Risk of Gastrointestinal Bleeding with Direct Oral Anticoagulants
Pharmacology of Direct Oral Anticoagulants
The anticoagulation effects of DOACs are exerted by targeting single enzymes. Apixaban,
edoxaban, and rivaroxaban are inhibitors of factor Xa, while thrombin is inhibited
directly by dabigatran. These characteristics allow for the administration of a predictable
dose without the need for plasma monitoring of coagulation factors. Dabigatran etexilate
is a prodrug that, following oral administration, is converted to its active form,
where it then functions as a reversible and competitive direct thrombin inhibitor.
Multiple doses in healthy volunteers show the drug to have a half-life of 12 to 14 hours,
although in patients whose creatinine clearance (CrCl) is less than 30 mL/min, this
increases to more than 24 hours. It was noted that 80% of dabigatran is eliminated
by renal excretion. It can be taken at a dose of 150-mg bis in die (b.i.d.). However,
this should be lowered to 110-mg b.i.d. in cases of renal deficiency, along with CrCl < 50 mL/min.
Dabigatran is instead contraindicated in the presence of severe renal impairment,
CrCl < 30 mL/min or in cases of advanced liver disease.[1 ]
[14 ] Rivaroxaban functions as an oxazolidinone-derived anticoagulant that inactivates
factor Xa. As a result, the intrinsic and extrinsic pathways of the blood coagulation
cascade are interrupted. Following oral administration, plasma concentration reaches
its maximum after 1 to 4 hours. While the effects last approximately 12 hours, factor
Xa activity requires more than 24 hours to return to normal levels, so it can therefore
be taken once a day. Elimination is 50% hepatobiliary and 35% renal, therefore patients
with CrCl ≤ 15 mL/min or child class-B or -C liver disease should not be administered
rivaroxaban.[1 ]
[15 ] It is given at a dose of 20 mg daily, or 15 mg daily if CrCl is < 50 mL/min. One
other oral selective inhibitor of factor Xa is apixaban, 30% of the drug is eliminated
via renal excretion with a half-life of approximately 5 hours. The kidneys excrete
25% of the absorbed drug, with a half-life of approximately 12 hour. Apixaban is taken
at a dose of 5-mg b.i.d., although this should be lowered to 2.5 mg if patients fall
into two or more of the following categories: aged 80 years or over, body weight 60 kg
or less, or serum creatinine 1.5 mg/dL or more.[1 ]
[5 ] An oral direct inhibitor of factor Xa that resembles both rivaroxaban and apixaban
is edoxaban. It reaches maximum serum concentrations within 1 hour to 2 hours and
is characterized by 50% renal excretion of 60 mg daily. However, this goes down to
30 mg daily if the patient presents CrCl < 50 mL/min or weighs less than 60 kg. Edoxaban
is contraindicated in patients with severe renal impairment (CrCl < 15 mL/min) and
advanced liver disease.[5 ]
[16 ] The characteristics of different DOACs are summarized in [Table 1 ].
Table 1
Characteristics of different novel oral anticoagulants
Characteristics
Dabigatran
Rivaroxaban
Edoxaban
Apixaban
Mechanism of action
Antithrombin
Antifactor Xa
Antifactor Xa
Anti-factor Xa
Bioavailability
3–7%
66% without food, 80–100% with food
50%
62%
Tmax (h)
1.5
2.5
3
1–5
T ½ (h)
12–17
5–9 (young)
11–13 (elderly)
12
10–14
Dosing
b.i.d
Once daily
b.i.d
Once daily
Clearance non renal (%)/renal of absorbed dose (%)
20/80
65/35
73/27
50/50
Liver metabolism: CYp3A4 involved
No
18%
25%
<4%
Absorption with food
No effect
+35% more (therefore needs to be taken with food)
No effect
6–22% more; minimal effect on exposure
Abbreviations: b.i.d., bis in die; Tmax, time to peak plasma level; T ½, half-life.
