American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: Management of Anticoagulants and ...
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CLINICAL GUIDELINES 1 American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period Neena S. Abraham, MD, MSc (Epi), FACG1, Alan N. Barkun, MD, MSc (Epi), FACG, CAGF2, Bryan G. Sauer, MD, MSc (Clin Res), FACG3, James Douketis, MD4, Loren Laine, MD, FACG5,6, Peter A. Noseworthy, MD7, Jennifer J. Telford, MD, MPH, FACG, CAGF8 and Grigorios I. Leontiadis, MD, PhD, CAGF9 We conducted systematic reviews of predefined clinical questions and used the Grading of Recommendations, Assessment, Development and Evaluations approach to develop recommendations for the periendoscopic management of anticoagulant and antiplatelet drugs during acute gastrointestinal (GI) bleeding and the elective endoscopic setting. The following recommendations target patients presenting with acute GI bleeding: For patients on warfarin, we suggest against giving fresh frozen plasma or vitamin K; if needed, we suggest prothrombin complex concentrate (PCC) compared with fresh frozen plasma administration; for patients on direct oral anticoagulants (DOACs), we suggest against PCC administration; if on dabigatran, we suggest against the administration of idarucizumab, and if on rivaroxaban or apixaban, we suggest against andexanet alfa administration; for patients on antiplatelet agents, we suggest against platelet transfusions; and for patients on cardiac acetylsalicylic acid (ASA) for secondary prevention, we suggest against holding it, but if the ASA has been interrupted, we suggest resumption on the day hemostasis is endoscopically confirmed. The following recommendations target patients in the elective (planned) endoscopy setting: For patients on warfarin, we suggest continuation as opposed to temporary interruption (1–7 days), but if it is held for procedures with high risk of GI bleeding, we suggest against bridging anticoagulation unless the patient has a mechanical heart valve; for patients on DOACs, we suggest temporarily interrupting rather than continuing these; for patients on dual antiplatelet therapy for secondary prevention, we suggest temporary interruption of the P2Y12 receptor inhibitor while continuing ASA; and if on cardiac ASA monotherapy for secondary prevention, we suggest against its interruption. Evidence was insufficient in the following settings to permit recommendations. With acute GI bleeding in patients on warfarin, we could not recommend for or against PCC administration when compared with placebo. In the elective periprocedural endoscopy setting, we could not recommend for or against temporary interruption of the P2Y12 receptor inhibitor for patients on a single P2Y12 inhibiting agent. We were also unable to make a recommendation regarding same-day resumption of the drug vs 1–7 days after the procedure among patients prescribed anticoagulants (warfarin or DOACs) or P2Y12 receptor inhibitor drugs because of insufficient evidence. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/C416, http://links.lww.com/AJG/C417, and http://links.lww.com/AJG/C418. Am J Gastroenterol 2022;00:1–17. https://doi.org/10.14309/ajg.0000000000001627; published online XXX INTRODUCTION (DOACs; apixaban, dabigatran, edoxaban, and rivaroxaban), Antithrombotic drugs including vitamin K antagonists (VKAs; antiplatelet drugs such as the P2Y12 receptor inhibitors (clopi- warfarin and acenocoumarol), direct oral anticoagulants dogrel, prasugrel, and ticagrelor), and acetylsalicylic acid (ASA) 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA; 2Division of Gastroenterology, Department of Medicine, McGill University, Montreal, Quebec, Canada; 3Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA; 4Department of Medicine, St. Joseph’s Healthcare Hamilton and McMaster University, Hamilton, Ontario, Canada; 5Yale School of Medicine, New Haven, Connecticut, USA; 6Virginia Connecticut Healthcare System, West Haven, Connecticut, USA; 7Department of Cardiovascular Diseases, Electrophysiology, Mayo Clinic, Rochester, Minnesota, USA; 8 Division of Gastroenterology, Department of Medicine, St. Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada; 9Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. This article is being published jointly in The American Journal of Gastroenterology and the Journal of Canadian Association of Gastroenterolgy. Correspondence: Neena S. Abraham, MD, MSc (Epi), FACG. E-mail: abraham.neena@mayo.edu. Received August 9, 2021; accepted November 28, 2021 Copyright © 2022 The American College of Gastroenterology and the Canadian Association of Gastroenterology. The American Journal of GASTROENTEROLOGY
2 Abraham et al.
are used in the management of patients with atrial fibrillation, gastroenterologists who served as the GRADE methodologists
ischemic heart disease, venous thromboembolism, and valvular (G.I.L. and B.S.). No patients were included in the guideline
heart disease. These drugs also increase the risk of gastrointestinal process. The panel developed, prioritized, and finalized the
(GI) bleeding from luminal sources such as ulcers or diverticula clinical questions in Population, Intervention, Comparator, and
and after endoscopic procedures (1–3). Standardized, evidence- Outcome (PICO) format through teleconferences before sys-
based protocols are lacking to inform best practices before and tematic literature reviews. The critical outcomes were 7-day
after endoscopic procedures in urgent and elective settings. further bleeding and 30-day thrombotic events for patients with
Furthermore, uncertainty regarding best practice recommenda- acute GI bleeding and 30-day bleeding and 30-day thrombotic
tions and associated levels of evidence has led to significant var- events after elective endoscopic procedures. The final PICO
iation in adherence to guideline-directed practices (4). questions were shared with the leadership of the ACG Practice
The American College of Gastroenterology (ACG) and the Parameters Committee and the CAG Clinical Affairs Committee.
Canadian Association of Gastroenterology (CAG) convened an The editorial office of the Cochrane Gut Group at McMaster
international, multisociety, and multidisciplinary working group University developed and ran searches in MEDLINE, EMBASE,
to create a focused, pragmatic guideline after distillation of pub- and CENTRAL for randomized controlled trials (RCTs), con-
lished literature to inform clinical practice in the periendoscopic trolled or uncontrolled observational studies, and systematic re-
period. In keeping with the Grading of Recommendations, As- views of any study design published in the English language as full
sessment, Development and Evaluations (GRADE) approach (5), text (conference abstracts were not included) between January 1,
the most pertinent clinical questions guided the systematic review 1995 (January 1, 1985, for some searches), and August 13, 2020.
of the literature, with the resulting rigorous methodological eval- Full details of search strategies can be found in Supplementary
uation of the available published data informing recommenda- Digital Content (see Appendix 1, http://links.lww.com/AJG/
tions. In this document, we propose an evidence-based approach to C416). Each identified abstract was screened for eligibility in
periprocedural antithrombotic drug management in common duplicate by at least 2 of the 4 voting gastroenterologists. Po-
emergent and elective settings addressing clinical questions related tentially eligible studies were assessed as full-text articles by the
to (i) temporary interruption of anticoagulant and antiplatelet GRADE methodologists or 1 of the 4 voting gastroenterologists.
