30–50 ml/min EMA: 110 mg twice daily
Severe renal impairment FDA: 75 mg twice daily
CrCl: 15–30 ml/min EMA: not approved
CrCl, creatinine clearance; FDA, US Food and Drug Administration; EMA, European Medicines Agency.
a
Dose modifications are recommended for atrial fibrillation patients. No dose modification is necessary if the patient’s CrCl is > 50 ml/min (i.e., normal).
Specific guidelines regarding dosing alterations have been pro-
vided by regulatory agencies (Table 2) for the non-valvular atrial
fibrillation patients. However, the required dose adjustments are
not widely known or understood resulting in bleeding among
patients with impaired renal function (40). The United States Food
and Drug Administration (FDA) and the European Medicines
Agency (EMA) also differ on their recommendations regarding
use of dabigatran among patients with severe renal dysfunction.
The FDA recommends dose reduction to 75 mg twice daily among
this population, however, the EMA has not approved dabigatran
for use with a CrCl of 15–30 ml/min. Dabigatran toxicity can
be removed by renal dialysis as it is poorly protein bound
(35%), however, the other three target-specific DOACs are highly
protein bound (87–95%) and are thus unlikely to be removed by
dialysis (16).
Hepatic disease
Restrictions for the use of DOACs in patients with liver disease
are based on the Child-Pugh classification system and exclusion
criteria applied in pivotal trials. Because all DOACs are dependent
on the liver for metabolism to some degree, patients with hepatic
dysfunction are not ideal candidates for these agents, especially
if there is pre-existent evidence of coagulopathy (i.e., prolonged
prothrombin times). Rivaroxaban, apixaban, and edoxaban are
substrates of CYP3A4 and the P-gp transporter system. Thus,
they are susceptible to drug–drug interactions and dose reduction
is required with concomitant prescription of strong inhibitors of
CYP3A4 or P-gp. Dabigatran is not metabolized by the hepatic
CYP enzymes but is a substrate for P-gp and the dominant path-
way is renal excretion (80%). Consequently, the plasma concen-
tration of dabigatran is more likely to increase in the presence of
renal dysfunction as opposed to hepatic dysfunction.
No dose adjustment of dabigatran or apixaban is required for
patients with mild hepatic disease (Child-Pugh A), and they can
be safely used in patients with mild increases in aminotransferase
levels. These agents can also be used with caution in patients with
moderate liver disease (Child-Pugh B). Rivaroxaban is not rec-
ommended for use in patients with Child-Pugh B disease or with
evidence of cirrhosis where the plasma concentration is increased
2.3-fold, which parallels an increase in factor Xa inhibition (41).
Conversely, in patients with Child-Pugh B liver disease, the area
under the plasma-concentration–time curve (AUC) of edoxaban
(15 mg single dose) is decreased by 4.8% and that of dabigatran
© 2016 by the American College of Gastroenterology
Prevention of GI Bleeding in Patients Receiving DOACs 5
Rivaroxaban Apixaban Edoxaban
FDA: 15 mg daily FDA: 2.5 mg twice daily FDA: 30 mg daily
EMA: 15 mg daily EMA: 2.5 mg twice daily EMA: 30 mg daily
FDA 15 mg daily FDA: 2.5 mg twice daily FDA: 30 mg daily
EMA: 15 mg daily EMA: 2.5 mg twice daily EMA: 30 mg daily
(150 mg single dose) is decreased by 5.6% (41). DOACs should
not be used with Child-Pugh C disease or with cirrhosis given the
likelihood of luminal evidence of portal hypertension (i.e., portal
hypertensive gastropathy, varices, etc.) and impaired ability to
metabolize the drug, further increasing the risk of GI bleeding.
Low body weight
It was during the early post-marketing days of DOACs that low
body weight was identified as a risk factor for bleeding events.
After the introduction of dabigatran in New Zealand, more than
half of the reported bleeding events occurred in patients with
a body weight < 60 kg (40). However, a similar effect was not
observed with rivaroxaban, the second DOAC to enter the mar-
ket; suggesting the reported adverse events in low body weight
patients was not related to reporting bias due to the novelty of
DOAC. However, interpretation of these data is difficult due to
