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Major Gastrointestinal Bleeding Often Is Caused by Occult Malignancy in Patients Receiving Warfarin or Dabigatran to Prevent Stroke and Systemic Embolism From Atrial Fibrillation

Published:October 17, 2016DOI:https://doi.org/10.1016/j.cgh.2016.10.011

      Background & Aims

      Gastrointestinal (GI) bleeding in patients receiving anticoagulation agents can be caused by occult malignancies. We investigated the proportions and features of major GI bleeding (MGIB) events related to occult GI cancers in patients receiving anticoagulation therapy.

      Methods

      We analyzed data from the Randomized Evaluation of Long Term Anticoagulant Therapy study (conducted between December 2005 and March 2009 in 951 clinical centers in 44 countries worldwide), which compared the abilities of dabigatran vs warfarin to prevent stroke and systemic embolism in 18,113 patients with atrial fibrillation. Two blinded gastroenterologists independently reviewed source documents of MGIB events (n = 595) that occurred during the study period. We collected data on MGIB events caused by previously unidentified GI malignancies, and compared characteristics of MGIB events in patients who received dabigatran vs warfarin (primary end point), and in patients with bleeding from cancer, vs patients bleeding from a nonmalignant or unidentified source.

      Results

      Of 546 unique MGIB events, 44 (8.1%) were found to be from GI cancers (34 of 398 MGIB events in dabigatran users and 10 of 148 MGIB events in warfarin users; P = .60). Colorectal cancer accounted for 35 of 44 of all cancers identified. There were more colorectal cancer–associated MGIB events in the dabigatran group (30 of 34) than in the warfarin group (5 of 10) (P = .02), but more gastric cancer–associated MGIB events in the warfarin group (5 of 10) than in the dabigatran group (1 of 34) (P = .001). There were no differences in the short-term outcomes of cancer-related MGIB events in the dabigatran vs the warfarin group, but 75% of all cancer-related MGIB events required at least 1 blood transfusion and the mean hospital stay was 10.1 days. Compared with MGIB events from a nonmalignant or unidentified source, MGIB from cancer occurred sooner (343.0 vs 223.1 d; P = .003), but the bleeding was more likely to be chronic (for >7 d) (27.3% vs 63.6%; P < .001).

      Conclusions

      In evaluating data from a study of the effects of anticoagulation therapy, we found approximately 1 of every 12 MGIB events to be related to an occult cancer. Approximately two thirds of cancer-related MGIB presents with chronic bleeding, and morbidity, and resource utilization is high.

      Keywords

      Abbreviations used in this paper:

