Am J Gastroenterol Suppl 2016; 3:212; doi:10.1038/ajgsup.2016.

Prevention of Gastrointestinal Bleeding in Patients

Receiving Direct Oral Anticoagulants
Open
Neena S Abraham MD, MSCE, FACG, FASGE, AGAF1,2,3
1
1. Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic,
Scottsdale, Arizona, USA
2
2. Division of Health Care Policy and Research, Department of Health Services Research,
Rochester, Minnesota, USA
3
3. Mayo 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

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Abstract

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.

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INTRODUCTION
Direct oral anticoagulants (DOACs) have a single enzymatic target for anticoagulation, thrombin
(dabigatran), or factor Xa (rivaroxaban, apixaban, edoxaban), permitting a predictable fixed dose
to be taken without plasma monitoring of coagulation factors (1, 2, 3). This pharmacokinetic
advantage has contributed to an unprecedented 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 market 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 interact with P-glycoprotein or the
cytochrome P450 system, can 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 (0.30.5% 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, 10, 11); thus, 0.40.7% of patients per year will
experience a DOAC-related GI bleed, which translates to 13,60023,800 DOAC-related GI
bleeds per year.

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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 1h and 4h following ingestion with a trough
plasma level occurring 1224h post 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 (3550%) 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 3550% 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 interaction 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 undergoes 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 recommended for the elderly
(>80 years), for those with moderate renal impairment (creatinine clearance [CrCl] of 30
50ml/min) or previous GI bleeding. In these vulnerable populations a lower dose of 110mg
twice daily may be considered. In the United States, a reduced dose of 75mg twice daily is
recommended for non-valvular atrial fibrillation patients with CrCl of <30ml/min instead of the
standard dose of 150mg 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
<15ml/min).

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POTENTIAL FOR DRUG, DIETARY, AND HERBAL SUPPLEMENT

INTERACTIONS

Harmful interactions are possible with concomitant use of certain drugs and dietary supplements,
and occur at multiple levelsabsorption, prodrug transformation (dabigatran etexilate),
metabolism, or elimination. Mechanisms of action include interaction 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 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 prescription 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.

Table 1 - Inhibitors and inducers of CYP3A4 and P-gp.

Full table

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 concentration 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 3050ml/min). In
the US, dose adjustment to 75mg twice daily is recommended in patients with moderate renal
impairment when concomitantly prescribed with dronedarone and ketoconazole. 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 recommended. 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
concomitant prescription of DOACs with herbal or dietary supplements. Prescribing physicians
should be aware of the potential for 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.

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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
serious adverse events reported, 2,367 cases of hemorrhage and 542 deaths were reported. The
unexpectedly large number of bleeding events was observed in the elderly, many of whom had
concomitant renal disease (19). Greater than 50% of atrial fibrillation patients >80 years of age
have concomitant moderate renal failure 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
generalizability 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 complications. 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, prescribed 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 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, 28, 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
(6574) 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
ACROBAT-NRSI (A Cochrane risk of bias assessment tool for non-randomized studies of
intervention) (30, 31). In the Lin meta-analysis, dabigatran 110 and 150mg, 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 6574 years (i.e., the younger elderly). In addition,
dabigatran 150mg was associated with a 1.5-fold higher risk (relative risk 1.51; 95% confidence
interval [CI]: 1.611.96) 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 150mg twice daily, when
compared with warfarin (=1.53; 95% CI: 1.102.14; 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 dabigatran, 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 150mg 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 fibrillation, and is known to increase anticoagulant-related bleeding
(35). All DOACs have some degree of renal excretion. One can expect >8085% renal clearance
for dabigatran, 3550% for rivaroxaban, 4050% for edoxaban, and 2740% for apixaban (36,
37, 38, 39).

The degree of renal impairment is determined using the CockroftGault equation to calculate the
patient's glomerular filtration 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.

Specific guidelines regarding dosing alterations have been provided 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 75mg
twice daily among this population, however, the EMA has not approved dabigatran for use with a
CrCl of 1530ml/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
(8795%) and are thus unlikely to be removed by dialysis (16).
Table 2 - Dosing modification of DOAC based on renal impairment.

Full table

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 drugdrug 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 pathway is renal excretion (80%). Consequently, the plasma concentration 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 recommended 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-concentrationtime curve (AUC) of edoxaban (15mg single dose) is
decreased by 4.8% and that of dabigatran (150mg 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 <60kg (40).
However, a similar effect was not observed with rivaroxaban, the second DOAC to enter the
market; 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
(<50kg) were again shown to have a higher risk of bleeding complications with apixaban due to
higher circulating plasma concentrations (up to 30% higher) when compared with patients who
weigh 6585kg (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 disease are often on ASA at a
cardioprotective dose (81mg/day) or full musculoskeletal dose (325mg/day), especially after
vascular surgery. 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 monotherapy 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, 45, 46). Concomitant NSAID prescription has also been
shown to increase DOAC (or warfarin) bleeding (47). NSAIDs increase overall antiplatelet
pharmacologic burden and may cause an acute deterioration of renal function 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 antiplatelet strategy is associated with a 13% reduction in myocardial
infarction (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
bleeding 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 infarction major bleeding (defined as
any intracranial bleeding or clinically overt signs of a hemorrhage that is associated with a drop
in hemoglobin of 5g/dl) (P-interaction=0.017) and clinically significant 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 concomitant 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 duration with antithrombotic regimens exacerbate
bleeding risk (52). National registry (53) and population-based cohorts (54, 55, 56) suggest 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 associated with concomitant DOAC and
DAPT prescription (58). In this important study, the addition of apixaban, at a dose of 5mg
twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome
increased the number of major bleeding 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.