unmatched comparison groups based on body-weight. Patients
with low body weight (< 50 kg) were again shown to have a higher
risk of bleeding complications with apixaban due to higher circu-
lating plasma concentrations (up to 30% higher) when compared
with patients who weigh 65–85 kg (16). Higher concentrations of
rivaroxaban have also been noted among patients with low body
weight (42). The magnitude of risk associated with low body
weight on the safety and tolerability of DOACs in patients of
varying body weight has yet to be fully explored in a real-world
setting.
Concomitant prescription with antiplatelet agents including
aspirin (ASA), NSAIDs, thienopyridine agents, and
protease-activated receptor-1 (PAR-1) inhibitors
Patients prescribed DOAC with concomitant ischemic heart dis-
ease are often on ASA at a cardioprotective dose (81 mg/day) or full
musculoskeletal dose (325 mg/day), especially after vascular sur-
gery. Thirty-five percent of atrial fibrillation patients prescribed
an anticoagulant also receive ASA, with no appropriate indication
in 40% (43). With stable vascular disease, anticoagulant mono-
therapy is recommended given the lack of benefit associated with
ASA + anticoagulant therapy and a 50% increased risk of major
bleeding (when compared with anticoagulant alone) (43). The
concurrent use of ASA with DOAC (or warfarin) has been shown
to increase risk of major bleeding (44–46). Concomitant NSAID
prescription has also been shown to increase DOAC (or warfarin)
bleeding (47). NSAIDs increase overall antiplatelet pharmaco-
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6 Abraham
logic burden and may cause an acute deterioration of renal func-
tion hampering excretion of the DOAC and increasing plasma
concentration.
Caution also needs to be exercised when DOACs are prescribed
concomitantly with thienopyridine agents or PAR-1 inhibitors.
PAR-1 inhibitors are antiplatelet agents that inhibit the protease-
activated receptor-1 inhibitor of the platelet. The first-in-class PAR-1
inhibitor vorapaxar was approved in January 2014 as an adjunct to
traditional dual antiplatelet therapy (DAPT). This triple antiplate-
let strategy is associated with a 13% reduction in myocardial inf-
arction (MI), stroke, cardiovascular death, and revascularization
in patients with a previous MI or peripheral artery disease (when
compared with placebo) (48). However, a 66% increase in bleed-
ing was observed and resulted in a black box warning in patients
with a past history of stroke, transient ischemic attack (TIA), or
intracranial hemorrhage. The pivotal vorapaxar trial demonstrated
a possible interaction between vorapaxar and the concomitant use
of thienopyridine with regard to thrombolysis in myocardial infarc-
tion major bleeding (defined as any intracranial bleeding or clini-
cally overt signs of a hemorrhage that is associated with a drop in
hemoglobin of ≥5 g/dl) (P-interaction = 0.017) and clinically signifi-
cant bleeding requiring medical attention (P-interaction = 0.012)
(49). Real-world GI bleeding risk associated with concomitant
vorapaxar and DOAC prescription has yet to be determined.
Current cardiology guidelines recommend at least 1 month of
thienopyridine therapy following bare-metal stent implantation
and at least 12 months of dual antiplatelet therapy (i.e., ASA plus
thienopyridine agent; DAPT) after implantation of a drug-eluting
stent (50). In the subset of ischemic heart disease patients with
concomitant atrial fibrillation/flutter or pulmonary embolism,
an anticoagulant can be prescribed in addition to DAPT (51).
The reduction in stroke or MI events associated with concomi-
tant prescription of DOAC and ASA or DAPT may be offset by a
greater than twofold increased risk of bleeding (16). Although the
ischemic risk tends to diminish with time, longer treatment dura-
tion with antithrombotic regimens exacerbate bleeding risk (52).
National registry (53) and population-based cohorts (54–56) sug-
gest GI bleeding risk is proportional to the number of antiplatelet
or anticoagulant agents used; and is greater still when dabigatran,
rivaroxaban, apixaban, and edoxaban are prescribed in elderly
patients (57) or in combination with DAPT (51).