      AF (atrial fibrillation), CRC (colorectal cancer), DOAC (direct oral anticoagulant), FOBT (fecal occult blood test), GI (gastrointestinal), Hgb (hemoglobin), ICU (intensive care unit), MGIB (major gastrointestinal bleeding), NSAID (nonsteroidal anti-inflammatory drug), OAC (oral anticoagulant), RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy trial), VKA (vitamin K antagonist)
      See editorial on page 691.
      Anticoagulation with a vitamin K antagonist (VKA) or a direct oral anticoagulant (DOAC) reduces the incidence of stroke and systemic embolism in patients with atrial fibrillation (AF).
      • Petersen P.
      • Boysen G.
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      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
      • Connolly S.J.
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      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Giugliano R.P.
      • Ruff C.T.
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      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      • Patel M.
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      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Granger C.B.
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      • McMurray J.J.V.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      Anticoagulation is associated with major bleeding, including major gastrointestinal bleeding (MGIB), which occurs at a rate of approximately 1% to 2% per year.
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      • Giugliano R.P.
      • Braunwald E.
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
      Most studies have suggested that MGIB is more common with DOACs than VKAs, which may reflect topical anticoagulant action by intraluminal DOAC.
      • Ruff C.T.
      • Giugliano R.P.
      • Braunwald E.
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
      • Graham D.J.
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      • Wernecke M.
      • et al.
      Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation.
      • Eikelboom J.W.
      • Wallentin L.
      • Connolly S.J.
      • et al.
      Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) Trial.
      • Sherid M.
      • Sifuentes H.
      • Sulaiman S.
      • et al.
      Gastrointestinal bleeding with dabigatran, a comparative study with warfarin: a multicenter experience.
      • Desai J.
      • Granger C.B.
      • Weitz J.I.
      • et al.
      Novel oral anticoagulants in gastroenterology practice.
      Despite the prevalence of MGIB in AF patients receiving anticoagulation therapy, there is a paucity of evidence to guide diagnosis and management.
      In a subset of patients receiving anticoagulation therapy, MGIB represents the first presentation of occult malignancy. It has been hypothesized that initiating an anticoagulant may represent a stress test, which can function to reveal an occult cancer.
      • Sherid M.
      • Sifuentes H.
      • Sulaiman S.
      • et al.
      Gastrointestinal bleeding with dabigatran, a comparative study with warfarin: a multicenter experience.
      • Desai J.
      • Granger C.B.
      • Weitz J.I.
      • et al.
      Novel oral anticoagulants in gastroenterology practice.
      • Bini E.J.
      • Rajapaksa R.C.
      • Weinshel E.H.
      Positive predictive value of fecal occult blood testing in persons taking warfarin.
      • Johannsdottir G.A.
      • Onundarson P.T.
      • Gudmundsdottir B.R.
      • et al.
      Screening for anemia in patients on warfarin facilitates diagnosis of gastrointestinal malignancies and pre-malignant lesions.
      • McCall K.L.
      • MacLaughlin E.J.
      Warfarin-associated bleeding complication saved life.
      • Michaels M.M.
      Bleeding from occult tumors during anticoagulant therapy.
      • Norton S.
      • Armstrong C.
      Lower gastrointestinal bleeding during anticoagulant therapy: a life-saving complication?.
      • Jaffin B.W.
      • Bliss C.M.
      • LaMont J.T.
      Significance of occult gastrointestinal bleeding during anticoagulation therapy.
      • Clemens A.
      • Strack A.
      • Noack H.
      • et al.
      Anticoagulant-related gastrointestinal bleeding—could this facilitate early detection of benign or malignant gastrointestinal lesions?.
      Unlike warfarin, dabigatran oral ingestion results in the presence of active intraluminal anticoagulant within the gastrointestinal tract, and this might promote bleeding from friable gastrointestinal cancers further; thus, dabigatran might represent a more intensive stress test than warfarin. Indeed, a previous analysis based on database search terms suggested that cancer-related bleeding with 3 DOACs (rivaroxaban, apixaban, and dabigatran) may appear sooner after treatment initiation than with VKAs.
      • Clemens A.
      • Strack A.
      • Noack H.
      • et al.
      Anticoagulant-related gastrointestinal bleeding—could this facilitate early detection of benign or malignant gastrointestinal lesions?.
      Dabigatran etexilate is a direct thrombin inhibitor that has a favorable safety and efficacy profile in comparison with warfarin, although dabigatran 150 mg twice daily is associated with increased MGIB.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (N = 18,113) provides a large comprehensive database related to MGIB in patients taking dabigatran vs warfarin. In the current study, we used individual chart review by experienced gastroenterologists to analyze the relationship between MGIB and underlying undiagnosed gastrointestinal (GI) tract malignancies in patients on DOACs and VKAs, and to characterize in detail these MGIB events related to occult maligancy.

      Methods

       Adjudication of Major Gastrointestinal Bleeding Events During the Randomized Evaluation of Long-Term Anticoagulation Therapy Trial

      The RE-LY trial was a randomized prospective trial comparing 2 blinded doses of dabigatran (110 mg and 150 mg twice daily) with open-label, adjusted-dose warfarin for stroke and systemic embolus prevention in 18,113 patients with nonvalvular AF. Approval of the study was obtained from local regulatory authorities and ethics committees, and all patients provided written informed consent. During RE-LY, which was conducted in 951 centers across 44 countries, an adjudication committee, composed of 3 cardiologists, 3 neurologists, 1 internist, and 1 sponsor representative, assessed all cases of major bleeding that occurred from the start of treatment to the end of the observation period by reviewing case report forms and medical records created at the study sites. Cases that, in the judgment of the adjudicators, met International Society on Thrombosis and Hemostasis criteria for major bleeding (fatal bleeding, and/or decrease in hemogobin [Hgb] level ≥2 g/dL, and/or transfusion of ≥2 units of blood, and/or symptomatic bleeding into a critical organ) were categorized as major bleeding events. Each MGIB event later was subclassified to the specific organ system where the bleeding occurred, or, if this could not be determined, to an unspecified site category.
      • Ezekowitz M.D.
      • Connolly S.
      • Parekh A.
      • et al.
      Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran.
      • Schulman S.
      • Kearon C.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.

