Patient Taking A Novel Oral Anticoagulant Presents With Major GI Bleeding
Amartya Kundu,MD1, Partha Sardar,MD2, Parijat Sen,MD3, Saurav Chatterjee,MD4, Jessica Huston,MD2, Ramez Nairooz,MD5, John J. Ryan,MBBCh 2, Wilbert S. Aronow,MD6
1Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.2Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, USA.3Department of Medicine, St. Michael’s Medical Center, Newark, NJ, USA.4Division of Cardiology, St. Luke’s-Roosevelt Hospital of the Mount Sinai Health System, New York, NY, USA.
Novel Oral Anticoagulants (NOACs) such as Dabigatran, Rivaroxaban, Apixaban and Edoxaban are becoming increasingly popular choices for anticoagulation in place of oral Vitamin K Antagonists in various clinical settings. However, they are thought to be associated with an increased risk of gastrointestinal bleeding. Moreover, no specific antidote is available which can rapidly reverse the anti-coagulant action of NOACs raising concern that gastrointestinal bleeding with NOACs could carry a worse prognosis than that associated with conventional agents.
In this review, we describe a case of gastrointestinal bleeding in the setting of NOAC use, followed by a brief overview of the pivotal trials involving NOACs. Clinical issues such as pathophysiology, diagnosis and management of NOAC induced GI bleeding have been described. Future trials will help elucidate the true incidence, risk factors and preventive strategies for NOAC associated gastrointestinal bleeding.
Key Words : Novel Oral Anticoagulants, Dabigatran, Rivaroxaban, Apixaban, Edoxaban, Gastrointestinal Bleeding.
Correspondence to: Partha Sardar, M.D.Division of Cardiovascular Medicine,University of Utah Health Science Center,30 North 1900 East, Room 4A100,Salt Lake City, Utah 84132, USA.
Vitamin K Antagonists (VKA) such as Warfarin have long been the agents of choice for oral anticoagulation in different clinical settings. However, warfarin poses problems of its own in terms of a narrow therapeutic range, need for regular INR monitoring and interactions with several drugs and food.1 Risk of major bleeding is another limiting factor while using warfarin. Almost 50 years after the approval of warfarin, novel oral anticoagulants (NOACs) such as the direct thrombin inhibitor Dabigatran, and Factor Xa inhibitors - Rivaroxaban, Apixaban and Edoxaban have been developed. These NOACs have a more predictable pharmacokinetic profile than warfa¬rin, fewer dietary and drug interactions, and do not require routine monitoring.2,3 NOACs are increasingly being considered to replace VKAs for indications such as thromboprophylaxis during orthopedic surgery, prevention of thromboembolic complications in patients with atrial fibrillation, treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT).4
Gastrointestinal Bleeding still remains one of the most dreaded complications of anticoagulation therapy and recent studies have suggested that NOACs carry an increased risk of GI bleeding compared to standard therapy.5 Prothrombin Complex Concentrates (PCC) administered for rapid reversal of effects of warfarin has been introduced fairly recently. However,, no specific antidote is available which can rapidly reverse the anti-coagulant action of NOACs raising concern that gastrointestinal bleeding with NOACs could carry a worse prognosis than that associated with conventional agents such as VKAs.6
We present a case of GI Bleeding in the setting of using a NOAC , followed by a brief review of literature on the topic.
A 72 year old female patient with a past medical history of diastolic heart failure with an ejection fraction (EF) of 60 % , recently diagnosed Atrial Fibrillation on renally dosed Rivaroxaban of 15 mg PO daily, Chronic Kidney Disease (CKD) with a baseline creatinine of 1.3 and Hypertension , was transferred to the Intensive Care Unit for worsening shortness of breath and a 12 hour history of 2 episodes of passing bright red blood per rectum. She had recently
returned home from a rehabilitation facility where she had
spent 2 weeks following a successful right knee replacement surgery.
On presentation, her vitals were as follows: T- 36 C, BP- 86/54,
Pulse- 120 bpm , RR- 24, O2 saturation- 94 % on Room Air. Her
H/H was 7.4/22 ( her baseline H/H is 10/30, probably secondary to
CKD). Platelet count was 180,000/ul and coagulation profile was
unremarkable with a PT of 14 s, PTT of 32 s and INR of 1.1 .