The APPRAISE-2 trial highlighted the bleeding risk associ-
ated with concomitant DOAC and DAPT prescription (58). In
this important study, the addition of apixaban, at a dose of 5 mg
twice daily, to antiplatelet therapy in high-risk patients after an
acute coronary syndrome increased the number of major bleed-
ing events (hazard ratio with apixaban, 2.59; 95% CI: 1.50–4.46;
P = 0.001) without a significant reduction in recurrent ischemic
events. Similar trials are ongoing with rivaroxaban (PIONEER
AF-PCI trial; ClinicalTrials.gov Identifier: NCT01830543),
dabigatran (RE-DUAL PCI; ClinicalTrials.gov Identifier:
NCT02164864), and edoxaban (EDOX-APT; ClinicalTrials.
gov identifier: NCT02567461). These trials will help clarify the
magnitude of bleeding risk associated with triple antithrombotic
therapy involving DOACs.
The American Journal of GASTROENTEROLOGY Supplements
THERAPY BASED ON PATIENT CHARACTERISTICS:
RISK PREDICTION SCORES
Risk prediction tools are commonly used in the atrial fibrilla-
tion population to predict thromboembolism (CHADS2 or
CHA2DS2-VASc score) and adverse bleeding (HAS-BLED, HEM-
ORR2HAGES, ATRIA, or Qbleed) (Table 3) (59,60). HAS-BLED
estimates risk of intracerebral hemorrhage in patients on warfarin
(not DOAC) and considers risk factors of hypertension, impaired
renal and/or liver function, previous history of stroke, bleeding,
labile INR, advanced age (≥65 years), and alcohol intake. Each
factor is assigned the same value and a score ≥3 is associated with
an intracerebral hemorrhage rate of 3.7–12.5/100 patient-years.
The HAS-BLED score is inappropriately extrapolated to predict
risk of GIB and considers risk of warfarin to be equivalent to
DOAC (2,61).
None of the current bleeding scoring systems (Table 3) has been
endorsed by the American Heart Association, American College
of Cardiology or the American College of Chest Physicians for the
assessment of bleeding risk. Nor has the 2016 American Society of
Gastrointestinal Endoscopy endorsed the current bleed-prediction
scoring systems (62). However, the European Society of Cardiology
endorses the use of the HAS-BLED system over HEMORR2HAGES
due to its greater simplicity (63). A HAS-BLED score of 3 or greater is
considered high-risk for adverse bleeding complications and anticoag-
ulants should be used with caution. Although a HAS-BLED score > 3
is not considered an absolute contraindication to anticoagulant use,
periodic monitoring and efforts to correct reversible risk factors for
bleeding is recommended by the European Society of Cardiology.
The ATRIA and HEMORR2HAGES models have similar vari-
ables to HAS-BLED but fail to consider the impact of concomitant
antiplatelet drug use, and require laboratory and genetic mark-
ers for complete risk assessment. Neither was designed to predict
non-intracerebral bleeding events due to low incidence of bleed-
ing events in the derivation population (64,65). The Qbleed score
(66) examines risk of intracranial hemorrhage or upper GIB both
before and after initiation of warfarin therapy, but requires more
than 14 variables for its calculation and does not predict lower GIB
(the most common site of GIB in cardiac patients), rendering it
clinically less useful. In general, these bleeding scores have modest
predictive value for GI bleeding (67) despite their ubiquitous use.
RISK MINIMIZATION STRATEGIES
Identification of modifiable and non-modifiable risk factors
before DOAC prescription can be helpful in formulating a risk
minimization strategy to mitigate overall risk of DOAC-related
GI bleeding. The following considerations represent GI bleeding
preventive strategies extrapolated from the existing antithrom-
botic literature. These clinical suggestions are likely to benefit the
patient requiring DOAC prescription. The benefit of such a multi-
pronged risk-minimization strategy has yet to be studied. Thus
at this time, these clinical pearls should be considered common-
sense recommendations.
1. DOAC prescription for indications other than those endorsed
by national guidelines should be avoided.
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 Prevention of GI Bleeding in Patients Receiving DOACs 7