       Re-evaluation of Major Gastrointestinal Bleeding Events by Gastroenterologists

      For the current study, the sponsor of RE-LY (Boehringer Ingelheim, Inc) provided the investigators with documents (case report forms, adjudication committee documents, and primary source documents) related to patients who experienced a MGIB event during RE-LY. This population included 451 patients who were adjudicated during RE-LY to have experienced a major gastrointestinal bleeding event,
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Newly identified events in the RE-LY trial.
      plus 82 patients who were recategorized as most likely having bled from a gastrointestinal source, rather than (as originally adjudicated during RE-LY) from an unspecified site during a post hoc analysis of all MGIB in RE-LY.
      • Eikelboom J.W.
      • Wallentin L.
      • Connolly S.J.
      • et al.
      Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) Trial.
      Thus, the total pool of probable MGIB patients in our study numbered 533. The trial sponsor did not otherwise participate in the current study.
      Two experienced gastroenterologists (J.D. and J.A.) who were blinded to drug treatment independently re-evaluated the primary source documents related to each MGIB event. The documents for 3 patients were not available, and thus these patients were eliminated before gastroenterologist review. In the interest of capturing the undiluted characteristics of cancer-related MGIB, stricter interpretations of the definition of a GI source were used during this re-evaluation. For example, bleeding events resulting from potentially nonluminal GI sources were excluded, and only first-time bleeding events from a given source were included. A second MGIB event in an individual patient was included only if it arose from a new unique lesion. The discrepancy between 546 events described in our study, and 533 patients with MGIB in the post hoc analysis of RE-LY, was attributable to the inclusion of patients (N = 35) who bled from more than 1 unique gastrointestinal source, and the exclusion of patients (N = 23) for 1 or more of the reasons enumerated earlier.

       Data Collection and Analysis

      Data regarding clinical presentation, diagnosis, and treatment of MGIB events were extracted from the primary source documents by the 2 treatment-blinded gastroenterologists. Nonblinded investigators extracted objective baseline characteristics and short-term outcomes from primary source documents and adjudication documents. Data related to follow-up visits or testing after trial completion were not available. In this analysis, patients were considered oral anticoagulant (OAC) naive if they had never received OACs before their enrollment in RE-LY. Patients were considered to be taking a baseline concomitant medication (eg, aspirin, clopidogrel, nonsteroidal anti-inflammatory drugs [NSAIDs], and proton pump inhibitor) if they were taking this medication at randomization. Patients’ cancer screening histories before their enrollment in RE-LY were largely unavailable.
      MGIBs were categorized as acute (<2 d), subacute (2–7 d), or chronic (>7 d). If a patient had multiple presenting signs, the following hierarchy was used to determine the primary presenting sign: hematemesis > hematochezia > melena > occult bleeding. Occult bleeding was defined as a composite of the following symptoms in the absence of overt bleeding: (1) a positive fecal occult blood test (FOBT), (2) constitutional signs or symptoms, (3) unexplained decrease in Hgb level, and (4) constitutional signs or symptoms with a positive FOBT or associated with a decrease in Hgb level. The time-to-bleed was defined as the number of days from the date of the first study drug dose to the date of the bleed. To be categorized as a fatal GIB, concordance between the gastroenterologists was required. Bleeding was classified as related to a cancer based on accepted histologic, endoscopic, and/or surgical criteria. In all cases, the MGIB preceded the cancer diagnosis. If a patient had multiple GI bleeds, the case was assessed based on the bleed that resulted in the cancer diagnosis.
      To compare the characteristics of MGIB resulting from cancer and MGIB resulting from other causes, a comparator group of events was created by pooling all MGIB events in which a luminal GI malignancy was not diagnosed (n = 502 MGIB events). This comparator group comprised MGIB events in which either a nonmalignant bleeding source was identified (n = 269 events; 53.6%) or no bleeding source was identified, either because the work-up was nondiagnostic (n = 138 events; 27.5%) or because the site investigator decided not to pursue a work-up (eg, because the likely source of bleeding had been determined during an endoscopy that was performed before the time of the RE-LY study) (N = 95 events; 18.9%). In designing this study’s protocol, we acknowledged that a fraction of the 95 uninvestigated MGIB events might reflect undiagnosed luminal GI cancer, but concluded that this fraction was acceptably small. Specifically, we estimated that less than 2.0% of the total events in the comparator group could reflect a missed cancer (cancer-related MGIB events equal < 10.0% of 95 total uninvestigated MGIB events; <9.5 cancer MGIB events/502 total MGIB events equal < 1.9%).

       Statistical Analyses

      Statistical analyses were performed using the Statistical Analysis System (SAS, Cary, NC) version 9.2. The Fisher exact test was used for categoric data and a t test for continuous variables (2-tailed, α = .05 without adjustment for multiple comparison). Kaplan–Meier curves were used to graphically show the time to MGIB. Comparisons were made between the study treatment groups and also between those with GI cancer–related MGIB and MGIB resulting from other causes. For the purpose of this analysis, patients on dabigatran 110 mg and 150 mg twice daily were analyzed as one group.