drugs; (ii) reversal of anticoagulant and antiplatelet drugs; (iii) A GRADE methodologist verified data extraction. An evidence
periprocedural heparin bridging; and (iv) postprocedural re- map was prepared for each PICO question. The panel reviewed
sumption of anticoagulant and antiplatelet drugs. the preliminary evidence map, proposed additional articles, and
This document does not cover all possible clinical situations assisted in supplementary literature searches targeting broader
where multidisciplinary guidance may be necessary to manage populations when gaps in the evidence were identified. Where
periendoscopic antithrombotic therapy. Nor does it address the appropriate, more recent publications available after the formal
rapidly evolving menu of endoscopic approaches developed to literature search and evidentiary review are discussed for con-
minimize intraprocedural and postprocedural bleeding in situa- textual information if deemed to provide critical additional
tions such as removing large colonic polyps (6). Because of in- contemporary insight.
sufficient evidence, the panel could not recommend a best The 2 GRADE methodologists prepared assessments of the
practice for all clinical questions. These clinical situations are risk of bias of each included study and developed complete evi-
identified as priorities for future research. dence reports, including a summary of evidence tables (see Ap-
pendix 2, Supplementary Digital Content, http://links.lww.com/
METHODS AJG/C417). The certainty of the evidence for each PICO question
These guidelines are established to support clinical practice and was categorized as very low, low, moderate, or high depending on
suggest preferable approaches to a typical patient with a particular the assessment of (i) limitations in the design and execution of the
medical problem based on the currently available published lit- studies, (ii) indirectness, (iii) inconsistency, (iv) imprecision, and
erature. When exercising clinical judgment, particularly when (v) other considerations including publication bias, according to
treatments pose significant risks, healthcare providers should the GRADE approach (7,8). Manuscripts initially deemed po-
incorporate this guideline in addition to patient-specific medical tentially eligible but eventually excluded are listed in Supple-
comorbidities, health status, and preferences to arrive at a patient- mentary Digital Content (see Appendix 3, http://links.lww.com/
centered care approach. AJG/C418) with reasons for exclusion. Each GRADE method-
The methods for this guideline were agreed on a priori by the ologist, in turn, prepared half of the evidence reports, whereas the
ACG and the CAG with the express intent to codevelop high- other methodologist double-checked them, providing feedback
quality multisociety guidelines that reduce duplication of effort until agreement was achieved. For each PICO, 3 versions of the
and improve impact. The methods have followed the GRADE wording of the potential recommendation were prepared a priori
approach (5). The target population of this guideline is patients (in favor, against, or unable to recommend). The opinions of
receiving anticoagulants or antiplatelet drugs who are (i) hospi- individual content experts were sought for specific issues. The
talized or under observation with acute GI bleeding or (ii) un- evidence reports and risk of bias tables were shared with the whole
dergoing inpatient or outpatient elective GI endoscopic panel on April 16, 2021, and discussed by email. The finalized
procedures. The target audience for this guideline includes document was shared before the voting videoconference meet-
healthcare providers, public health policymakers, patients, and ings on May 8 and 15, 2021.
caregivers. One cochair (A.N.B.) and 1 GRADE methodologist (G.I.L.)
The guideline panel was led by 2 gastroenterology cochairs moderated the voting videoconference meetings. For each PICO,
(N.S.A. and A.N.B.). It included 6 voting content experts—4 the GRADE methodologist presented a summary of the evidence,
gastroenterologists (N.S.A., A.N.B., L.L., and J.T.), 1 cardiolo- including the direction and magnitude of effect for desirable and
gist (P.A.N.), 1 thrombosis expert (J.D.), and 2 nonvoting undesirable outcomes and the certainty of the evidence. After
The American Journal of GASTROENTEROLOGY VOLUME 00 | MONTH 2022 www.amjgastro.comACG-CAG Clinical Practice Guideline 3
Table 1. Guideline statements, the strength of recommendation, Table 2. Guideline statements, the strength of recommendation,
and certainty of the evidence for the management of and certainty of the evidence for the management of
antithrombotic agents in the setting of acute GI bleed antithrombotic agents in the elective endoscopy setting
Management of antithrombotic agents in the setting of acute GI bleed Management of antithrombotic agents in the elective endoscopy setting
Vitamin K antagonist reversal Anticoagulant interruption vs continuation
1. For patients on warfarin who are hospitalized or under observation with 11. For patients on warfarin undergoing elective/planned endoscopic GI
acute GI bleeding, we suggest against FFP administration (conditional procedures, we suggest warfarin be continued, as opposed to temporarily
recommendation, very low certainty of evidence). interrupted (1–7 d) (conditional recommendation, very low certainty of
2. For patients on warfarin who are hospitalized or under observation with evidence).
acute GIB, we could not reach a recommendation for or against PCC 12. For patients on warfarin, who hold warfarin in the periprocedural
administration. period for elective/planned endoscopic GI procedures, we suggest against
3. For patients on warfarin who are hospitalized or under observation with bridging anticoagulation (conditional recommendation, low certainty of
acute GIB, we suggest PCC administration compared with FFP evidence).
administration (conditional recommendation, very low certainty of 13. For patients on DOACs who are undergoing elective/planned
evidence). endoscopic GI procedures, we suggest temporarily interrupting DOACs
4. For patients on warfarin who are hospitalized or under observation with rather than continuing DOACs (conditional recommendation, very low
acute GIB (upper and/or lower), we suggest against the use of vitamin K certainty of evidence).
(conditional recommendation, very low certainty of evidence). Antiplatelet interruption vs continuation
Direct thrombin inhibitor reversal (dabigatran) 14a. For patients on dual antiplatelet therapy for secondary prevention
5. For patients on dabigatran who are hospitalized or under observation who are undergoing elective endoscopic GI procedures, we suggest
with acute GIB, we suggest against the administration of idarucizumab temporary interruption of the P2Y12 receptor inhibitor while continuing
(conditional recommendation, very low certainty of evidence). ASA (conditional recommendation, very low certainty of evidence).
Reversal of rivaroxaban/apixaban with andexanet alfa 14b. For patients on single antiplatelet therapy with a P2Y12 receptor
inhibitor who are undergoing elective endoscopic GI procedures, we
6. For patients on rivaroxaban or apixaban who are hospitalized or under
could not reach a recommendation for or against temporary interruption of
observation with acute GIB, we suggest against andexanet alfa administration
the P2Y12 receptor inhibitor.
(conditional recommendation, very low certainty of evidence).