Serum creatinine was 1.42, which was close to her baseline and estimated
creatinine clearance was 35 ml/min. On examination, lungs
were clear to auscultation and there was no jugular venous distention
(JVD) or pedal edema. Cardiovascular examination was unremarkable
apart from tachycardia with a normal rhythm. Her abdomen
appeared soft and non tender with normoactive bowel sounds and no
organomegaly. Rectal examination was positive for bright red blood
with no evidence of hemorrhoids. Chest X Ray was unremarkable
and EKG revealed sinus tachycardia. She was kept NPO and started
on aggressive IV fluid replacement. Group and Cross Match was
taken and patient was transfused 3 units of Packed Red Blood Cells
(PRBC). She was monitored closely and she responded well to therapy.
Her blood pressure improved to 122/76 and she was saturating
at 98 % on room air with symptomatic improvement of her dyspnea.
Once she was stable for imaging, a CT scan of her abdomen was
performed which did not reveal any overt pathology. Of note, her
last upper GI endoscopy was done 2 months ago and was normal
with no evidence of ulceration or gastritis. She was kept under close
observation and there were no further episodes of bleeding per rectum.
Post transfusion H/H was 10.3/30.8, indicating an appropriate
response. The following morning, she was taken for colonoscopy
which turned out to be completely normal with no areas of
active bleeding. Repeat upper GI endoscopy was again unremarkable.
As the patient was no longer actively bleeding, it was decided
not to proceed with further imaging studies such as video capsule
endoscopy to evaluate the small bowel. With the exclusion of any
obvious gastrointestinal pathology, it was concluded that her GI
bleed was likely an adverse effect of her daily rivaroxaban therapy
and this was subsequently discontinued. She was eventually stable
for discharge and went home. On follow up a week later, she denied
any further episodes of bleeding and her H/H appeared stable
at 10.1/30. She was later started on warfarin therapy with serial INR
checks and dose adjustments. She was followed closely as an outpatient
and no further events of major GI bleeding were observed.
Gastrointestinal bleeding is one of the most serious adverse effects
and a major limitation in the use of new oral anticoagulants.
However, the exact risk of gastrointestinal bleeding with NOACs
is still unknown and precise risk related to individual NOACs
remains inconclusive. A brief overview of the NOAC’s used
in clinical practice, as well as a review of results from the major
trials exploring their efficacy and safety are described below.
Dabigatran is a direct thrombin inhibitor that is FDA approved
for prevention of stroke in non valvular atrial fibrillation as well as
for treatment and reduction in risk of recurrence of DVT/PE.
The RE-COVER trial showed that dabigatran 150 mg twice
daily was as effective as dose adjusted warfarin for the treatment
of acute venous thromboembolism. Major bleeding episodes occurred in 1.6 % patients assigned to dabigatran and 1.9
% patients assigned to warfarin (HR 0.82; 95% CI, 0.45 to 1.48)
while episodes of any bleeding were observed in 16.1 % patients
assigned to dabigatran and 21.9 % patients assigned to warfarin
(HR 0.71; 95% CI, 0.59 to 0.85). Gastrointestinal bleeding occurred
in 53/1274 subjects in the dabigatran group and 35/1265
subjects in the warfarin group (OR 1.52; 95 % CI, 0.99 to 2.32).7
The RE-LY (Randomized Evaluation of Long-Term Anticoagulation
Therapy) trial compared the efficacy and safety of dabigatran
110 mg or 150 mg twice a day with dose adjusted warfarin for prevention
of stroke in atrial fibrillation. Dabigatran 150 mg twice daily
was superior to warfarin (P=0.001) for reduction of the risk of stroke
or systemic embolism, while dabigatran 110 mg twice daily dosage
was non inferior to warfarin in reducing the risk of stroke or systemic
embolism (P=0.001). However, dabigatran 110 mg twice a day was
associated with a lower risk of major bleeding compared to Warfarin
(2.87 % versus 3.57 % ; P= 0.002), whereas dabigatran 150 mg twice a
day was associated with a similar risk of major bleeding (3.31 % versus
3.57 %; P = 0.32). Bleeding rates were higher among patients who
received treatment with dual antiplatelet agents than those who did
not. The risk of bleeding was progressively higher with increasing age,
possibly due to higher drug concentrations from age related decline in
renal function and drug clearance. The risk of gastrointestinal bleeding
was higher with dabigatran 150 mg twice daily than with warfarin
(1.85% vs 1.25 %; P < 0.001), but was similar in the dabigatran
110 mg twice daily and warfarin groups ( 1.36 % vs 1.25 % ;P=0.43).8
In the dabigatran group, 53% had bleeding from the upper gastrointestinal
tract, and 47% had bleeding from the lower gastrointestinal
tract. In the warfarin group, 75% had bleeding from the upper
gastrointestinal tract, and 25% had bleeding from the lower gastrointestinal
tract. Metabolism of the pro-drug dabigatran etexilate by
esterases in the gut flora may lead to progressively higher concentrations
of the active drug during transit through the gastrointestinal
tract. In contrast, warfarin has a high bioavailability and first
requires hepatic biotransformation to exert its anticoagulant effect,
which is why unabsorbed warfarin the lower gut would not be expected
to cause significantly higher localized bleeding. With advancing
age, there is also an increase in gastrointestinal tract pathology
such as diverticulosis and angiodysplasia.9 The risk of bleeding from
affected areas may increase due to direct exposure to dabigatran.