      Results

       Major Gastrointestinal Bleeding Event Case Recruitment

      Of the 18,113 patients randomized in RE-LY to receive drug treatment, 533 patients were determined by RE-LY investigators to have experienced a MGIB (Figure 1).
      • Eikelboom J.W.
      • Wallentin L.
      • Connolly S.J.
      • et al.
      Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) Trial.
      During the gastroenterologists’ source document–based re-evaluation of 595 MGIB events performed for the current study, 49 events did not meet the current study criteria for unique MGIB events; 22 such events were removed from the current analysis because they were considered repeat events with bleeding from the same source as the initial MGIB, and 27 events were removed from the analysis because the anatomic site was not considered to be intraluminal GI by the 2 expert gastroenterologists. Thus, the analysis for this study was performed on 546 unique MGIB events.
      Figure thumbnail gr1
      Figure 1Flow chart of MGIB events in the RE-LY trial (N = 18,113) and those included in the current trial. The distribution of events of bleeding from GI cancers and those bleeding from noncancer or undiagnosed lesions is shown.

       Major Gastrointestinal Bleeding Caused by Cancer

      Of all MGIB in RE-LY, 44 of 546 (8.1%) were owing to previously undiagnosed luminal GI tract cancer. Cancer was responsible for 34 of 398 (8.5%) MGIB in patients receiving dabigatran and 10 of 148 (6.8%) MGIB in patients receiving warfarin (P = .60). Of the 34 dabigatran users experiencing cancer-related MGIB, 14 were in the dabigatran 110 mg twice-daily treatment group and 20 were in the dabigatran 150 mg twice-daily treatment group.

       Classification of Gastrointestinal Tract Cancers

      Colorectal cancer (CRC) accounted for 35 of 44 (79.5%) malignancies diagnosed after MGIB. CRC accounted for 88.2% of MGIB resulting from luminal GI malignancy in the dabigatran group (colonic, n = 25, 73.5%; rectal, n = 5, 14.7%) and 50.0% in the warfarin group (colonic, n = 4, 40.0%; rectal n = 1, 10.0%) (P = .02). Gastric cancer accounted for 50.0% of MGIB resulting from luminal GI malignancy in the warfarin group (5 of 10) compared with 2.9% in the dabigatran group (1 of 34) (P = .001). CRC and gastric cancer accounted for all cancer-related MGIB with the exception of 1 ampullary cancer, and 1 each of renal cell carcinoma and melanoma that were metastatic to the luminal GI tract.

       Characteristics of Patients With Major Gastrointestinal Bleeding Caused by Cancer