Risk of Direct Oral Anticoagulants–Related Gastrointestinal Bleeding in Randomized
Clinical Trials
The efficacy and safety of DOACs have been studied in several clinical trials and
risk of GIB depends on the DOAC regimen. The four landmark phase-III RCTs are summarized
in [Table 2 ].
Table 2
Major DOAC RCTs
Drug and dose compared with warfarin
Clinical trial
Relative risk and 95% IC
Dabigatran 150-mg twice daily
RE-LY
1.48 (1.18–1.85)
Dabigatran 110-mg twice daily
RE-LY
1.08 (0.85–1.38)
Rivaroxaban 20-mg once daily
ROCKET-AF
1.61 (1.30–1.99)
Apixaban 5-mg twice daily
ARISTOTELE
0.89 (0.70–1.15)
Edoxaban 60-mg once daily
ENGAGE-TIMI 48
1.23 (1.02–1,50)
Edoxaban 30-mg once daily
ENGAGE-TIMI 48
0.67 (0.53–0.83)
Abbreviations: CI, confidence interval; DOAC, direct oral anticoagulant; RCT, randomized
clinical trial.
RE-LY was an RCT in which warfarin was compared with dabigatran at twice-daily doses
of 110 and 150 mg, respectively.[17 ] In comparison with warfarin and dabigatran administered at a dose of 110 mg, dabigatran
150 mg twice daily was linked to an increased prevalence of GIB (hazard ratio [HR]:
1.48; 95% confidence interval [CI]: 1.18–1.85 and HR: 1.36; 95% CI: 1.09–1.70, respectively).
However, incidences of major GIB in patients given twice-daily doses of dabigatran
110 mg did not increase.[18 ]
The ROCKET-AF trial compared patients taking rivaroxaban at a dose of 20 mg daily
(reduced to 15 mg in cases of CrCl = 30–50 mL/min) with those taking warfarin. Results
indicated a greater prevalence of GIB, both major and minor, in those who were given
rivaroxaban (HR: 1.42; 95% CI: 1.22–1.66).[19 ] A second analysis of the ROCKET-AF trial revealed a higher incidence of major GIB
in patients aged 75 years or older: 2.81/100 patient-years versus 1.41 in those aged
below 75 years.[20 ]
The ARISTOTLE trial indicated that the rate of major bleeding with apixaban 20 mg
was 2.13% per year, as opposed to 3.09% per year in the group administered warfarin
group (HR: 0.69; 95% CI: 0.60–0.80). Respective death rates due to any cause were
3.5 and 3.9% (HR: 0.89; 95% CI: 0.80–0.99). The possibility of major GIB associated
with apixaban 20 mg was similar to that of warfarin, with advanced age increasing
the risk. In patients taking apixaban instead of warfarin, there was less of a risk
of nonmajor bleeding including GIB (HR: 0.69; 95% CI: 0.63–0.75).[21 ]
The ENGAGE AF-TIMI 48 trial studied the administration of edoxaban 60 mg daily, edoxaban
30 mg daily, and warfarin. The primary objectives of the study were the prevention
of stroke or systemic embolism, wherein neither dose of edoxaban was inferior to warfarin.
They were, however, linked to lower incidences of bleeding and death from cardiovascular
causes. High doses of edoxaban were linked to a higher annualized rate of major GIB
(1.51%) compared with warfarin (1.23%). However, the rate was lowest with low-dose
edoxaban (0.82%).[22 ]
The GIB risk of DOACs has been assessed in several systematic reviews and meta-analyses.