15. For patients on ASA 81–325 mg/d (i.e., cardiac ASA monotherapy) for
Reversal of direct oral anticoagulant with PCC
secondary prevention, we suggest against interruption of ASA (conditional
7. For patients on DOACs who are hospitalized or under observation with recommendation, very low certainty of evidence).
acute GIB, we suggest against PCC administration (conditional
Timing of anticoagulant resumption after endoscopy
recommendation, very low certainty of evidence).
16. In patients who are undergoing elective endoscopic GI procedures
Reversal of antiplatelet with platelet transfusion
whose warfarin was interrupted, we could not reach a recommendation for
8. For patients on antiplatelet agents who are hospitalized or under or against resuming warfarin the same day vs 1–7 d after the procedure.
observation with acute GIB, we suggest against platelet transfusions
17. In patients who are undergoing elective endoscopic GI procedures whose
(conditional recommendation, very low certainty of evidence).
DOAC was interrupted, we could not reach a recommendation for or against
Holding ASA vs continuing ASA resuming the DOAC on the same day of the procedure vs 1–7 d after the
9. For patients with GI bleeding on cardiac ASA for secondary prevention, we procedure.
suggest against holding the ASA (conditional recommendation, very low Timing of P2Y12 inhibitor resumption after endoscopy
certainty of evidence).
18. In patients who are undergoing elective endoscopic GI procedures
Resumption of ASA after endoscopic hemostasis whose P2Y12 inhibitor was interrupted, we could not reach a
10. For patients with GI bleeding on ASA for secondary cardiovascular recommendation for or against resuming P2Y12 inhibitor on the same day
prevention whose ASA was held, we suggest the ASA be resumed on the of the procedure vs 1–7 d after the procedure.
day hemostasis is endoscopically confirmed (conditional ASA, acetylsalicylic acid; DOAC, direct oral anticoagulant; GI, gastrointestinal.
recommendation, very low certainty of evidence).
ASA, acetylsalicylic acid; FFP, fresh frozen plasma; DOAC, direct oral anticoagulant;
GI, gastrointestinal; GIB, GI bleeding; PCC, prothrombin complex concentrate.
dissenting opinions. The 6 voting panel members then voted on
the direction of the recommendation (in favor vs against) for that
which, the panel discussed results. All domains of the Evidence- PICO question with its corresponding wording. The pre-
to-Decision Framework (9), including the certainty of evidence determined threshold vote for consensus was 75% (i.e., 5 of 6
on the balance between desirable and undesirable outcomes, ev- panel members). If consensus was not reached, the topic was
idence and assumptions about patient values and preferences, further discussed, and reasons for disagreement were sought, with
feasibility, acceptability, and resource use associated with alter- the panel voting for a second time. If the 75% threshold could still
native management options, were reviewed, agreed on, summa- not be reached, the conclusion that “we could not reach a rec-
rized, and tabulated in real time for the PICO question being ommendation for or against” the intervention was assigned to
assessed (7,9). Notes were taken with regards to qualifiers and that PICO question.
Copyright © 2022 The American College of Gastroenterology and the Canadian Association of Gastroenterology. The American Journal of GASTROENTEROLOGY4 Abraham et al.
If the 75% threshold was reached, provided the certainty of the Summary of evidence. For this recommendation, no eligible
evidence was moderate or high, panel members intended to discuss studies specifically addressing patients with GI bleeding were
and vote on the strength of recommendation (strong vs condi- identified by literature searches. The observational studies
tional). If 75% of the members voted for strong, the recommen- identified were cohort studies without a comparator arm, or
dation would begin with “we recommend that ….” Strong the study did not report separate results for clinical outcomes
recommendations imply that most informed patients would in patients with GI bleeding. It is thus not possible to infer with
choose the recommended course of action, and clinicians should any certainty whether administering FFP can benefit, harm, or
provide it to most patients (7). If less than 75% of the members make no difference in these patients compared with no
voted for strong, the recommendation would be considered con- reversal.
ditional and began with the words “we suggest that….” Conditional Pertinent studies included a small cohort of 41 warfarin-
recommendations indicate that most individuals in this situation treated patients requiring rapid reversal (12), with 12 receiving
would want the suggested course of action. Still, others would not, FFP, 29 receiving clotting factor concentrates, and all receiving
and clinicians should help each patient make decisions consistent vitamin K 1–5 mg intravenously. No clinical outcomes were
with their risks, values, and preferences, ideally using decision aids. measured, but in the 12 patients given FFP, the international
Recommendations with low or very low certainty of evidence were normalized ratio (INR) did not normalize (range 1.6–3.8,
designated as conditional by default (without voting on the mean 2.3), indicating an ongoing anticoagulated state in all
strength), although such recommendations could have still been patients. In a case-control study of 267 patients with major
considered as strong if they had fulfilled criteria for 1 of the 4 bleeding prescribed VKA for venous thromboembolism, 78
“paradigmatic situations” (10). A search of contemporary studies patients had GI bleeding, but no results were reported for the
and recent systematic reviews was also performed and detailed in GI bleeding outcomes (13). In a multivariable analysis that
the evidence profile to inform the panel deliberations concerning failed to adjust sufficiently for confounding, FFP use was as-
the preferences of providers and patients for a cardiovascular event sociated with a higher risk of thrombotic events (OR: 4.22; 95%
vs a GI bleeding event (see Appendix 2, Supplementary Digital CI: 1.25–14.3) (13).
Content, http://links.lww.com/AJG/C417 pages 3–6). Three additional RCTs which lacked the comparator of in-
Each voting panel member, including the 2 cochairs, prepared terest (i.e., placebo) provide cohort-type data that further in-
a draft for designated sections after the voting videoconference form this recommendation. Sarode et al. randomized 202
meeting. The 2 cochairs subsequently edited and merged these patients on a VKA with an INR $2.0 and major bleeding to FFP
into a single manuscript. The final version was reviewed and (n 5 104) vs 4-factor prothrombin complex concentrate (PCC),
approved unanimously. The final manuscript was peer-reviewed while both arms received vitamin K (5–10 mg intravenously). In
by the ACG Practice Parameters Committee, CAG Clinical Af- the FFP arm, 58 patients had GI bleeding with excellent or good
fairs Committee, the ACG Board of Trustees, the CAG chair of hemostatic efficacy achieved in 75.9% (14). Additional outcome
Clinical Practice, the CAG vice president for Clinical Affairs, the measures were reported only for all-cause bleeding and included
CAG Board of Directors, and the CAG membership at large (to thrombotic events in 7 of 109, mortality in 6 of 103, rapid INR
whom the document was made available for 2 weeks). For each reduction in 10 of 109, and fluid overload after 10–45 days in 14
PICO question, the evidence table that summarizes the data and of 109. Smaller RCTs by Steiner et al. (15) (N 5 50, 23 in the FFP
the grading of that evidence is in Supplementary Digital Content arm) and Boulis et al. (16) (N 5 13, 8 in the FFP arm) assessed
(see Appendix 2, http://links.lww.com/AJG/C417). A complete patients with intracranial hemorrhage, reporting thromboem-
list of guideline statements, the strength of recommendation, and bolic events in 2 of 23 and 1 of 8 patients, respectively, and an
the certainty of the evidence is found in Tables 1 and 2. INR #2 within 3 hours of treatment in 2 of 23 patients; signif-
icant complications from fluid overload were noted in 5 of 8
GUIDELINE STATEMENTS patients.