Table 3. Risk prediction scores

Risk elements CHADS2 CHA2DS2-VASc HEMORR2HAGES HAS-BLED ATRIA

CHF 1 point 1 point

HTN 1 point 1 point 1 point 1 point 1 point
Age 1 point (≥75) 2 points (≥75) 1 point (≥75) 1 point (≥65) 2 (≥75)
1 point (65–74)
Diabetes mellitus 1 point 1 point
Prior CVA or TIA 2 points 2 points 1 point 1 point
CAD, PAD, or aortic plaque 1 point
Female 1 point
Chronic liver disease, cirrhosis 1 point 1 point
Chronic renal insufficiency 1 point 1 point 3 points
Alcoholism 1 point 1 point
Malignancy 1 point
Thrombocytopenia/antiplatelet use 1 point
Prior bleeding event 2 points 1 point
Anemia 1 point 3 points
History of falls 1 point
Genetic factors 1 point
Prior bleeding event or anemia 1 point
Time in therapeutic range < 60% 1 point
ASA, clopidogrel, prasugrel, ticagrelor, NSAIDs 1 point
Low risk 0–1 0–1 0–1 0 0–3
Intermediate risk 2 2 2–3 1–2 4
High risk 3+ 3+ 4+ 3+ 5–10

ASA, aspirin; CAD, coronary artery disease; CHF, congestive heart failure; CVA, cerebrovascular accident; HTN, hypertension; NSAIDs, non-steroidal anti-inflamma-
tory drugs; PAD, peripheral artery disease; TIA, transient ischemic attack.

2. Consider a vitamin K antagonist in patients > 75 years (espe-
cially if they have multiple concomitant risk factors for GI bleed-
ing); those with hepatorenal dysfunction (as outlined in prior
sections); or low body weight (< 50–60 kg).
3. Regularly review the patient’s medication list and assess over-
the-counter use of dietary and herbal supplements. Exercise cau-
tion when prescribing DOACs to patients requiring concomitant
prescription of antiplatelet agents or inhibitors of CYP3A4 or
P-gp. Counsel patients regarding the GI bleeding risk associated
with concomitant prescription of antiplatelet agents or inhibitors
of CYP3A4 and/or P-gp.
4. Non-NSAID pain relievers should be recommended to pre-
vent deterioration of renal function and impairment of DOAC
elimination. Attention to dosing modifications based on impair-
ments of absorption, metabolism, or excretion have previously
been discussed and should be followed.
5. Testing for and eradicating Helicobacter pylori (H. pylori) in
patients with a history of ulcer disease is recommended before
starting chronic ASA therapy in cardiac patients (68) and is likely
appropriate in patients requiring lifelong anticoagulation with
DOAC. Prior history of H. pylori infection is associated with a
fourfold risk (hazard ratio 4.75; 95% CI: 1.93–11.68) of GI bleeding
among atrial fibrillation patients prescribed dabigatran (69).
6. Chronic ASA or DAPT in patients with a prior history of
upper GI bleeding should prompt proton pump prescription
(proton pump inhibitor [PPI]) to decrease future risk of anti-
platelet-related upper GI bleeding (37,70). PPI effectively prevents
recurrent upper GI bleeding with low-dose aspirin use despite
failure of H. pylori eradication and concomitant use of non-ASA
NSAIDs (68). A recent study in dabigatran users revealed ~50%
risk-reduction (incidence rate ratio 0.53; 95% CI: 0.35–0.77) in
upper GI bleeding among patients with a prior history of peptic
ulcer prescribed PPI gastroprotection (71). There is no evidence
to support a reduction in thromboembolic protection among
patients prescribed a PPI and a thienopyridine antiplatelet agent
(70,72,73). Nor is there any evidence that PPIs interact with
DOACs and diminish antithrombotic effect.
7. Luminal mapping for vulnerable mucosa (angiodysplasia
or arteriovenous malformation) may be helpful to proactively
treat and prophylax against future anticoagulant-related bleeding
(74,75). Prophylactic hemostatic therapy of vascular lesions, to
prevent future GI bleeding, has yet to be shown as beneficial, but