A meta-analyses of phase-III RCTs showed that, compared with warfarin, rivaroxaban
(risk ratio [RR]: 1.46; 95% CI: 1.2–1.8), high dosage of edoxaban (RR: 1.22; 95% CI:
1.01–1.47) and dabigatran (RR: 1.50; 95% CI: 1.20–1.88) significantly increased bleeding
while null effect was detected with apixaban.[23 ] Another meta-analysis pooled the results of 19 RCTs and was thus able to analyze
75,081 patients. It indicated a higher risk of GIB associated with DOACs in comparison
with standard care (RR: 1.45; 95% CI: 1.07–1.97).[24 ] The study was a standard and high-quality meta-analysis, including all available
RCTs. However, it was limited in two ways: first, both major and minor GIB were combined
in establishing the outcome, and second, acute coronary syndrome studies were included
in which controls were placebos and antiplatelet agents provided the basis for the
administration of DOACs. Such an approach ran the risk of producing biased results
and thus overestimating the risk of major GIB. An opposite result was reported in
a 2015 study by Caldeira et al[24 ]
[25 ] which used a precise definition of major GIB and pooled data by all indications.
AMPLIFY-EXT and RE-SONATE, two trials that compared the effects of DOACs with placebos,
were also included. The authors reported that there was no increased risk of major
GIB associated with any of the individual DOACs. It should be noted that different
controls (vitamin-K antagonists [VKAs], low molecular weight heparin [LMWH], aspirin,
and placebo) were used to obtain the results for each individual DOAC. This approach,
however, was restricted by a limited sample size in each subgroup, inevitably lessening
the statistical power of the results.
A more recent meta-analysis included a total of 43 randomized trials, totaling 166,289
patients. They showed no difference between DOACs and conventional anticoagulants
in the risk of major bleeding (1.5 vs. 1.3%, respectively; HR: 0.98; 95% CI: 0.80–1.21)
or clinically relevant nonmajor bleeding (0.6 vs. 0.6%, respectively; HR: 0.93; 95%
CI: 0.64–1.36). Dabigatran (2.0 vs. 1.4%, respectively; HR: 1.27; 95% CI: 1.04–1.55)
and rivaroxaban (1.7 vs. 1.3%, respectively; HR: 1.40; 95% CI: 1.15–1.70) were linked
with an increased likelihood of major GIB when compared with conventional anticoagulation.
However, no such difference was observed for apixaban (0.6 vs. 0.7%, respectively;
HR: 0.81; 95% CI: 0.64–1.02) or edoxaban (1.9 vs. 1.6%, respectively; HR: 0.93; 95%
CI: 0.78–1.11).[26 ] Therefore, the data indicate that an increased risk of GIB is associated with use
of dabigatran and rivaroxaban compared with warfarin. However, it should be noted
that the patients who participated in these trials had different numbers of comorbidities
and risk factors, thus a cautious approach to this conclusion is advisable.
Risk of Direct Oral Anticoagulants–Related Gastrointestinal Bleeding in Observational
Studies
Since the majority of RCTs adhered to stringent inclusion and exclusion criteria,
so as to include only those patients with a relatively low risk of GIB, it may not
be possible to generalize the results with respect to the general population. Furthermore,
RCTs that separately investigated GIB did so only for major GIB. Thus, the risk of
all GIB may have been underestimated.[24 ] Studies performed by Graham et al[27 ] and Hernandez et al[28 ] utilized population-based data which revealed that dabigatran was associated with
an increased rate of GIB relative to warfarin in patients with AF.