      The mean age of patients with cancer-related MGIB (n = 44) was 76.8 years, and 65.9% were men (Table 1). At the time of randomization, 63.6% of patients with MGIB owing to cancer had previously taken an OAC, 18.2% were taking a proton pump inhibitor, and 45.5% were taking aspirin. In the cancer-related MGIB group, there were no significant differences in clinical characteristics between the 2 drug treatment groups.
      Table 1Clinical Characteristics of Patients on Dabigatran and Warfarin With MGIB Events During the RE-LY Trial
      Bleeding from cancer
      All P values, D vs W, were nonsignificant.
      Bleeding from noncancer or from undiagnosed lesion
      All P values, D vs W, were nonsignificant, except for age, mean (SD), D vs W, P < .001.
      Total (N = 44)Dabigatran (N = 34)
      A pooled dabigatran group including both patients on dabigatran 110 mg twice daily and dabigatran 150 mg twice daily.
      Warfarin (N = 10)Total (N = 502)Dabigatran (N = 364)
      A pooled dabigatran group including both patients on dabigatran 110 mg twice daily and dabigatran 150 mg twice daily.
      Warfarin (N = 138)
      Male sex, n (%)29 (65.9)22 (64.7)7 (70.0)329 (65.5)234 (64.3)95 (68.8)
      Age, mean (SD), y76.8 (6.7)76.4 (6.3)78.0 (8.4)76.0 (7.2)76.8 (6.6)74.1 (8.3)
      Body mass index, mean (SD)29.7 (6.2)29.8 (5.5)29.3 (7.5)28.8 (6.1)28.7 (6.0)29.0 (6.3)
      Baseline creatinine level, mean (SD), mg/dL1.2 (0.3)1.2 (0.3)1.1 (0.4)
      N = 9; 1 patient had a missing baseline creatinine level.
      1.2 (0.4)1.3 (0.4)
      N = 359; 5 patients had a missing baseline creatinine level.
      1.2 (0.4)
      N = 135; 3 patients had a missing baseline creatinine level.
      Receiving treatment at time of event, n (%)35 (79.5)27 (79.4)8 (80.0)377 (75.2)269 (74.1)
      N = 363; 1 patient had missing data on randomized treatment use at time of event.
      108 (78.3)
      OAC naive, n (%)16 (36.4)13 (38.2)3 (30.0)141 (28.1)103 (28.3)38 (27.5)
      Aspirin at baseline, n (%)20 (45.5)15 (44.1)5 (50.0)261 (52.0)191 (52.5)70 (50.7)
      Clopidogrel at baseline, n (%)2 (4.5)2 (5.9)0 (0.0)53 (10.6)36 (9.9)17 (12.3)
      NSAID at baseline, n (%)0 (0.0)0 (0.0)0 (0.0)51 (10.2)38 (10.4)13 (9.4)
      PPI at baseline, n (%)8 (18.2)7 (20.6)1 (10.0)93 (18.5)64 (17.6)29 (21.0)
      NOTE. For all comparisons of cancer vs noncancer/undiagnosed lesions, P values were nonsignificant, except for NSAID at baseline, total vs total, P = .03.
      PPI, proton pump inhibitor.
      a All P values, D vs W, were nonsignificant.
      b All P values, D vs W, were nonsignificant, except for age, mean (SD), D vs W, P < .001.
      c A pooled dabigatran group including both patients on dabigatran 110 mg twice daily and dabigatran 150 mg twice daily.
      d N = 9; 1 patient had a missing baseline creatinine level.
      e N = 359; 5 patients had a missing baseline creatinine level.
      f N = 135; 3 patients had a missing baseline creatinine level.
      g N = 363; 1 patient had missing data on randomized treatment use at time of event.
      Patients with cancer-related MGIB were less likely than patients in the noncancer MGIB comparator group (n = 502) to be taking NSAIDs at baseline (0 of 44 [0%] vs 51 of 502 [10.2%]; P = .03), but the baseline clinical demographics and medication utilization in cancer-related MGIB and in the noncancer comparator group MGIB were otherwise similar.

       Time to Cancer-Related Major Gastrointestinal Bleeding

      Cancer-related MGIB events occurred across the study period (Figure 2). The mean time interval between study drug initiation and MGIB resulting from cancer did not differ between dabigatran users and warfarin users (P = .12). In dabigatran-treated patients, 19 of 34 (55.9%) cancer-related MGIB events occurred during the 4 months immediately after study drug initiation, whereas in warfarin-treated patients, 1 of 10 (10%) occurred during this time period. In both the cancer group and the comparator group, there were no significant differences between OAC-naive and OAC-experienced patients in time to MGIB.
      Figure thumbnail gr2
      Figure 2Time from treatment initiation to MGIB in patients on (A) dabigatran and (B) warfarin. Comparisons between MGIB from cancer (solid line) vs MGIB from a noncancer or an unidentified source (dashed line).
      The mean time interval between anticoagulant initiation and MGIB was shorter in the cancer-related bleeding group than the comparator group (223.1 vs 343.0 d; P = .003). This difference reflected a difference in patients receiving dabigatran (195.9 vs 335.9; P = .003) (Figure 2A), but not those receiving warfarin (317.9 vs 361.8; P = .59) (Figure 2B).