© 2016 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY Supplements
8 Abraham
does make sense in patients who require chronic anticoagulation
and present with obscure occult or overt GI bleeding.
8. DOAC-related diverticular bleeding is common and accounted
for a large proportion of lower GI bleeds in the RE-LY and ARIS-
TOTLE trials (76,77). By the fifth decade > 15% of patients have
diverticulosis (78) and diverticular bleeding, or diverticulitis are
the most common GI discharge diagnoses following inpatient hos-
pitalization (79). A substantial amount of active apixaban, rivar-
oxaban, and edoxaban is recovered in the feces (36) and may exert
a topical anticoagulant effect on vulnerable GI tissues (mucosal
defects, diverticulosis, vascular lesions, etc.). Differences in DOAC
bioavailability dictate the amount of active anticoagulant effect
along the mucosal surface of the gut and contribute to the differ-
ent GI bleeding risks of specific DOAC. For example, dabigatran is
known to have incomplete absorption across the GI mucosa and
the non-absorbed prodrug is converted to active dabigatran by gut
esterases causing a higher risk of lower GI bleeding when com-
pared with warfarin (76).
Patients with known diverticulosis should be counseled regard-
ing the symptoms and signs of diverticular bleeding. ASA and
NSAIDs are both known to increase the risk of diverticular bleed-
ing (hazard ratio 1.70 and 1.74, respectively) (80). Patients should
be instructed to avoid NSAIDs to decrease the risk of diverticular
bleeding, especially if they are concomitantly prescribed ASA or
DAPT. Finally, use of laxatives or fiber should be recommended
to decrease constipation and aggravation of diverticular complica-
tions. The impact of treating constipation to prevent development
of diverticular complications is controversial. Traditionally, fluid
and fiber has been recommended to prevent diverticular compli-
cations (78), however, this notion has been challenged by recently
published data (79). Avoidance of constipation with regular use of
a polyethylene glycol laxative may also be appropriate to prophylax
against bleeding complications in this population.
9. At this time, the use of a risk score to predict DOAC-related
GI bleeding cannot be recommended. The CHA2DS2-VASc score
can be helpful in predicting thromboembolic risk among patients
with atrial fibrillation.
10. In patients with known renal dysfunction or who use
nephrotoxic drugs, CrCl and estimated GFR should be periodi-
cally monitored to ensure no deterioration, which may result in
impaired DOAC excretion.
11. The risk-benefit of continued DOAC use should be re-
addressed when a patient has a clinically significant GI bleed.
Factors such as cardioembolic risk, the number and type of con-
comitant risk factors, location of the GI bleed, optimization of risk-
minimization strategies, and likelihood of bleed recurrence should
be carefully considered before individualizing patient recommen-
dations.
PERI-ENDOSCOPIC BLEEDING PREVENTION AND
TEMPORARY DOAC INTERRUPTION
DOACs should be temporarily discontinued in patients undergo-
ing an invasive procedure when there is a 2–4% increased risk
of post-procedural bleeding. High-risk endoscopic procedures
The American Journal of GASTROENTEROLOGY Supplements
include polypectomy, variceal treatment, biliary sphincterotomy,
endosonography with fine needle aspiration, and pneumatic dila-
tation (62). There is rarely a need to interrupt DOAC for diag-
nostic endoscopic procedures with a low-likelihood of procedural
or post-procedural bleeding (0–2%) (62). Gastrointestinal endos-
copy with or without biopsy, enteroscopy, biliary stent placement
without sphincterotomy and endosonography without fine nee-
dle aspiration generally do not require temporary interruption of
anticoagulation (38,62).
When DOACs are held before an elective procedure, the degree
of residual anticoagulant effect can be anticipated by estimating
the patient’s CrCl and knowledge of the last dose of the drug. A
residual anticoagulant effect is acceptable for minor interventions
(procedures with low risk of bleeding, i.e., < 2%), but minimal or
no anticoagulant effect is desirable for those endoscopic proce-
dures with moderate to high risk of bleeding. The anticoagulant
should be held for the shortest period possible given the risk of the
planned procedure and the patient’s estimated circulating residual
anticoagulant effect (Table 4) (62).
An important caveat to DOAC temporary interruption is the
risk of arterial or venous thromboembolism due to the short half-
life of the drug. When held, DOAC plasma concentration declines
rapidly as half-lives elapse. Fifty percent of the anticoagulant effect
remains after one half-life elapses. The DOAC plasma concen-
tration decreases to as low as 12% after three half-lives and only
3% after five half-lives have elapsed (81). The risk of decreased
anticoagulant effect is greatest among those at moderate to high
thromboembolic risk (5 to > 10% risk). These patients include
those with atrial fibrillation and recent ( < 6 months prior) stroke
or transient ischemic event or with a CHADS2 or CHA2DS2-VASc
score > 3; those with a mechanical heart valve (caged-ball or tilting
disc valve in mitral or aortic position; any mitral valve prosthesis;
or given a stroke or transient ischemic attack in the last 6 months); a
history of venous thromboembolism in the last 3 months; or those
with antiphospholipid antibodies, deficiency of protein C, protein S
or antithrombin or multiple thrombophilias (see Table 5) (82). In
all patients, re-initiation of anticoagulant immediately following
endoscopic hemostasis is desired. In most patients, DOAC can be
restarted immediately following the procedure (62).
In patients in whom hemostasis is not assured and at moderate
to high thromboembolic risk (Table 5) the use of bridge therapy
with a low molecular weight heparin has been traditionally rec-
ommended. However, a recent RCT conducted in atrial fibrillation
patients undergoing elective procedures has challenged this notion
(83). In this landmark study, the discontinuation of warfarin with-
out the use of low molecular weight heparin in the peri-procedural
period was non-inferior to the use of bridging anticoagulation,
and was associated with a lower risk of major bleeding (1.3 vs.
3.2%; relative risk, 0.41; 95% CI: 0.20–0.78; P = 0.005 for superi-
ority). The results of this study are intriguing and their applica-
bility to the DOAC population is unclear (62). Similar results
were found in a sub-study of the RE-LY trial demonstrating
dabigatran-treated patients who were bridged with low molecular
weight heparin before an elective procedure had increased rates
of major bleeding (6.5 vs. 1.8%, P < 0.001) with no significant
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 Prevention of GI Bleeding in Patients Receiving DOACs 9