Thus, local effects of dabigatran on diseased mucosa could account
for the relative increase in lower gastrointestinal bleeding seen with
dabigatran compared with warfarin patients in the RE-LY trial.8
Rivaroxaban is an oxazolidinone derivative capable of inhibiting
both free Factor Xa and Factor Xa bound in the prothrombinase
complex.10 This highly selective direct Factor Xa inhibitor has high
oral bioavailability , a rapid onset of action and a predictable pharmacokinetic
profile across a wide spectrum of patients with respect
to age, gender, weight and race.11
Rivaroxaban is FDA approved for both DVT/PE Prophylaxis in
adults undergoing hip/ knee replacement surgery and for prevention
of stroke in patients with non valvular atrial fibrillation.
The ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa
Inhibition Compared with Vitamin K Antagonism for Prevention of
Stroke and Embolism Trial in Atrial Fibrillation) Trial showed that
rivaroxaban 20 mg daily was non inferior to dose adjusted warfarin for prevention of stroke or systemic embolism in patients with non valvular
atrial fibrillation (HR 0.79; 95 % CI 0.66 to 0.96; P<0.001 for non
inferiority). However, superiority was not shown in the intention to
treat analysis (HR 0.88; 95% CI, 0.74 - 1.03;P = 0.12 for superiority).12
The rate of major and clinically relevant non major bleeding
was 14.9% per year in the rivaroxaban group and 14.5% per year in
the warfarin group. (HR, 1.03; 95% CI, 0.96 - 1.11;P = 0.44). The
composite principal safety endpoint for GI bleeding events (upper,
lower, rectal) occurred more frequently in patients receiving rivaroxaban
than warfarin (HR 1.39; 95% CI 1.19-1.61). Despite the
increased rate of major GI bleeding with rivaroxaban, the incidence
of life-threatening GI bleeding (i.e. requiring transfusion of <3
units of red blood cells) was similar with rivaroxaban and warfarin
(n= 52 and 47, respectively) and there were fewer fatal GI bleeding
events with rivaroxaban than warfarin (n= 1 and 5, respectively).
The following clinical characteristics were associated with an
increased risk for major GI bleeding in patients receiving rivaroxaban:
concurrent aspirin or NSAID use; concomitant use of H2
receptor antagonist or proton pump inhibitors ; prior vitamin K
antagonist use; decreased creatinine clearance; transient ischemic
attack or systemic embolism ;cigarette smoking; male gender; prior
stroke,; chronic obstructive pulmonary disease, and prior upper and
lower GI bleeding. The majority of major GI bleeding in the setting
of rivaroxaban (like dabigatran) was from the lower GI tract.13
The EINSTEIN study showed that Rivaroxaban (15 mg twice
daily for 3 weeks, followed by 20 mg once daily) was non inferior
to standard therapy with enoxaparin followed by an adjusted-dose
vitamin K antagonist for treatment of acute DVT and for prevention
of recurrence. (HR 0.68; 95% CI 0.44 -1.04; P < 0.001). First major
or clinically relevant non major bleeding rates were similar in both
groups (HR 0.97; 95% CI 0.74-1.22; P = 0.77) . Rivaroxaban was
associated with a lower risk of major bleeding (HR 0.65 ; 95 % CI
0.33–1.30;P=0.21) in the acute DVT study. However, 4 patients in
the rivaroxaban group had gastrointestinal bleeding in the Continued
Treatment Study, compared to none in the comparator group.14
Apixaban is a direct and competitive inhibitor of factor Xa. which
has about 50% bioavailability, and is approximately 25% excreted by
the kidney.15
The AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent
Stroke in Atrial Fibrillation Patients who have Failed or are Unsuitable
for Vitamin K) trial showed that Apixaban 5mg twice daily
lowered the risk of stroke or systemic embolism when compared
to 81mg-324 mg Aspirin in patients with prior stroke /TIA ( HR
0.29 ; 95% CI 0.15–0.60) as well as in patients with no prior stroke/
TIA ( HR 0.29; 95% CI 0.15–0.60).16 Major bleeding was more
frequent in patients with history of stroke or TIA than in patients
without this history (HR 2.88; 95% CI 1.77–4.55) but risk of this
event did not differ between treatment groups. The rate of gastrointestinal
bleeding with apixaban was similar to that of aspirin ( HR
0.86; 95% CI 0.4-1.86, P=0.71). Overall, apixaban was well tolerated
and showed a profile of adverse events similar to that of aspirin.17
The ARISTOTLE (Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation) Trial showed that
Apixaban 5 mg twice daily was superior to dose adjusted Warfarin
for prevention of stroke or systemic embolism in patients with atrial
fibrillation. (HR 0.79; 95% CI 0.66 -0.95; P = 0.01 for superiority).18
The rate of major bleeding was 2.13% per year in the apixaban group,
as compared with 3.09% per year in the warfarin group (HR 0.69; 95%
CI, 0.60 - 0.80; P<0.001). In a modified intention-to-treat sensitivity
analysis over the entire treatment period, there was a 27% relative reduction
in rate of major bleeding in the apixaban group, as compared
with the warfarin group (P<0.001). The risk of gastrointestinal bleeding
was similar between both apixaban and warfarin groups (OR 0.88,
95 % CI 0.67-1.14). Apixaban had an acceptable side-effect profile
with no unexpected events, and the rate of discontinuation of the study
drug was lower in the apixaban group than in the warfarin group.18
Edoxaban is a direct oral Factor Xa inhibitor that was approved
by the FDA as recently as January 2015, for the prevention of
stroke and non–central-nervous-system (CNS) systemic embolism
in patients with nonvalvular atrial fibrillation. Pharmacokinetically,
edoxaban has a 62 % bioavailability,19 achieves maximum
concentrations within 1-2 hours and is 50% renally excreted.20
Most of the data on edoxaban comes from the ENGAGE AFTIMI
48 trial which showed that edoxaban (60 mg and 30 mg once
daily) was non inferior to dose adjusted warfarin for reduction in the
risk of stroke or systemic embolism (modified intent-to-treat population,
P=0.001 and P=0.005 for noninferiority, respectively; intentto-
treat population, P=0.08 and P=0.10 for superiority, respectively).
The annualized rate of major bleeding was 3.43% with warfarin
versus 2.75% with high dose edoxaban (HR, 0.80; 95% CI, 0.71 to
0.91; P<0.001) and 1.61% with low-dose edoxaban (HR, 0.47; 95%
CI, 0.41 to 0.55; P<0.001). Compared with Warfarin, there were
lower rates of major bleeding with both high dose edoxaban ( 3.43
% vs 2.75 %; P<0.001) and low dose edoxaban.( 3.43 % vs 1.61 %;
P<0.001). However, the risk of gastrointestinal bleeding was higher
with high dose edoxaban compared to warfarin ( 1.51% vs 1.23
%; P=0.03) but lower with low dose edoxaban compared to warfarin
(0.82% vs 1.23%;P<0.01). Bleeding was more common from
the Upper GI tract than the Lower GI tract in all 3 subgroups.21
Thus we see that the risk of GI Bleeding varied in different
trials and with different NOAC’s, but overall NOAC’s
were associated with a higher risk of GI Bleeding.