In a retrospective cohort study conducted by Hernandez et al, 1,302 patients taking
dabigatran were compared with 8,102 patients taking warfarin. The study analyzed four
subgroups of high-risk patients as follows: (1) those with chronic kidney disease,
(2) African American patients, (3) patients aged 75 years or over, and (4) patients
with seven or more concomitant comorbidities. Results indicated that all subgroups
were subject to a greater risk of major GIB (HR: 1.85; 95% CI: 1.64–2.07), highlighting
African American patients and patients with chronic kidney disease as those most at
risk.[28 ]
In a study by Abraham et al,[29 ] rivaroxaban or dabigatran was not found to differ when compared with warfarin, with
the exception of patients aged 75 years or over where both drugs were associated with
an increased risk of GIB. However, other studies indicated that these drugs did not
increase the risk.[30 ]
[31 ]
[32 ] In a recent propensity-matched cohort study in patients with AF, results revealed
that rivaroxaban, dabigatran, and apixaban were associated with increased, equivalent,
and decreased risks, respectively, when compared with warfarin.[33 ]
Several observational studies have compared the risk of GIB with respect to different
DOAC regimens. However, the results were limited due to several factors such as inconsistent
definition of GIB, selective bias as a result of the observational nature of the study,
lack of comparative study of all DOAC regimens, and it are often observed prescription
of lower doses of DOACs and poor adherence among patients. Therefore, it becomes difficult
to make a comparison between these results and those from meta-analysis.
The current data, when viewed together, indicate possible variability across DOACs
with regard to GIB risk. They also highlight increased probability of GIB associated
with rivaroxaban and dabigatran. However, such a link was not suggested for apixaban
or edoxaban. This potential difference in GIB risk has yet to be explained in terms
of biology. With respect to dabigatran, one possible cause could be the tartaric acid
coating which exerts a direct caustic effect on the intestinal lumen. DOACs have also
been shown to present some degree of intraluminal anticoagulant activity as a result
of incomplete absorption across the GI mucosa. This is not the case for warfarin,
which is almost completely absorbed and parenteral anticoagulants which are not taken
orally.[34 ] Such a hypothesis could be useful in explaining why dabigatran and rivaroxaban are
associated with an increased risk when compared with conventional therapy. However,
the difference among DOACs remains unclear. It should also be noted that, independent
of GIB risk, all four studied agents were associated with a lower risk of intracranial
bleed.
Risk Factors for Gastrointestinal Bleeding with Anticoagulants
Varying factors have been associated with a higher risk of major GIB in patients administered
DOACs. Observational studies and RCTs both commonly investigate risk factors, particularly
observational studies, due to the fact that high-risk patients are often left out
by RCTs.
Several studies suggest that patients aged 75 years or over were at a greater risk
of GIB associated with DOACs.[29 ]
[30 ]
[35 ]
[36 ] Since elimination of DOACs is dependent on renal excretion, there is a higher likelihood
of drug accumulation in patients with impaired renal function, and therefore a higher
risk of bleeding.[28 ] Patients with a past history of peptic ulcer disease or GIB are at a 2.3-fold increased
risk of GIB.[30 ] Another well-known risk factor is concomitant antiplatelet therapy.[30 ]
[37 ]
[38 ] Ethnicity was also established as a risk factor. This was observed in Chinese patients
administered dabigatran where a higher incidence rate of GIB (4.2 per 100 person-years)
was recorded.[39 ] This is in contrast to the lower incidence rate observed in western populations
(1.2–1.5 per 100 person-years in Denmark and 0.6 to 3.4 per 100 person-years in the
United States).[34 ]
[35 ] This difference could be explained by genetic factors, in particular, the V Leiden
mutation which is extremely rare in Asians.[40 ] A higher risk of GIB was also associated with liver cirrhosis (HR: 5.6; 95% CI:
1.7–18.8)[41 ] which increases the likelihood of both gastric or esophageal varices as a complication
of portal hypertension and coagulation function abnormalities, and thus GIB.