       Presentation of Cancer-Related Major Gastrointestinal Bleeding

      MGIB resulting from cancer presented as chronic bleeding in 63.6% of patients and acute/subacute bleeding in 27.3% (11.4% subacute and 15.9% acute) (Table 2). Cancer-related MGIB presented as overt bleeding in 65.9% of patients (hematemesis, 2.3%; hematochezia, 40.9%; and melena, 22.7%) and as occult in 34.1% (FOBT+, 4.5%; decrease in Hgb level, 20.5%; constitutional symptoms and decrease in Hgb level, 6.8%; and constitutional symptoms and FOBT+, 2.3%). Cancer-related MGIB was more likely to present as hematochezia in patients taking dabigatran compared with warfarin (50.0% vs 10.0%; P = .03), and there was a trend toward this cancer-related MGIB presenting more commonly as chronic bleeding in patients taking warfarin compared with dabigatran (90.0% vs 55.9%; P = .07).
      Table 2Presentation and Diagnosis of MGIB Events During the RE-LY Trial
      Bleeding from cancer
      All P values, D vs W, were nonsignificant except for hematochezia (P = .03) and radiology (P = .03).
      Bleeding from noncancer or from undiagnosed lesion
      All P values, D vs W, were nonsignificant.
      Bleeding from cancer vs from noncancer/undiagnosed lesion
      Total (N = 44)Dabigatran (N = 34)
      A pooled dabigatran group including both events on dabigatran 110 mg twice daily and dabigatran 150 mg twice daily.
      Warfarin (N = 10)Total (N = 502)Dabigatran (N = 364)
      A pooled dabigatran group including both events on dabigatran 110 mg twice daily and dabigatran 150 mg twice daily.
      Warfarin (N = 138)Total vs total, P valueD vs D, P valueW vs W, P value
      Time course of bleeding
      Chronic was defined as >7 days, subacute was defined as 2 to 7 days, and acute was defined as <2 days.
       Chronic28 (63.6)19 (55.9)9 (90.0)137 (27.3)106 (29.1)31 (22.5)<.001.003<.001
       Acute/subacute12 (27.3)11 (32.4)1 (10.0)302 (60.2)212 (58.2)90 (65.2)<.001.006<.001
       Unknown4 (9.1)4 (11.8)0 (0.0)63 (12.5)46 (12.6)17 (12.3).006.02.61
      Primary presenting sign
       Hematemesis1 (2.3)0 (0.0)1 (10.0)38 (7.6)24 (6.6)14 (10.1).35.25>.99
       Hematochezia18 (40.9)17 (50.0)1 (10.0)181 (36.1)132 (36.3)49 (35.5).52.14.17
       Melena10 (22.7)7 (20.6)3 (30.0)170 (33.9)127 (34.9)43 (31.2).18.13>.99
       Occult
      Occult was defined as a composite of a positive FOBT, constitutional signs or symptoms, a decrease in Hgb level, constitutional signs or symptoms with a decrease in Hgb level, and constitutional signs or symptoms with a positive FOBT, without overt bleeding.
      15 (34.1)10 (29.4)5 (50.0)108 (21.5)77 (21.2)31 (22.5).06.28.06
       Unknown0 (0.0)0 (0.0)0 (0.0)5 (1.0)4 (1.1)1 (0.7).003.003>.99
      Mode of source diagnosis
      Bleeding events could be counted in more than 1 category.
       Surgery1 (2.3)0 (0.0)1 (10.0)4 (0.8)4 (1.1)0 (0.0).34>.99.07
       Endoscopy43 (97.7)34 (100.0)9 (90.0)257 (51.2)185 (50.8)72 (52.2)<.001<.001.02
       Radiology4 (9.1)1 (2.9)3 (30.0)21 (4.2)17 (4.7)4 (2.9).13>.99.007
      a All P values, D vs W, were nonsignificant except for hematochezia (P = .03) and radiology (P = .03).
      b All P values, D vs W, were nonsignificant.
      c A pooled dabigatran group including both events on dabigatran 110 mg twice daily and dabigatran 150 mg twice daily.
      d Chronic was defined as >7 days, subacute was defined as 2 to 7 days, and acute was defined as <2 days.
      e Occult was defined as a composite of a positive FOBT, constitutional signs or symptoms, a decrease in Hgb level, constitutional signs or symptoms with a decrease in Hgb level, and constitutional signs or symptoms with a positive FOBT, without overt bleeding.
      f Bleeding events could be counted in more than 1 category.
      MGIB in the cancer cohort was more likely to be chronic than MGIB in the comparator cohort in the dabigatran group, warfarin group, and overall (55.9% vs 29.1%, P = .003; 90.0% vs 22.6%, P < .001; and 63.6% vs 27.3%, P < .001, respectively). Conversely, MGIB in the comparator cohort was more likely to be acute or subacute in comparison with MGIB in the cancer cohort in patients taking dabigatran (58.2% vs 32.4%; P = .006), warfarin (65.2% vs 10.0%; P < .001), and overall (60.2% vs 27.3%; P < .001).