Comparison Of Different Agents For GI Bleeding Risk
A number of meta-analyses have been performed comparing the
risk of GI Bleeding with NOACs used for various indications, to
that of standard therapy. A meta-analysis of 19 Randomized Control
Trials (RCT) showed that the overall Odds Ratio for Gastrointestinal
Bleeding among patients taking NOAC was 1.45 (95%
CI 1.07- 1.97). Subgroup analyses showed that the OR for atrial
fibrillation was 1.21 (95% CI 0.91- 1.61), for thromboprophylaxis
after orthopedic surgery the OR was 0.78 (95% CI 0.31- 1.96), for
treatment of venous thrombosis the OR was 1.59 (95% CI 1.03 -
2.44), and for acute coronary syndrome the OR was 5.21 (95% CI
2.58 - 10.53). Among the drugs studied, the OR for apixaban was
1.23 (95% CI 0.56- 2.73), the OR for dabigatran was 1.58 (95%
CI, 1.29- 1.93), the OR for edoxaban was 0.31 (95% CI 0.01-
7.69), and the OR for rivaroxaban was 1.48 (95% CI 1.21- 1.82).5
Another meta-analysis evaluating 6 trials also suggested higher
GI bleeding with NOACs. (RR, 1.30; 95 % CI 0.97 - 1.73).22
We performed a meta analysis of 17 RCTs including 91,933 patients
to evaluate the risk of gastrointestinal bleeding with NOACs compared with conventional anticoagulants.23 We found that NOACs
were associated with a significantly higher GI bleeding compared
with conventional anticoagulants [Peto’s odds ratio (POR)
1.23, 95% CI 1.10 to 1.36; number needed to harm (NNH)=295
patients]. Trial sequential analysis (TSA) showed a 20% relative
risk increase of any GI bleeding with NOACs versus conventional
agents.. Compared with controls, the risk of GI bleeding was significantly
higher with dabigatran (POR 1.31, 1.10 to 1.57; NNH=205)
and rivaroxaban (POR 1.35, 1.16 to 1.57; NNH=139) but not with
apixaban (POR 0.85, 0.67 to 1.08). TSA showed a relative risk increase
of 20% for dabigatran and rivaroxaban but showed insufficient
data for apixaban. NOACs caused significantly higher risk of
any GI bleeding compared with warfarin (NNH=212) and LMWH
followed by warfarin (NNH=134), but not against low molecular
weight heparin alone.23 Thus we saw heterogeneity in risk - while
there was a statistically significant excess risk of GI bleeding with
dabigatran and rivaroxaban, the risk of GI bleeding remained inconclusive
for apixaban, when compared with controls. Although this
suggests that apixaban may be safer than other NOACs, further trials
are needed to exclude true bleeding risks associated with apixaban .
Gastrointestinal bleeding in the anticoagulated patient may occur
at any level along the GI tract . The mucosa of the GI tract has a
rich blood supply that can be sensitive to bleeding by various endogenous
or exogenous insults. Orally administered anticoagulants
may cause bleeding by different mechanisms such as (a) systemic anticoagulant
effect; (b) topical anticoagulant effect; (c) topical direct
caustic action; (d) topical biological action of the drug unrelated to
coagulation (e.g. inhibition of mucosal healing). These mechanisms
may occur alone or in combination.24 As Warfarin requires systemic
absorption and activation prior to exerting its anticoagulant effect,
the increase in GI Bleeding with warfarin is not a topical effect and
is likely a manifestation of its systemic anticoagulation action. In
contrast, NOACs have variable absorption and active anticoagulant
is present within the lumen of the GI Tract which could, in theory,
cause topical anticoagulation effects in addition to systemic action.
Warfarin has a narrow therapeutic window and monitoring of its
anticoagulant activity by measuring the INR range is necessary to
reduce the risk of bleeding. However, INR is not an useful test to
gauge the anticoagulant effect of NOACs because INR is calibrated
for use with vitamin K antagonists only.25 Although NOAC use may
be associated with an increase in INR, this increase does not relate to
the effectiveness of therapy or provide a linear correlation of concentration
and effect that is seen when measuring warfarin levels.26 As
dabigatran directly inhibits Thrombin, measurement of Prothrombin
Time [PT] lacks the sensitivity to detect therapeutic levels and often
a sub-therapeutic level is noted, regardless of the concentration of
dabigatran.27 Other appropriate tests include partial thromboplastin
time (aPTT), and diluted thrombin time (dTT). aPTT however, is
not very sensitive for low doses of dabigatran. A very sensitive test
for measurement of dabigatran activity is the Ecarin Clotting Time
(ECT) as a close linear relationship has been shown between pro¬longation
of ecarin clotting time and plasma concentrations of dabigatran.