improvement in the risk of thromboembolism, when compared from Denmark highlighted morbidity and mortality associated
with those who were not bridged between 7 days before until 30 with anticoagulant use in post-acute coronary syndrome patients
days after the procedure (84). with atrial fibrillation, and noted a high risk of bleeding when
patients were prescribed anticoagulant (warfarin), ASA, and
clopidogrel. Of the 11,480 subjects in the national registry, 6.3%
GI-CARDIOLOGY DIALOGUE AND PRINCIPLES OF had bleeding events, including 0.7% fatal events. Of these fatal
PATIENT EDUCATION events, nine of ten events were GI in nature (85). As clinicians
The current recommendations for atrial fibrillation, venous use DOACs in combination regimens with other antithrombotic
thromboembolism, and ischemic heart disease expose a growing agents, especially in vulnerable patients (the elderly, the highly co-
population to the risk of GI bleeding by virtue of advancing age morbid, those with prior history of GI bleeding), we will better
(57,70). Mortality and morbidity associated with anticoagulant- understand the true morbidity and mortality risks of DOACs.
related bleeding in the atrial fibrillation population post-acute Given the potential for significant morbidity and mortality
coronary syndrome is not yet fully explored. A population study (86,87), a discussion of DOAC-related GI bleeding must become
routine with cardiac patients (3). Cardiologists and gastroenterolo-
gists must carefully navigate together the best approach for patients
Table 4. Temporary interruption of DOAC before endoscopic
procedure while including the patient’s wishes and preferences in the equa-
tion (88). Patients must be realistically educated regarding the risks
Give last dose prior Give last dose prior of DOAC-related GI bleeding. Some investigators have reported
Drug (creatinine to low-risk endo- to high-risk endo-
clearance) scopic procedurea scopic procedureb that most patients prefer to avoid stroke, even at the risk of GI
bleeding (89,90), however, others have noted that patient prefer-
Dabigatran 1 day 2 days
( > 50 ml/min)
ences change over time as a patient gains new experiences with the
adverse events associated with anticoagulant agents (1,38,54,91).
Dabigatran 2 days 4 days
(31–50 ml/min)
Thus, these discussions must be iterative in nature and be tailored
to consider an individual’s specific risk factors (age, hepatorenal
Dabigatran 4 days 6 days
( < 30 ml/min)
dysfunction, low body weight, known pre-existing GI risk factors
including luminal abnormalities [diverticulosis, recurrent angio-
Rivaroxaban/apixaban/ 1 day 2 days
edoxaban ( > 50 ml/min) dysplasia, etc.] and concomitant drug prescription) that increase
GI bleeding risk.
Rivaroxaban/apixaban/ 1–2 days 3–4 days
edoxaban (31–50 ml/min) An important part of the patient–doctor discussion includes
education regarding the symptoms and signs of GI bleeding.
Rivaroxaban/apixaban/ 2 days 4 days
edoxaban ( < 30 ml/min) Patients need to be taught the common signs and patterns of overt
a
GI bleeding (diverticular bleeding with its painless large volume
A low-risk endoscopic procedure is estimated to have a 48-h risk of major
bleeding of 0–2%. rectal bleeding; ischemic colitis with its abdominal cramping and
b
A high-risk endoscopic procedure is estimated to have a 48-h risk of major hematochezia or melena; peptic or upper GI inflammatory causes
bleeding of 2–4%. of bleeding with hematemesis, melena, or coffee ground emesis)