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THERAPY BASED ON PATIENT CHARACTERISTICS: RISK PREDICTION

SCORES

Risk prediction tools are commonly used in the atrial fibrillation population to predict
thromboembolism (CHADS2 or CHA2DS2-VASc score) and adverse bleeding (HAS-BLED,
HEMORR2HAGES, 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 3.712.5/100 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).

Table 3 - Risk prediction scores.

Full table

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 anticoagulants 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 variables to HAS-BLED but fail to
consider the impact of concomitant antiplatelet drug use, and require laboratory and genetic
markers for complete risk assessment. Neither was designed to predict non-intracerebral bleeding
events due to low incidence of bleeding 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.

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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 antithrombotic 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.

2. Consider a vitamin K antagonist in patients >75 years (especially if they have multiple
concomitant risk factors for GI bleeding); those with hepatorenal dysfunction (as outlined in
prior sections); or low body weight (<5060kg).

3. Regularly review the patient's medication list and assess over-the-counter use of dietary and
herbal supplements. Exercise caution 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 prevent deterioration of renal function

and impairment of DOAC elimination. Attention to dosing modifications based on impairments
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: 1.9311.68) 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 antiplatelet-
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: 0.350.77) 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 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 ARISTOTLE 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 hospitalization (79). A substantial amount of active
apixaban, rivaroxaban, 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 different 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 compared with warfarin (76).

Patients with known diverticulosis should be counseled regarding the symptoms and signs of
diverticular bleeding. ASA and NSAIDs are both known to increase the risk of diverticular
bleeding (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 complications. The impact of treating constipation to
prevent development of diverticular complications is controversial. Traditionally, fluid and fiber
has been recommended to prevent diverticular complications (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 periodically 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
concomitant risk factors, location of the GI bleed, optimization of risk-minimization strategies,
and likelihood of bleed recurrence should be carefully considered before individualizing patient
recommendations.

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PERI-ENDOSCOPIC BLEEDING PREVENTION AND TEMPORARY DOAC

INTERRUPTION

DOACs should be temporarily discontinued in patients undergoing an invasive procedure when

there is a 24% increased risk of post-procedural bleeding. High-risk endoscopic procedures
include polypectomy, variceal treatment, biliary sphincterotomy, endosonography with fine
needle aspiration, and pneumatic dilatation (62). There is rarely a need to interrupt DOAC for
diagnostic endoscopic procedures with a low-likelihood of procedural or post-procedural
bleeding (02%) (62). Gastrointestinal endoscopy with or without biopsy, enteroscopy, biliary
stent placement without sphincterotomy and endosonography without fine needle 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
procedures 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).

Table 4 - Temporary interruption of DOAC before endoscopic procedure.

Full table
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 concentration 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).

Table 5 - Annual thromboembolic risk associated with DOAC temporary interruption.

Full table

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
recommended. 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 without 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: 0.200.78; P=0.005 for superiority). The
results of this study are intriguing and their applicability 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 improvement in the
risk of thromboembolism, when compared with those who were not bridged between 7 days
before until 30 days after the procedure (84).

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GI-CARDIOLOGY DIALOGUE AND PRINCIPLES OF PATIENT

EDUCATION

The current recommendations for atrial fibrillation, venous thromboembolism, and ischemic
heart disease expose a growing population to the risk of GI bleeding by virtue of advancing age
(57, 70). Mortality and morbidity associated with anticoagulant-related bleeding in the atrial
fibrillation population post-acute coronary syndrome is not yet fully explored. A population
study from Denmark highlighted morbidity and mortality associated with anticoagulant use in
post-acute coronary syndrome patients 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% had bleeding events, including 0.7% fatal events. Of these
fatal events, nine of ten events were GI in nature (85). As clinicians use DOACs in combination
regimens with other antithrombotic agents, especially in vulnerable patients (the elderly, the
highly co-morbid, those with prior history of GI bleeding), we will better understand the true
morbidity and mortality risks of DOACs.

Given the potential for significant morbidity and mortality (86, 87), a discussion of DOAC-
related GI bleeding must become routine with cardiac patients (3). Cardiologists and
gastroenterologists must carefully navigate together the best approach for patients while
including the patient's wishes and preferences in the equation (88). Patients must be realistically
educated regarding the risks of DOAC-related GI bleeding. Some investigators have reported
that most patients prefer to avoid stroke, even at the risk of GI bleeding (89, 90), however, others
have noted that patient preferences change over time as a patient gains new experiences with the
adverse events associated with anticoagulant agents (1, 38, 54, 91). Thus, these discussions must
be iterative in nature and be tailored to consider an individual's specific risk factors (age,
hepatorenal dysfunction, low body weight, known pre-existing GI risk factors including luminal
abnormalities [diverticulosis, recurrent angiodysplasia, etc.] and concomitant drug prescription)
that increase GI bleeding risk.

An important part of the patientdoctor discussion includes education regarding the symptoms
and signs of GI bleeding. Patients need to be taught the common signs and patterns of overt GI
bleeding (diverticular bleeding with its painless large volume rectal bleeding; ischemic colitis
with its abdominal cramping and hematochezia or melena; peptic or upper GI inflammatory
causes of bleeding with hematemesis, melena, or coffee ground emesis) 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 bleeding, 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 bleeding 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 incorporates 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 characteristics, should guide the formulation of a GI bleeding risk-
minimization strategy. Dose adjustment, discontinuation of concomitant antithrombotic drugs, or
elimination of the necessity for anticoagulation with occlusion or amputation of the left atrial
appendage, can be considered in patients with limited reserve to withstand the morbidity and
mortality of refractory GI bleeding events. Greater experience 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.

Top of page

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.

Top of page

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Acknowledgments

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