       Outcomes of Major Gastrointestinal Bleeding

      Patients with cancer-related MGIB (n = 44) were hospitalized in 81.4% (n = 35) of cases and 25.6% (n = 11) required admission to the intensive care unit (ICU) (Table 3). The average length of stay was 10.1 nights. Two (4.5%) of the MGIBs required emergent endoscopic treatment, 1 (2.3%) required emergent surgical treatment, and 33 (75.0%) required at least 1 red blood cell transfusion. No patients died as a result of cancer-related MGIB.
      Table 3Outcomes of MGIB Events in Patients Receiving Warfarin or Dabigatran During the RE-LY Trial
      Bleeding from cancer
      All P values, D vs W, were nonsignificant.
      Bleeding from noncancer or from undiagnosed lesion
      All P values, D vs W, were nonsignificant.
      Total (N = 44)Dabigatran (N = 34)
      A pooled dabigatran group including both those on dabigatran 110 mg twice daily and dabigatran 150 mg twice daily.
      Warfarin (N = 10)Total (N = 502)Dabigatran (N = 364)
      A pooled dabigatran group including both those on dabigatran 110 mg twice daily and dabigatran 150 mg twice daily.
      Warfarin (N = 138)
      Hospitalization, n (%)35 (81.4)29 (85.3)6 (66.7)
      N = 9; 1 patient was missing data on hospitalization, nights in the hospital, and ICU admission.
      441 (87.8)321 (88.2)120 (87.0)
      Nights in hospital, mean (SD)10.1 (10.4)11.3 (11.0)5.4 (6.4)
      N = 9; 1 patient was missing data on hospitalization, nights in the hospital, and ICU admission.
      8.0 (17.8)8.1 (19.5)
      N = 363; 1 patient was missing data on nights in the hospital.
      7.6 (11.8)
      N = 137; 1 patient was missing data on nights in the hospital.
      Required ICU admission, n (%)11 (25.6)8 (23.5)3 (33.3)
      N = 9; 1 patient was missing data on hospitalization, nights in the hospital, and ICU admission.
      99 (19.7)71 (19.5)28 (20.3)
      Required transfusion, n (%)33 (75.0)26 (76.5)7 (70.0)347 (69.1)259 (71.2)88 (63.8)
      Required emergent endoscopic treatment of bleeding site, n (%)2 (4.5)2 (5.9)0 (0.0)69 (13.7)54 (14.8)15 (10.9)
      Required emergent surgical treatment of bleeding site, n (%)1 (2.3)1 (2.9)0 (0.0)7 (1.4)7 (1.9)0 (0.0)
      Death resulting from MGIB, n (%)0 (0.0)0 (0.0)0 (0.0)12 (2.4)9 (2.5)3 (2.2)
      Death, possibly resulting from MGIB, n (%)0 (0.0)0 (0.0)0 (0.0)4 (0.8)3 (0.8)1 (0.7)
      NOTE. For all comparisons of cancer vs noncancer/undiagnosed lesions, P values were nonsignificant.
      a All P values, D vs W, were nonsignificant.
      b All P values, D vs W, were nonsignificant.
      c A pooled dabigatran group including both those on dabigatran 110 mg twice daily and dabigatran 150 mg twice daily.
      d N = 9; 1 patient was missing data on hospitalization, nights in the hospital, and ICU admission.
      e N = 363; 1 patient was missing data on nights in the hospital.
      f N = 137; 1 patient was missing data on nights in the hospital.
      There were no significant differences between dabigatran- and warfarin-treated patients in short-term outcomes including hospitalization rate, mean nights in the hospital, ICU requirement, transfusion requirement, and need for endoscopic and surgical intervention. Likewise, hospitalization rate, mean nights in the hospital, ICU requirement, transfusion requirement, need for endoscopic intervention, and need for surgical intervention were similar in the cancer and comparator cohorts. A total of 12 patients died as a result of bleeding in 502 MGIB events in the comparator group (2.4%) vs 0 patients in 44 cancer-related bleeds.