Table 5. Annual thromboembolic risk associated with DOAC temporary interruption

High risk ( > 10%a) Moderate risk (5–10%a) Low risk ( < 5%a)

Atrial fibrillation: Atrial fibrillation: Atrial fibrillation:

-Stroke or TIA ( < 3 months) -CHADS2 score 3 or 4 -CHADS2 score < 2 with no prior stroke
-CHADS2 score 5 or 6 or TIA event
-Rheumatic valvular disease
Mechanical heart valve: Mechanical heart valve: Mechanical heart valve:
- Any caged ball or tilting disc in the mitral or aortic - Bileaflet aortic valve prosthesis with risk factors - Bileaflet aortic valve without atrial
position; any mitral prosthesis; any valve patient with for stroke fibrillation or stroke risk factors
stroke or TIA event in last 6 months
Venous thromboembolism: Venous thromboembolism: Venous thromboembolism:
-Recent event ( < 3 months) -Event in last 3–12 months - History of event > 12 months ago
-Associated with thrombophiliab or multiple thrombo- -Recurrent events - No history of thrombophilia
philias or antiphospholipid antibodies -Factor V Leiden or prothrombin gene mutation
thrombophilia
-Cancer treatment within the past 6 months or
palliative therapy

TIA, transient ischemic attack.

a
Risk represents an annual risk.
b
Thrombophilia includes deficiency of protein C, protein S, or antithrombin.

© 2016 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY Supplements
10 Abraham
and the subtle signs of symptomatic anemia (fatigue, lassitude,
shortness of breath with exertion, chest pain) associated with an
obscure occult bleeding lesion. They should understand when to
seek emergent medical attention and the information that is helpful
in the rapid assessment and management of DOAC-related bleed-
ing, such as timing of the last dose, currently used medications and
herbal supplements, details of any hepatorenal dysfunction, etc.
Once a GI bleed has been endoscopically treated, a re-appraisal
of the patient’s underlying risk for future DOAC-related GI bleed-
ing is required. The patient and provider must once again engage
in shared-medication decision-making regarding the risk-benefit
of continued DOAC therapy. These efforts are hampered by the
absence of a comprehensive risk-stratification tool that incorpo-
rates both the known cardiology (pharmacologic) and GI (upper
and lower) bleeding risk factors. Such a clinical tool needs to be
developed and validated to ensure accuracy in thrombosis and
bleeding risk assessment (2).
Extrapolation of clinical data and appreciation of the synergistic
risks associated with patient clinical and pharmacologic character-
istics, should guide the formulation of a GI bleeding risk-minimi-
zation strategy. Dose adjustment, discontinuation of concomitant
antithrombotic drugs, or elimination of the necessity for anticoagu-
lation with occlusion or amputation of the left atrial appendage, can
be considered in patients with limited reserve to withstand the mor-
bidity and mortality of refractory GI bleeding events. Greater expe-
rience with DOAC-related GI bleeding is needed to inform future
practice recommendations and collaborative discussion between
cardiologist, hematologist, and gastroenterologist is required to
better anticipate and protect the high-risk DOAC patient.
ACKNOWLEDGMENTS
The author meets criteria for authorship as recommended by the
International Committee of Medical Journal Editors (ICMJE). The
author received no direct compensation related to the development
of publication and views expressed in this publication represent the
personal opinion, and not that of Boehringer Ingelheim Pharmaceu-
ticals, Inc. (BIPI). Writing, editorial, and formatting for this publica-
tion was done by the author, independent of BIPI. BIPI was given
the opportunity to review the publication for medical and scientific
accuracy as well as intellectual property considerations.
CONFLICT OF INTEREST
Guarantor of the article: Neena S. Abraham, MD, MSCE, FACG,
FASGE, AGAF.
Specific author contributions: Writing, editorial, and formatting for
this publication was done by the author, independent of BIPI.
Financial support: This supplement is sponsored by a grant from
Boehringer Ingelheim Pharmaceuticals, Inc.
Potential competing interests: The author declares no conflict of
interest.
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