Management of antithrombotic agents in the setting of acute Conclusions. Although there is biological plausibility of FFP
GI bleeding administration to reverse VKA in patients with GI bleeding, there
The first 10 guideline statements address the management of antith- exists only very low certainty evidence, given serious concerns of
rombotic agents in the setting of acute GI bleeding. Acute GI bleeding is risk of bias, imprecision, and indirectness. The panel also con-
defined as patients hospitalized or under observation with acute overt sidered the low cost of FFP, relevant patient utilities, and the
GI bleeding (upper and/or lower) manifesting as melena, hema- potential increased risk of transmission of infectious agents with
tochezia, or hematemesis. Life-threatening hemorrhage is defined as FFP administration. The panel suggested that FFP should not be
major clinically overt or apparent bleeding, resulting in hypovolemic used routinely but could be considered for patients with a life-
shock or severe hypotension requiring pressors or surgery; or associ- threatening GI bleed or a supratherapeutic INR substantially
ated with a decrease in hemoglobin of .5 g/dL, or requiring trans- exceeding the therapeutic range. Its use could also be considered
fusion of $ 5 units of packed red blood cells, or causing death (11). in those for whom massive blood transfusion is undesirable
because of its effect on coagulopathy or dilution of blood
VKA reversal. components when PCC is unavailable (see below).
1. For patients on warfarin who are hospitalized or under observation
with acute GI bleeding, we suggest against fresh frozen plasma (FFP) 2. For patients on warfarin who are hospitalized or under observation
administration (conditional recommendation, very low certainty of with acute GI bleeding, we could not reach a recommendation for or
evidence). against prothrombin complex concentrate administration.
The American Journal of GASTROENTEROLOGY VOLUME 00 | MONTH 2022 www.amjgastro.comACG-CAG Clinical Practice Guideline 5
Summary of evidence. The panel made an a priori decision to 0.55–2.00). However, the study’s definition of successful hemo-
consider 3-factor PCC and 4-factor PCC equivalent for the stasis allowed for up to 2 additional units of blood products after
intervention (PCC for reversal of warfarin and other VKAs). No receiving FFP or PCC. It did not report whether this coin-
eligible studies were identified exclusively in patients with GI tervention differed between the 2 groups. Furthermore, a higher
bleeding. A backward (snowballing) citation search of previous proportion of patients in the FFP arm received vitamin K, in-
guidelines was used to identify supporting evidence, including cluding intravenously.
noncomparative cohort data derived from the PCC arms of 2 A prospective cohort study of patients with acute upper GI
RCTs that compared PCC vs FFP (14,15). We also considered a bleeding who received intravenous vitamin K and either FFP or
cohort study of GI patients, which provided clinical outcomes and PCC found that the absolute risk of further bleeding was nu-
results on the indirect outcome of INR reversal (17). This study merically lower in the PCC arm with zero of 20 patients di-
was regarded as noncomparative data with the inclusion of the agnosed with bleeding compared with 7 of 20 patients (35%) in
PCC group only. the FFP arm but without statistical significance (RR 0.07, 95%
From 7 studies, there were 223 patients on warfarin, all ex- CI: 0–1.09) (17). An additional 3 patients in the FFP arm de-
periencing major bleeding and treated with PCC (14,15,17–21). veloped recurrent bleeding, but it was unclear whether these 3
Of these, 38.6% had GI bleeding. All patients received 4-factor patients were independent of the 7 patients already attributed.
PCC at various doses, with vitamin K administered to most pa- Regardless, their inclusion would not change the direction of the
tients. Further bleeding was observed in 25.5%, with a 7.2% in- effect nor certainty of evidence.
cidence of thrombotic events and 30-day mortality of 7.0% The risk of thromboembolic events in patients on warfarin ran-
(14,15,17–21). One study estimated transfusion-related events domized to receive either FFP or PCC was evaluated in 2 studies. In 1
(fluid overload) of 4.9% within 7 days of PCC use (14). All studies study, the bleeding site was intracranial, whereas in the second study,
demonstrated consistently rapid INR reduction of a large mag- the bleeding site varied and included GI bleeding in some patients
nitude. Given the pharmacodynamics of warfarin treatment, it (14,15). Combining results from both studies, although not signifi-
was implausible that this dramatic INR change could have oc- cant, the absolute risk of thromboembolic events was numerically
curred because of bias, confounding, or chance. higher in the PCC arm (RR 5 1.60, 95% CI: 0.70–3.62), whereas the
Studies were downrated for serious or very serious risk of bias 30-day mortality (RR 5 0.64, 95% CI: 0.17–2.49) and transfusion-
(no comparator cohorts), indirectness of the outcome (“hemo- related adverse events (1 transfusion-related anaphylaxis in the FFP
static efficacy” or active bleeding visualized at the time of en- group) (14) were numerically lower in the PCC arm. Both studies
doscopy), and the concomitant use of vitamin K. The small demonstrated a more rapid INR reduction in patients receiving PCC
number of events contributed to serious imprecision. Only a than FFP (RR 5 6.99, 95% CI: 3.61–13.53). The heterogeneous study
small proportion of the patients had GI bleeds, although the type populations, variability in outcome definition and timing of assess-
of bleed would not have influenced the effect of PCC on the INR. ment, and the wide confidence intervals for clinical outcomes led to a
Finally, the speed of INR correction is a surrogate outcome, not a very low certainty of evidence.
clinical outcome.