In a recent study, chronic obstructive pulmonary disease (COPD) was associated with
increased risk of GIB (HR: 4; 95% CI: 1.4–11.2), although the precise mechanism behind
this has yet to be explained. However, it is plausible that patients with COPD may
have a long history of smoking which is a known risk factor for acute GIB.[36 ]
[41 ] Analysis of data from 114,835 patients indicated that a higher risk of GIB was associated
with concomitant use of oral anticoagulants (OACs) and other gastrotoxic drugs when
compared with any of the drugs used alone: OAC + nonsteroidal anti-inflammatory drugs
(NSAIDs; RR: 8.7; 95% CI: 7.3– 10.4), OAC + aspirin (RR: 6.9; 95% CI: 5.9–8.2), and
OAC + COX-2 inhibitors (coxibs; RR: 5.0; 95% CI: 3.2–7.8).[42 ] When OACs are used concurrently with other drugs, such as gemfibrozil, a higher
risk of GIB was also observed (HR: 1.8; 95% CI: 1.4–2.4).[43 ] Anemia is often seen in patients with AF, and it could possibly be linked to a greater
risk of new-onset AF.[44 ]
[45 ] VKAs also put patients with anemia at a greater risk of bleeding.[46 ]
[47 ]
[48 ] However, majority of randomized controlled trials of DOACs have not included patients
with hemoglobin <10 g/dL.[17 ]
[21 ]
[24 ]
[49 ] Furthermore, the current guidelines contain no specific recommendation regarding
anticoagulant therapy in anemic patients with AF and hemoglobin <10 g/dL in current
guidelines.[2 ]
[50 ] A recent cohort study classified 8,356 patients with AF into two subgroups as follows:
(1) patients with hemoglobin ≥10 g/dL and (2) patients with hemoglobin <10 g/dL. Compared
with warfarin, DOACs were associated with a reduced risk of major bleeding or gastrointestinal
tract bleeding in patients with <10 g/dL (HR: 0.43; 95% CI: 0.30–0.62). However, no
such difference was observed in the incidence of ischemic stroke, systemic embolism,
or death in anemic (HR: 0.79; 95% CI: 0.53–1.17).[51 ] Heart failure (HF) and AF often coexist.[52 ] Patients with HF are at a higher risk of bleeding in comparison to non-HF controls.[53 ] A history of HF also serves as a greater predictor of major bleeding than of thromboembolic
risk.[54 ] The efficacy and safety outcomes of DOACs compared with warfarin in patients with
AF and HF have been examined by several studies. A meta-analysis conducted recently
observed no difference in HF and GIB (RR: 1.11; 95% CI: 0.79–1.55).[55 ]
Prevention of Gastrointestinal Bleeding Associated to Direct Oral Anticoagulants Treatment
Before DOACs are prescribed, a strategy should be implemented to minimize risk. Should
this fail, the identified risk factors should be considered so as to choose an appropriate
prescription and dose.
Initially, the bleeding risk in patients with AF taking warfarin was derived by using
the HAS-BLED (hypertension, abnormal liver/renal function, history of stroke, bleeding
tendency, labile international normalized ratios [INRs], elderly aged ≥65 years, and
drug/alcohol use; [Table 3 ]) score.[56 ]
[57 ] A score of ≥3 indicates a high-risk patient, with a score of 3, conferring 3.74
bleeding events per 100 patient years. It is important to recognize, however, that
patients with a greater risk of thromboembolism usually present one or more of the
comorbidities listed in the HAS-BLED criteria. They are therefore more predisposed
to bleeding. DOACs should not be prescribed until patients have been screened for
hepatic and kidney disease. In this way, a drug can be chosen which is compatible
with the patient's comorbidities ([Tables 4 ] and [5 ]). Drug interactions must be considered, as patients are commonly prescribed multiple
drugs. This is especially important with drugs that are metabolized via the cytochrome
P450 system and the P-gp efflux transporter. If possible, clarithromycin, fluconazole,
itraconazole, amiodarone, cimetidine, rifampicin, carbamazepine, phenobarbital, and
protease inhibitors should be not be used.[58 ] This is also the case with combinations of any anticoagulant used with NSAIDs and
coxibs. However, cases may arise where this is not possible. Should this occur, coxibs
are preferred to traditional NSAIDs.[59 ] A history of peptic ulcer may necessitate testing for Helicobacter pylori to prevent upper GIB. Proton pump inhibitor (PPI) treatment lowers the probability
of upper GIB,[60 ]
[61 ]