28 However, ECT assay is not widely used in the United States.
As rivaroxaban, apixaban and edoxaban are direct inhibitors of Factor Xa , the anti factor Xa assay is the most sensitive method of
monitoring their anticoagulant activity.29
The incidence of NOAC associated GI bleeding can be significantly
reduced by successful preventive strategies. Adherence to appropriate
indications for NOAC use and proper drug dosing is imperative
as usage of NOACs beyond their approved indications or at different
doses can induce supra-therapeutic anticoagulation, and this may be
associated with an increased risk of severe or even fatal GI bleeding.30
Identification of modifiable and non-modifiable bleeding risk factors
will help stratify patients at risk and also ascertain the degree of risk.
Tools such as the HAS-BLED score can be used for this purpose.31
Management of GI Bleeding from use of NOACs is similar to the
standard management of GI bleeding and resuscitation takes precedence
before anything else in the hemodynamically compromised
patient. Measurement and monitoring of the degree of anticoagulation
using the different tests described above should be initiated and
administration of the NOAC should be stopped immediately. If the
patient is also receiving anti platelet agents, these should be withheld
as well. Unlike VKAs, there is no drug specific antidote to reverse the
effect of NOACs. Administration of Prothrombin Complex Concentrates
have been suggested as a potential agent to reverse NOAC anticoagulation
, but data regarding their absolute efficacy is lacking.32,33
Recently however, Idarucizumab - a monoclonal antibody fragment
that binds free and thrombin-bound dabigatran thereby neutralizing
its activity, was developed to reverse the anticoagulant effects
of dabigatran. The Reversal Effects of Idarucizumab on Active
Dabigatran (RE-VERSE AD) Study was a prospective cohort study
undertaken to examine the efficacy and safety of idarucizumab for
the reversal of anticoagulant effects of dabigatran in patients who
presented with serious bleeding or who required urgent surgery
or intervention. Results of this study were recently published and
showed that 5g intravenous idarucizumab rapidly and completely
reversed the anticoagulant effect of dabigatran in 88 to 98% of
the patients who had had elevated clotting times at baseline.34
In current clinical practice however , reduction of NOAC exposure
mostly depends on the short half lives of these novel agents (
5-17 h), causing rapid reductions in anticoagulant levels with time
in patients without renal or hepatic dysfunction. In contrast, it takes
a much longer time to reverse the effects of warfarin as it causes
a biologic reduction of active clotting factors. This temporal advantage
over warfarin is important in the setting of bleeding into the
GI tract lumen because intra-luminal bleeding over time can occur
without creating high local pressure and its sequelae, unlike bleeding
into a closed space such as the skull which can quickly develop
catastrophic consequences. Therefore, if after resuscitation, the patient
is hemodynamically stable, it is reasonable to postpone endoscopic
evaluation , while providing supportive care and close observation.
24 If the patient experiences rapid GI bleeding and remains
hemodynamically unstable despite resuscitation efforts, urgent intervention
is necessary in the form of emergency upper GI endoscopy
and colonoscopy, followed as required by other studies such as
small bowel enteroscopy, computed tomography- or catheter-based
angiography and nuclear scintigraphy. These interventions entail
numerous strategies for control of GI bleeding, including thermal
modalities, mechanical tamponade, and embolization.24 If these
interventions are unsuccessful, surgery remains the final option.
The convenience of no routine monitoring and a wide
therapeutic window make the NOACs desirable first-line options
for anticoagulation. In addition, all NOACs have been associated
with lower risk of intracranial hemorrhage compared to standard
antithrombotic therapy.35 However, NOAC use may be related to
higher rates of GI bleeding and this notion has been supported by
many meta-analyses which have compared NOACs to conventional
VKAs. Analysis from our group showed that GI bleeding risk is
definitely higher with dabigatran and rivaroxaban, but we lacked
sufficient evidence for apixaban.23 Further trials are needed to
test whether the risks of GI bleeding associated with dabigatran
and rivaroxaban is dose dependent and can be overcome by using
low dose dabigatran or rivaroxaban, provided that such doses show
superiority or equivalence to conventional anticoagulants regarding
thromboembolic complications.
There is a paucity of recommendations on how to transition
patients from one NOAC to another in the setting of adverse effects
such as GI bleeding and care should be taken to ensure continuous
anticoagula¬tion when stopping, interrupting, or switching between
NOACs to avoid an increased risk of stroke. Thus, increased risk of
GI bleeding should be kept in mind prior to starting therapy with
NOACs. It is fortunate that the majority of the GI bleeds associated
with NOAC use is not life threatening. Future trials will help
elucidate the true incidence, risk factors and appropriate preventive
strategies for NOAC associated gastrointestinal bleeding.