Conclusions. The effect of PCC compared with FFP on further
Conclusions. There is insufficient evidence to judge the balance GI bleeding in patients on warfarin is unknown; however, the
between desirable and undesirable effects with PCC adminis- more rapid and reliable correction of the INR provides for a
tration; thus, the panel was unable to issue a recommendation. biological rationale supporting the efficacy of PCCs. Although
The guideline panel implicitly considered evidence from the there was a very low certainty of evidence, the panel de-
comparison of PCC with FFP for warfarin reversal that did termined that the anticipated desirable effects of PCC com-
reveal a favorable profile for PCC use and benefit in studies pared with FFP were greater than the undesirable effects in
using the surrogate endpoint of INR correction. PCC is not patients with acute GI bleeding. The panel concluded that
necessary for most patients on warfarin with a GI bleed. PCC although most patients with acute GI bleeding on warfa-
administration could be considered in patients with a life- rin would not require PCC administration, PCC use could
threatening GI bleed, those with a supratherapeutic INR be considered in patients with a life-threatening GI bleed,
substantially exceeding the therapeutic range, or in patients in those with a supratherapeutic INR substantially exceeding
in whom massive blood transfusion is undesirable because of its the therapeutic range, or those in whom massive blood
effect on coagulopathy or dilution of blood components. transfusion is undesirable because of its effect on
coagulopathy or dilution of blood components.
3. For patients on warfarin who are hospitalized or under observation 4. For patients on warfarin who are hospitalized or under observation
with acute GI bleeding, we suggest prothrombin complex concentrate with acute GI bleeding, we suggest against the use of vitamin K
administration compared with FFP administration (conditional (conditional recommendation, very low certainty of evidence).
recommendation, very low certainty of evidence).
Summary of evidence. We identified 2 randomized trials (14,15)
and 1 cohort study (17) comparing PCC with FFP in patients on Summary of evidence. In patients receiving a VKA such as
warfarin with bleeding. The 2 studies that included patients with warfarin, low-dose oral vitamin K 1–2 mg can be used when there
GI bleeding reported inconsistent results (14,17). The RCT by is an elevated INR (typically an INR $10) to restore therapeutic-
Sarode et al. (14) did not find a difference in further bleeding level anticoagulation (i.e., INR 2.0–3.0) (22). In the setting of
among patients with acute GI bleeding with PCC (25.4%) com- clinically significant GI bleeding requiring therapeutic
pared with FFP (24.1%) (relative risk [RR] 1.05, 95% CI: intervention, vitamin K 2–5 mg (oral or intravenous)
Copyright © 2022 The American College of Gastroenterology and the Canadian Association of Gastroenterology. The American Journal of GASTROENTEROLOGY6 Abraham et al.
reverses anticoagulant effect (to INR #1.3) in 24–48 hours. clotting time), and the reduction in the concentration of unbound
Vitamin K use does not achieve rapid hemostasis in patients dabigatran, both indirect measures of the outcome of interest. In a
with acute bleeding (22). Consequently, the clinical value of subgroup analysis of 137 patients with GI bleeding (27), Van der
vitamin K is limited in most patients with acute GI bleeding, Wall et al. reported 30-day mortality and thrombotic event rates
especially if the bleed is self-limiting, treatable through direct of 11.1% and 3.6%, respectively, among patients receiving
endoscopic hemostatic intervention, or if the INR is mildly idarucizumab.
elevated (e.g., INR 1.5–2.5). Vitamin K can be administered in
patients with a supratherapeutic INR if the intent is to reverse Conclusions. Given the limited evidence of benefit and the high
the effect of a VKA over an extended period (i.e., 2–4 weeks) or cost of idarucizumab, the panel felt it could not recommend
if the objective is to stop the VKA altogether. This decision routine use of idarucizumab for patients with GI bleeding who
should be undertaken in consultation with hematologists, have taken dabigatran. However, selective use may be appropriate
cardiologists, or other clinicians involved in patients’ in patients with a life-threatening GI bleed who have taken
anticoagulant management. dabigatran within the past 24 hours.
No prospective studies have assessed whether giving vitamin
Reversal of rivaroxaban or apixaban with andexanet alfa.
K in VKA-treated patients with acute bleeding affects clinically
meaningful outcomes. In a meta-analysis involving nonbleeding
patients on a VKA with a supratherapeutic INR, administration
6. For patients on rivaroxaban or apixaban who are hospitalized or
of vitamin K was associated with small, nonsignificant increases under observation with acute GI bleeding, we suggest against
in mortality (RR 5 1.24; 95% CI: 0.62–2.47) and thrombotic andexanet alfa administration (conditional recommendation, very low
events (RR 5 1.29; 95% CI: 0.35–4.78) (23). One retrospective certainty of evidence).
case-control study involving patients with VKA-associated
bleeding (from both GI and non-GI sites) found vitamin K ad- Summary of evidence. Andexanet alfa, or “coagulation factor Xa
ministration was associated with a significant decrease in mor- (recombinant) inactivated-zhzo,” is a modified recombinant
tality (adjusted OR 5 0.47; 95% CI: 0.24–0.92). However, this human factor Xa decoy protein that binds and sequesters apix-
study had significant methodological limitations, including aban and rivaroxaban. It also binds and inhibits tissue factor
cointerventions that confounded an association between vitamin pathway inhibitor and has an elimination half-life of 5 hours (28).
K administration and clinical outcomes (13). In clinical trials, andexanet alfa decreased apixaban activity by
94% and rivaroxaban activity by 92%. It restored thrombin
Conclusions. Overall, there is no clinical evidence that vitamin K generation in 100% of patients within 2–5 minutes.
administration in VKA-treated patients with acute GI bleeding A prospective, single-group cohort of 352 patients with major
prevents further bleeding or improves mortality or other bleeding within 18 hours of factor Xa inhibitor administration
clinically meaningful outcomes. Moreover, evidence is very (rivaroxaban n 5 128, apixaban n 5 194, enoxaparin n 5 20, or
weak that giving or not giving vitamin K will affect the risk of edoxaban n 5 10) examined outcomes after giving andexanet alfa. A
thromboembolism, such as stroke or venous thrombosis, subgroup (90 patients) suffered an episode of GI bleeding with
presumed to be because of normalization of the INR. all contributing to the ‟safety group,” whereas 62 contributed to the
Direct thrombin inhibitor reversal. ‟efficacy group” (those with a baseline anti-Xa activity of at least
75 ng/mL and confirmed major bleeding) (29). Overall, the surrogate
marker of median anti-F Xa activity decreased from 149.7 to 11.1 ng/mL
5. For patients on dabigatran who are hospitalized or under (92% reduction; 95% CI: 91–93) in the apixaban group and from 211.8 to
observation with acute GI bleeding, we suggest against the 14.2 ng/mL (92% reduction; 95% CI: 88–94) in the rivaroxaban group.