[62 ] but it is possible that the preventive effect of taking DOACs is not as great as
that observed when PPIs are given in conjunction with gastrotoxic drugs such as NSAIDs
or aspirin.[63 ]
[64 ] It has been suggested that PPIs potentially interact with anticoagulants due to
their shared liver metabolism via P450-cytocrome. However, this was ruled out in a
multicenter case-control study.[65 ] PPIs will not, however, prevent GIB from the lower GI tract, and further investigation
is warranted regarding the potentially negative effect they have on intestinal microbiota.[66 ]
Table 3
Items of HAS-BLED[56 ]
[57 ] bleeding risk score
Clinical characteristics
Definition
Points
Hypertension
Systolic blood pressure > 160 mm Hg
1
Abnormal liver or renal function
Chronic liver disease (e.g., cirrhosis) or biochemical evidence of significantly impaired
liver function (e.g., bilirubin > 2 times the ULN plus one or more liver enzymes > 3
times the ULN
Chronic dialysis, renal transplantation, or serum creatinine ≥ 200 µmol/L
1 or 2
Stroke
Previous history of stroke
1
Bleeding tendency or predisposition
Bleeding disorder or previous bleeding episode requiring hospitalization or transfusion
1
Labile INRs
Labile INRs in patients taking warfarin (failure to maintain a therapeutic range at
least 60% of the time)
1
Elderly
Age > 65 years
1
Drugs
Concomitant antiplatelet agents or NSAIDs excessive alcohol use (≥ 8 units per week)
1 or 2
Abbreviations: INR, international normalized ratio; NSAID, nonsteroidal anti-inflammatory
drugs; ULN, upper limit of normal.
Table 4
Use of DOACs according to renal function
CrCl
Dabigatran
Rivaroxaban
Edoxaban
Apixaban
≥50 mL/min
2 × 150 mg
20 mg
60 mg
2 × 5 mg or 2 × 2.5 mg[a ]
50–30 mL/min
2 × 150 mg or 2 × 110 mg[b ]
15 mg
30 mg
2 × 5 mg or 2 × 2.5 mg[a ]
30–15 mL/min
No
15 mg
30 mg
2 × 2.5 mg
Dialysis
No
No
No
No
Abbreviations: CrCl, creatinine clearance; DOAC, direct oral anticoagulant.
Note: 2 × 2.5 mg only if at least two out of the following three: age ≥ 80 years,
body weight ≤ 60 kg, and/or creatinine ≥ 1.5 mg/dL.
a 2 × 110 mg in patients at high risk of bleeding.
b Other dose reduction criteria may apply (weight ≤ 60 kg, concomitant potent P-Gb
inhibitor therapy).
Table 5
Use of DOACs in liver failure
Child–Pugh category
Dabigatran
Rivaroxaban
Edoxaban
Apixaban
A
No dose reduction
No dose reduction
No dose reduction
No dose reduction
B
Use with caution
Do not use
Use with caution
Use with caution
C
Do not use
Do not use
Do not use
Do not use
Abbreviation: DOAC, direct oral anticoagulant
Location of Gastrointestinal Bleeding: Upper versus Lower
The lower GI tract is a common source of GIB in DOAC users.[67 ] In a post hoc analysis of patients experiencing GIB during RELY, 47% of patients
taking dabigatran 110-mg twice daily and 47% of patients taking dabigatran 150-mg
twice daily were noted to have experienced lower GI bleeding. In contrast, only 25%
of warfarin-associated GIB was from the lower tract.[35 ] Dabigatran appears to increase the risk of lower GIB compared with warfarin. A retrospective
study found a 30% increased risk of lower GIB with dabigatran (HR: 1.30; 95% CI:1.04–1.62).[68 ] In the ROCKET-AF trial, patients taking rivaroxaban had similar rates of upper and
lower GIB as patients on warfarin: 48 and 47% of rivaroxaban and warfarin users, respectively,
had upper GIB; 22 and 24% had lower GIB, respectively; and 30 and 29% had rectal bleeding,
respectively.[4 ] Similarly, in a postmarket retrospective cohort study of GIB in anticoagulated patients,
57% of patients taking rivaroxaban were found to have a lower GI source, as were 75%
of the patients taking dabigatran.[69 ]. In ARISTOTLE, the most frequent specified site of major bleeding in patients taking
apixaban was the digestive tract. Apixaban showed similar rates in terms of the location
of bleeding; the event rate for upper versus lower GI bleeds in patients taking apixaban
was 0.43 per 100 patient-years versus 0.25 per 100 patient-years. The event rate for
upper versus lower GI bleeds in patients taking warfarin was 0.56 per 100 patient-years
versus 0.24 per 100 patient-years.[37 ] In the ENGAGE-AF-TIMI trial, the annualized rate of major bleeding events was 3.43%
with warfarin versus 2.75% with high-dose edoxaban and 1.61% with low-dose edoxaban.