administration of idarucizumab (conditional recommendation, very Among the 62 patients with GI bleeding, excellent or good he-
low certainty of evidence). mostatic efficacy was noted 12 hours after the andexanet alfa infusion
in 85% (95% CI: 76–94), although the clinical applicability of the
Summary of evidence. The available evidence addressing this chosen criteria may not reflect contemporary clinical standards in GI
recommendation included 1 cohort study that compared idar- bleeding. In addition, methodological limitations included the ab-
ucizumab with no treatment and 2 additional cohort studies sence of an intention-to-treat analysis, possible confounding cova-
without a comparator. Singh et al. (24) performed a retrospective riates, and insufficient reporting of resuscitative, endoscopic, and
cohort study in the United States that included patients hospi- pharmacological management. Surprisingly, there was no significant
talized for dabigatran-associated major nontraumatic GI relationship between hemostatic efficacy and a reduction in anti-FXa
bleeding or intracranial bleeding. Among those with GI activity during andexanet alfa treatment. Adverse events were
bleeding (159 who received idarucizumab vs 1124 who did reported only at the whole group level and included thrombotic
not), nonsignificant differences in mortality (OR: 1.39, 95% CI: events and mortality within 30 days in 9.7% of 352 patients and
0.51–3.45) and venous thromboembolism (OR: 0.35, 95% CI: 13.9%, respectively. Infusion-related events at 7 days were noted in 2
0.08–1.58) were observed. In the Reversal Effects of Idarucizumab patients but not in the 90 patients with GI bleeding.
on Active Dabigatran study (25,26), Pollack et al. examined
patients on dabigatran with multiple causes of acute bleeding, Conclusions. The only published study presents a serious risk of
including GI (45.5%) and other patients on dabigatran about to bias because it lacks a control group. Indirectness of the outcomes
undergo an urgent surgery or procedure. The reversal of is also a significant concern because data on patients with GI
dabigatran anticoagulant effect (before and up to 24 hours after bleeding are limited, with missing information concerning spe-
the administration of idarucizumab) was assessed by dabigatran- cific management. Additional methodological limitations include
specific coagulation function tests (dilute thrombin time or ecarin very serious imprecision as event rates are low and the use of
The American Journal of GASTROENTEROLOGY VOLUME 00 | MONTH 2022 www.amjgastro.comACG-CAG Clinical Practice Guideline 7
surrogate laboratory rather than clinical outcomes. Notably, the with severe GI bleeding (36,37). However, the possibility of thrombotic
cost of using the drug is high (up to $49,500 at high-dose regimen, events with an infusion of functional platelets in patients taking
with the low-dose regimen costing half as much) (30). antiplatelet drugs, who are at higher cardiovascular risk, along with
Accordingly, the panel could not recommend the routine use of potential risks related to the transfusion of blood products, also needs to
andexanet alfa in patients with GI bleeding. This intervention be considered.
could be considered in the setting of life-threatening GI bleeding A single fully published study directly relevant to this PICO
in hospitalized patients who have taken apixaban or rivaroxaban was identified: a cohort study in patients without thrombocyto-
within the past 24 hours. penia taking antiplatelet agents and admitted with GI bleeding.
This study compared 204 patients who received platelet trans-
Reversal of DOACs with PCC. fusion with a matched control group of 204 patients who did not.
Adjusted analyses revealed a significant increase in mortality
(OR 5 5.57, 95% CI: 1.52–27.1) and small, nonsignificant in-
7. For patients on direct oral anticoagulants who are hospitalized or creases with platelet transfusion vs no transfusion in further
under observation with acute GI bleeding, we suggest against bleeding (OR 5 1.47, 95% CI: 0.73–3.05) and thrombotic events
prothrombin complex concentrate administration (conditional
(OR 5 1.35, 95% CI: 0.74–2.49) (36).
recommendation, very low certainty of evidence).
Studies of platelet transfusion in patients for indications other
Summary of evidence. The literature search identified only 2 than GI bleeding provide additional indirect evidence. An RCT of
cohort studies with comparator arms (no PCC) (31,32), both of 190 patients with intracerebral hemorrhage reported an increase
which have limitations. Schulman et al. (31) examined the re- in the primary endpoint of death or dependence (because of
versal of dabigatran-associated major bleeding with activated significant neurological deficit) with platelet transfusion vs
prothrombin concentrate in a small prospective cohort study standard care (adjusted OR 5 2.05, 95% CI: 1.18–3.56), as well as
(N 5 14). Among the 5 patients with GI bleeding compared with a small, nonsignificant increase in mortality (RR 5 1.38, 95% CI:
matched patients (N 5 28) from 5 Phase III trials, the 0.78–2.44) and a large, nonsignificant increase in thrombotic
“effectiveness” rating was assessed at 24 hours by the treating events (RR 5 3.84, 0.44–33.68) with platelet transfusion (38). A
physicians for GI bleeding. The effectiveness was considered good retrospective analysis of data from double-blind placebo-
in 4 patients and moderate in 1, which was not statistically controlled RCTs of patients undergoing coronary artery bypass
different from the comparator group. Smythe et al. (32) reported graft surgery reported higher mortality with platelet transfusion
that among 28 patients with GI bleeding on dabigatran, 2 received on multivariable analysis with propensity scoring (OR 5 4.76,
4-factor PCC, and both (100%) died within 30 days. However, the 95% CI: 1.65–13.73) (39).
mortality results were not adjusted for confounding, and the
comparator group’s death rate is unknown. Several systematic Conclusions. Given a possible mortality increase in patients
reviews (33–35) have reported mainly on low-quality, single-arm with GI bleed and other medical conditions, and the lack of
cohort studies. benefit in decreasing further bleeding in patients with GI
bleeding, the panel suggests against platelet transfusion in pa-
Conclusions. Given the uncertainty of the available evidence, the tients with antiplatelet-related GI bleeding who are not
panel felt they could not recommend routine use of PCC for thrombocytopenic.
patients with GI bleeding who have taken DOACs. However,
Holding ASA vs continuing ASA.
selective use may be clinically justifiable in some patients who
have taken DOACs within the past 24 hours with a life-
threatening GI bleed. 9. For patients with GI bleeding on cardiac ASA for secondary
cardiovascular prevention, we suggest against holding the ASA
Reversal of antiplatelet with platelet transfusion (conditional recommendation, very low certainty of evidence).
10. For patients with GI bleeding on ASA for secondary cardiovascular
prevention whose ASA was interrupted, we suggest the ASA be
8. For patients on antiplatelet agents who are hospitalized or under resumed on the day hemostasis is endoscopically confirmed
observation with acute GI bleeding, we suggest against platelet (conditional recommendation, very low certainty of evidence).
transfusions (conditional recommendation, very low certainty of
evidence). Summary of evidence. Current recommendations suggest that
patients with upper GI bleed undergo endoscopy within 24 hours,
Summary of evidence. ASA and the thienopyridine P2Y12 re- and in those with a lower GI bleed, diagnostic testing be per-
ceptor inhibitors clopidogrel and prasugrel irreversibly block formed within ;24–36 hours (40–42). In addition, hemostasis
platelet function for the 7–10-day life span of platelets, whereas generally occurs before endoscopy or, in the minority with active
ticagrelor is a reversible nonthienopyridine P2Y12 receptor bleeding identified endoscopically, at the time of endoscopy after
inhibitor (a cyclopentyltriazolopyrimidine) that impairs platelet hemostatic therapy is applied. ASA’s pharmacodynamic effect
function for 3–5 days. For this guideline, we refer most frequently occurs through irreversible inhibition of platelet cyclooxygenase-
to thienopyridine antiplatelet agents in discussing P2Y12 receptor 1, which mediates thromboxane synthesis. After ASA ingestion,
inhibitors because the evidence reviewed examined clopidogrel or thromboxane synthesis normalizes by 7–10 days, although in
prasugrel. However, the mechanism of action of the nonthienopyridine vitro studies suggest 70% of arachidonic acid–mediated platelet
P2Y12 receptor inhibitor, ticagrelor, is similar, permitting reasonable function may normalize by 3 days after ASA ingestion (43,44).
extrapolation of results. Previous guidelines have suggested platelet Therefore, interruption of ASA in patients presenting with GI
administration as a therapeutic option in patients on antiplatelet agents bleeding will have little impact on the initial clinical course
Copyright © 2022 The American College of Gastroenterology and the Canadian Association of Gastroenterology. The American Journal of GASTROENTEROLOGY8 Abraham et al.
because of the persistent antiplatelet effect of ASA in the first day
or 2 after the patient’s presentation. Furthermore, the suggestion Table 3. Empiric endoscopic procedural bleeding risk
to resume ASA immediately after hemostasis means that ASA stratification
resumption will occur in most cases well before the antiplatelet
Low/moderate bleeding risk
effect has substantially waned. Thus, the initial interruption of
High bleeding risk procedures procedures (30-d risk of major
ASA after presentation would not be expected to have much
(30-d risk of major bleed >2%) bleed £ 2%)
impact on either bleeding or cardiovascular clinical outcomes if
ASA is restarted once endoscopic hemostasis is established. Polypectomy ($1 cm) EGD with/without biopsy
Only 1 study was identified relevant to the PICO regarding PEG/PEJ placement Colonoscopy with/without biopsy
interruption vs continuation of ASA when patients present with ERCP with biliary or pancreatic Flexible sigmoidoscopy with/without
GI bleeding (GIB); this was a retrospective study in patients sphincterotomy biopsy
hospitalized with acute myocardial infarction who subsequently
EMR/ESD ERCP with stent (biliary or pancreatic)
developed ulcer bleeding during hospitalization (45). This com-
placement or papillary balloon dilation
parison of 64 patients interrupting ASA vs 38 continuing ASA
without sphincterotomy
reported similar 30-day rates for both further bleeding and for
mortality of 16% (10/64) vs 11% (4/38) (RR 5 1.48, 0.50–4.41), EUS-FNA EUS without FNA
respectively. The results for further bleeding are opposite than Endoscopic hemostasis Push enteroscopy and diagnostic
expected for interruption of ASA (i.e., slightly more bleeding (excluding APC) balloon-assisted enteroscopy
reported with interrupted ASA), although confidence intervals Radiofrequency ablation Enteral stent deployment
are wide and consistent with benefit or harm. No statistical ad-
POEM Argon plasma coagulation
justments were made for potential confounders, limiting the
utility of the results. Furthermore, since outcomes were at 30 days, Treatment of varices (including Balloon dilation of luminal stenoses
the results may be viewed as primarily relevant to the timing of variceal band ligation)
ASA resumption after bleeding stops. Therapeutic balloon-assisted Polypectomy (,1 cm)
The most pertinent study relevant to the PICO regarding enteroscopy
resumption of ASA after hemostasis is an RCT in patients taking
Tumor ablation ERCP without biliary or pancreatic
ASA for secondary cardiovascular protection with high-risk
sphincterotomy
ulcer bleeding requiring endoscopic therapy. In this RCT, 156
patients with peptic ulcer bleeding and high-risk endoscopic Cystogastrostomy Marking (including clipping,
stigmata treated with successful endoscopic therapy and proton electrocoagulation, and tattooing)
pump inhibitor were randomized to continued low-dose ASA for Ampullary resection Video capsule endoscopy
secondary prevention vs placebo for the 8 weeks of the study (a much Pneumatic or bougie dilation
longer interruption than typical in current clinical practice) (46). Re-
Laser ablation and coagulation
current bleeding rates at 30 days were not significantly greater in the
ASA group (10.3% vs 5.4%); difference 4.9% (95% CI: 23.6 to 13.4), The sources used for the empiric classification of procedures included the
whereas 8-week mortality attributable to cardiovascular, cerebrovas- International Society on Thrombosis and Haemostasis Guidance Statement, the
BRIDGE trial, previously published guidelines, and expert opinion by the
cular, or GI complications was significantly greater in the placebo group
authors.
(1.3% vs 10.3%; difference 9% [95% CI: 1.7–16.3]). Thrombotic events APC, argon plasma coagulation; EGD, esophagogastroduodenoscopy; EMR,
at 30 days did not differ between groups (3/78 vs 9/78 favoring early endoscopic mucosal resection; ERCP, endoscopic retrograde
ASA resumption, RR 5 0.33 [95% CI: 0.09–1.19]) with 6 nonfatal, cholangiopancreatography; ESD, endoscopic submucosal dissection; EUS,
recurrent acute ischemic events reported (2 in the ASA and 4 in the endoscopic ultrasound; FNA, fine-needle aspirate; PEG, percutaneous
placebo group). However, the 2-month interruption of ASA in the endoscopic gastrostomy; PEJ, percutaneous endoscopic jejunostomy; POEM,
peroral endoscopic myotomy.
placebo group imparts serious indirectness of observed outcomes.
There also exists very serious imprecision because of very low event
rates.