The corresponding rates for upper GIB were 0.71, 0.91, and 0.56 with warfarin, high-dose
edoxaban, and low-dose edoxaban, respectively; these rates were 30 to 50% higher than
those reported for lower GIB (0.52, 0.62, and 0.28, respectively).[22 ]
Management of Direct Oral Anticoagulants Therapy after a Gastrointestinal Bleeding
Episode
Patients taking DOACs who present with overt, nonmajor GIB require specific management
consisting of drug cessation and endoscopic management.[34 ]
[70 ]
[71 ] Should a non–life-threatening major bleeding event occur in patients with normal
renal function, plasma levels of DOACs should normalize within 12 to 24 hours, although
patients with renal insufficiency may require more time, particularly for dabigatran.[34 ]
[50 ] In cases of severe bleeding and/or hemodynamic instability, options may include
activated charcoal, hemodialysis/hemoperfusion, and reversing anticoagulation.
If the last dose of DOAC is given within 2 hours, activated charcoal can be used to
reduce intestinal absorption of residual drug. This potential benefit must be weighed
against subsequent impairment of endoscopic visualization.[72 ] Should life-threatening GIB or renal failure occur, hemodialysis or hemoperfusion
could also be considered for dabigatran.[73 ] However, they should not be used for direct factor Xa inhibitors due to the fact
they are highly protein bound.[71 ] Nonspecific reversal agents include prothrombin complex concentrates (PCCs; either
weight based three-factor or four-factor PCCs), activated (aPCCs) and recombinant
factor VIIa (rFVIIa), although they have been shown to increase the risk of thromboembolism.[74 ]
[75 ] However, a recent study has demonstrated that four-factor PCCs possess a similar
safety profile when compared with fresh frozen plasma in terms of thromboembolic events
(around 7%) and deaths.[75 ] Due to their uncertain efficacy and potential risk of thromboembolism, these agents
should only be administered in the following situations: life-threatening GIB, ongoing
bleeding despite standard measures, or delayed clearance of DOACs in patients with
renal failure.[70 ] Availability of PCC and aPCC, as well as the experience of the treatment center,
generally determine which is used. This is particularly true in the case of aPCC which,
since it induces a strong procoagulant effect, should only be administered by physicians
with prior experience in its use. PCC and aPCC are preferred over rFVIIa due to the
absence of outcome data and the latter's strong procoagulant effect.[76 ]
[77 ] Antifibrinolytic agents (tranexamic acid) have been used to manage DOAC-related
GIB, particularly in cases of severe bleeding where many factors of the coagulation
cascade are often deficient, but the experience is still limited.[70 ]
[78 ] Specific reversal agents have also been developed. Idarucizumab is a humanized monoclonal
antibody fragment (Fab) against dabigatran which has been shown to be capable of rapidly
reversing the anticoagulation activity of dabigatran within minutes in almost all
patients.[79 ] Andexanet alfa is a recombinant modified human factor Xa decoy protein which functions
as a universal factor Xa reversal agent by binding to the factor Xa inhibitors.[70 ] It has been shown to greatly reverse antifactor Xa activity and promote hemostasis
in approximately 80% of patients with acute major bleeding.[79 ] The severity of GIB and patients' hemodynamic status determines the timing of endoscopy.