Two additional cohort studies that compared patients who Conclusions. The panel weighed the important and well-
continued ASA after GIB to others who discontinued ASA and documented cardiovascular benefit of secondary preventive ASA
did not resume ASA could not be included. In 1, the life-table therapy and the potential risk of further GI bleeding with continued
analysis curves did not permit accurate extraction of results for ASA therapy. The trend to reduced mortality in an observational
the first 1–7 days (the relevant timeframe for this recommenda- study of patients with myocardial infarction with continued aspirin
tion) (47). The second study was unclear when patients along the (45) coupled to the significant reduction in mortality among patients
x axis were on or off ASA (48). with high-risk ulcer bleeding who had aspirin resumed immediately
We wish to stress that our recommendations do not apply to after endoscopic hemostasis (46) were important considerations in
patients taking ASA for primary cardiovascular prevention. Recent the panel’s decision to recommend continuation rather than an
RCTs suggest little if any benefit of primary prevention for re- interruption of aspirin therapy. If ASA is discontinued at clinical
duction of cardiovascular outcomes despite significant increases in presentation, we recommend rapid resumption within 24 hours of
serious GI bleeding (49–51), and current guidelines suggest ASA successful endoscopic hemostasis.
for primary prevention be considered only in a very limited pop- Increased further bleeding with continued ASA at pre-
ulation and should not be used in those with increased risk of sentation was not shown in the observational study, but results of
bleeding (52,53). the RCT did raise the possibility of increased rebleeding with early
The American Journal of GASTROENTEROLOGY VOLUME 00 | MONTH 2022 www.amjgastro.comACG-CAG Clinical Practice Guideline 9
venous thromboembolism (comprising lower-limb deep vein throm-
Table 4. Empiric periprocedural thromboembolic risk bosis or pulmonary embolism), stroke, or transient ischemic attack
stratification for patients receiving anticoagulant therapy (Table 4); and patients within 3 months of acute coronary syndrome
(ACS) event, within 6 months of a drug-eluting stent or 1 month of a
Indication for anticoagulation
bare-metal coronary stent placement without ACS history (54); or after
Risk Mechanical heart Venous ACS event within 12 months of a drug-eluting stent placement or 2
stratum valve Atrial fibrillation thromboembolism months of bare-metal stent placement (54). Recent data suggest that
Higha • Any mitral valve • CHADS2 score: 5 • Recent (within 3 dual antiplatelet therapy (DAPT) with ASA and P2Y12 receptor in-
prosthesis or 6 mo) VTE hibitor can be converted to platelet P2Y12 receptor inhibitor mono-
• Any caged-ball or • CHA2DS2VaSc • Severe therapy among patients at 3 months or less in patients with a drug-
tilting disc aortic score: $ 7 thrombophilia eluting stent placed after ACS event (55,56).
valve prosthesis • Recent (within 3 (e.g., deficiency of A review of published guidelines highlights the lack of consensus
• Recent (within 3 mo) stroke or protein C, protein regarding high vs low baseline risk of endoscopic procedures (Table 3)
mo) stroke or transient ischemic S or antithrombin, (37,57–59). Procedural bleeding risk and patient-specific thrombo-
transient ischemic attack antiphospholipid embolic risk were empirically framed using the risk stratification en-
attack • Rheumatic antibodies, and dorsed by the International Society on Thrombosis and Haemostasis
valvular heart multiple Guidance Statement (60), the BRIDGE Trial (61), previously pub-
disease abnormalities) lished guidelines, and expert opinion (Table 4) (37,57–59,61). A
Moderate • Bileaflet aortic • CHADS2 score: • VTE within the structured and exhaustive GRADE assessment of procedural bleeding
valve prosthesis 2–4 (no previous past 3–12 mo risk is beyond the scope of this clinical practice guideline.
and $1 of the stroke or transient • Nonsevere Also pertinent to this section are considerations of patient pref-
following: atrial ischemic attack) thrombophilia erence. The targeted review performed for this guideline initiative (see
fibrillation, • CHA2DS2VaSc (e.g., Appendix 2, Supplementary Digital Content, http://links.lww.com/
previous stroke or score: 5 or 6 heterozygous AJG/C417) demonstrated substantial variability in the threshold
transient ischemic factor V Leiden or number of bleeds observed for oral anticoagulation therapy to be
attack, prothrombin gene considered acceptable both within individuals and between different
hypertension, mutation) studies (62). Furthermore, country-specific differences exist in pa-
diabetes, • Recurrent VTE tients’ perceptions of atrial fibrillation, concerns about stroke, and
congestive heart • Active cancer preference for involvement in oral anticoagulation therapy treatment
failure, and age (treated within 6 decisions, with recent experience of stroke and GI bleeding both sig-
.75 yr mo or palliative) nificantly influencing patient values and preferences (63,64). Indeed,
patients placed more weight (more disutility) on stroke prevention
Low • Bileaflet aortic • CHADS2 score: • VTE more than 12
than GI bleeding unless they had previously experienced a GI bleed
valve prosthesis 0 or 1 mo ago and no
(64). Among the latter, 87% placed the highest utility on rebleeding
without atrial • CHA2DS2VaSc other risk factors
risk followed by thrombosis risk (64). The panel members concluded
fibrillation and no score: 1-4
that for most PICOs, there is possibly significant uncertainty about or
other risk factors
variability in how much people value the critical outcomes.
for stroke
The sources used for the empiric classification of procedures included the Anticoagulant interruption vs continuation.
International Society on Thrombosis and Haemostasis Guidance Statement, the
BRIDGE trial, previously published guidelines, and expert opinion by the
authors. VTE, venous thromboembolism.
a
High-risk patients may also include patients with a previous stroke or transient 11. For patients on warfarin undergoing elective/planned endoscopic
ischemic attack occurring .3 mo ago and a CHADS2 score ,5, patients with GI procedures, we suggest warfarin be continued, as opposed to
previous thromboembolism during temporary interruption of VKAs, or those temporarily interrupted (1–7 days) (conditional recommendation, very
patients undergoing certain types of surgery (e.g., cardiac valve replacement, low certainty of evidence).
carotid endarterectomy, and major vascular surgery).
Summary of evidence. The published data examining uninterrupted
warfarin before endoscopic procedures and associated GI bleeding risk
resumption of ASA in patients with high-risk ulcer bleeding. The is heterogeneous and methodologically flawed. When formulating our
panel also weighed the preferences of providers and patients for a recommendation, we considered 3 cohort studies with a control group
cardiovascular event vs a GIB event, as discussed in Supple- (temporary interruption of warfarin) (65–67) and 2 cohort studies
mentary Digital Content (see Appendix 2, http://links.lww.com/ without a control group (68,69). These 5 studies provided very low
AJG/C417) in formulating their recommendation. certainty of evidence because of imprecision of the results, lack of
adjustment for confounders, lack of standardized procedure technique
Management of antithrombotic agents in the elective (e.g., biopsy, cold snare polypectomy, hot snare polypectomy, and
endoscopy setting. routine hemostatic clipping), comparator groups that differ in prog-
The 9 remaining statements inform antithrombotic therapy manage- nostic factors for bleeding, differences in population, lack of blinding of
ment in patients undergoing scheduled, elective endoscopic proce- the endoscopist, and incomplete follow-up.
dures. These recommendations exclude patients at high risk of The desirable anticipated effect with continued warfarin (com-
thromboembolic events in whom elective procedures should be de- pared with interrupted warfarin) is reduced thromboembolic events.
ferred. Such high-risk patients include those within 3 months of acute A single small cohort study without adjustment for confounding
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