In situations of mild GIB, it is possible to defer endoscopic evaluation for 12 to
24 hours.[31 ]
[75 ]
[80 ] This delayed approach presents many advantages, such as increasing effectiveness
of endoscopic intervention once the drug effects have worn off, increasing safety
in a nonemergency setting, and improving endoscopic visualization due to attenuation/cessation
of bleeding and better colonic cleansing. However, patients who either have GIB or
hemodynamically unstable should undergo emergency endoscopy promptly after resuscitation.
If endoscopic management fails, radiological and/or surgical interventions should
be considered as a last resort.[81 ] It is possible to restart nuisance or minor bleeding anticoagulation in the majority
of cases, sometimes done by delaying or skipping a single dose. In other cases of
bleeding, particularly those which are life-threatening, careful reassessment of the
risks and benefits or restarting anticoagulation is required. Specific data regarding
restarting DOAC after GIB is lacking, thus there is an absence of randomized data
on restarting medication post-GIB. The benefits and risks of resuming anticoagulant
therapy following GIB were examined in a meta-analysis performed by Chai-Adisaksopha
et al[82 ] which involved the selection of three studies, including patients on warfarin for
various reasons. Where warfarin was resumed (in 53% of patients), a substantial reduction
in thromboembolic events (9.9 vs. 16.4%, HR: 0.68; 95% CI: 0.52–0.88) and mortality
(24.6 vs. 39.2%, HR: 0.76; 95% CI: 0.66–0.88) was observed. However, it also revealed
a numerically increased rate of recurrent GIB in cases where warfarin was resumed
(10.1 vs. 5.5%, HR: 1.20; 95% CI: 0.97–1.48; p = 0.10). The risk greatly increased where warfarin was resumed within 7 days as opposed
to resuming later. In accordance with these findings, the European Society of Gastrointestinal
Endoscopy (ESGE) guideline recommends that patients taking DOAC with moderate-to-severe
GIB cease DOAC and resume 7 to 15 days after the GIB episode. Patients at an increased
thrombotic risk, such as those with mechanical heart valve, cardiac assist device,
or CHA2 DS2-VASc score ≥4 may benefit from earlier (first week) resumption.[83 ] However, many additional factors should also be considered. This is especially true
in situations of severe and life-threatening bleeding without an obvious secondary
or reversible/treatable cause, where the potential benefits may not be worth the risks
of resuming anticoagulation. Should such a case arise, implantation of a left atrial
appendage (LAA) occluder, or surgical LAA occlusion may represent a potential substitute
for long-term anticoagulation. LAA occlusion appears to be a promising option for
AF patients who are not candidates for long-term OAC. Recently increasing evidence
of the utility of LAA occlusion in patients who are not candidates for long-term oral
anticoagulation. Long-term data from two continued access registries, PROTECT-AF[84 ] and PREVAIL,[85 ] to support LAA occlusion as a safe and effective long-term anticoagulation therapy.
This new evidence led to class-IIb recommendation for left atrial appendage occlusion
(LAAO) in nonvalvular atrial fibrillation patients not eligible for long-term OAC.
PRAGUE-17 randomized controlled trial showed LAA occlusion is noninferior to DOAC.[86 ] Additionally, a lower dose or apixaban should be considered for patients with GIB
while on DOAC[2 ] ([Fig. 1 ]).
Fig. 1 Management of anticoagulant therapy after major gastrointestinal bleeding. GI, gastrointestinal;
LAA, left atrial appendage; NOAC, non–vitamin K antagonist oral anticoagulants; PCI,
percutaneous coronary intervention.