      Discussion

      The current study represents a large cohort study that used primary source documents to verify and characterize MGIB resulting from cancer in patients receiving DOACs and VKAs. Most prior studies on cancer bleeding have been case reports and case series in patients receiving warfarin.
      • McCall K.L.
      • MacLaughlin E.J.
      Warfarin-associated bleeding complication saved life.
      • Michaels M.M.
      Bleeding from occult tumors during anticoagulant therapy.
      • Norton S.
      • Armstrong C.
      Lower gastrointestinal bleeding during anticoagulant therapy: a life-saving complication?.
      • Hashash J.G.
      • Shamseddeen W.
      • Skoury A.
      • et al.
      Gross lower gastrointestinal bleeding in patients on anticoagulant and/or antiplatelet therapy: endoscopic findings, management, and clinical outcomes.
      Our study is relevant because of the increasing prevalence of AF and anticoagulation in the aging global population,
      • Mozaffarian D.
      • Benjamin E.J.
      • Go A.S.
      • et al.
      Heart disease and stroke statistics—2016 update.
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      the increasing prescription of DOACs, and the morbidity, mortality, and complex decision making associated with MGIB and especially cancer-related MGIB in patients receiving anticoagulation therapy.
      • Manatsathit W.
      • Al-Hamid H.
      • Leelasinjaroen P.
      • et al.
      Management of gastrointestinal bleeding in patients anticoagulated with dabigatran compared with warfarin: a retrospective, comparative case review.
      • Ghate S.R.
      • Biskupiak J.
      • Ye X.
      • et al.
      All-cause and bleeding-related health care costs in warfarin-treated patients with atrial fibrillation.
      The pivotal, global studies of the DOACs, such as RE-LY, upon which the approval of dabigatran in chronic AF was based, provide a novel opportunity to understand anticoagulation-related GI hemorrhage. It has been reported previously that MGIB overall is higher with dabigatran 150 twice daily (but not 110 twice daily) than with warfarin, that the highest GI bleeding rate is soon after initiation of anticoagulation,
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Graham D.J.
      • Reichman M.E.
      • Wernecke M.
      • et al.
      Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation.
      • Eikelboom J.W.
      • Wallentin L.
      • Connolly S.J.
      • et al.
      Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) Trial.
      • Sherid M.
      • Sifuentes H.
      • Sulaiman S.
      • et al.
      Gastrointestinal bleeding with dabigatran, a comparative study with warfarin: a multicenter experience.
      and that a higher proportion of dabigatran- than warfarin-associated bleeds are from a lower gastrointestinal source.
      • Eikelboom J.W.
      • Wallentin L.
      • Connolly S.J.
      • et al.
      Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) Trial.
      • Sherid M.
      • Sifuentes H.
      • Sulaiman S.
      • et al.
      Gastrointestinal bleeding with dabigatran, a comparative study with warfarin: a multicenter experience.
      The principal findings of our study were as follows: (1) approximately 1 in 12 MGIBs in patients receiving anticoagulation therapy reflects an underlying GI tract malignancy, most commonly CRC; (2) cancer-related MGIB in patients taking anticoagulants presents with chronic bleeding in approximately two thirds of cases, as opposed to MGIB in patients in whom cancer is not diagnosed, in whom approximately two thirds of cases present as recent-onset bleeding; (3) MGIB in dabigatran users owing to gastrointestinal cancer presents sooner after initiation of anticoagulation than MGIB in dabigatran users in whom gastrointestinal cancer has not been diagnosed; and (4) cancer-related MGIB in patients receiving anticoagulation therapy results in significant morbidity and resource consumption.
      Our observations suggest several recommendations. First, as suggested in prior studies, MGIB, in particular chronic MGIB, in the patient receiving anticoagulation therapy requires investigation and is not dismissible as an incidental manifestation of anticoagulation.
      • McCall K.L.
      • MacLaughlin E.J.
      Warfarin-associated bleeding complication saved life.
      • Norton S.
      • Armstrong C.
      Lower gastrointestinal bleeding during anticoagulant therapy: a life-saving complication?.
      • Jaffin B.W.
      • Bliss C.M.
      • LaMont J.T.
      Significance of occult gastrointestinal bleeding during anticoagulation therapy.
      • Hashash J.G.
      • Shamseddeen W.
      • Skoury A.
      • et al.
      Gross lower gastrointestinal bleeding in patients on anticoagulant and/or antiplatelet therapy: endoscopic findings, management, and clinical outcomes.
      Second, because cancer-related MGIB in AF patients receiving anticoagulation is common and results in significant morbidity and resource consumption, proactive diagnostic strategies may be worthwhile. For example, guideline-based GI cancer screening before initiating anticoagulation or periodic noninvasive screening for occult GI bleeding during anticoagulation treatment (eg, by programmatic stool or blood testing) may allow earlier cancer detection and thereby decrease morbidity and resource utilization.
      • Johannsdottir G.A.
      • Onundarson P.T.
      • Gudmundsdottir B.R.
      • et al.
      Screening for anemia in patients on warfarin facilitates diagnosis of gastrointestinal malignancies and pre-malignant lesions.
      • Clemens A.
      • Strack A.
      • Noack H.
      • et al.
      Anticoagulant-related gastrointestinal bleeding—could this facilitate early detection of benign or malignant gastrointestinal lesions?.
      Prospective studies of these strategies are needed. Thus far, most studies have shown that anticoagulant use has no deleterious effect on the positive predictive value of FOBT for detecting gastrointestinal malignancy.
      • Bini E.J.
      • Rajapaksa R.C.
      • Weinshel E.H.
      Positive predictive value of fecal occult blood testing in persons taking warfarin.
      • Mandelli G.
      • Radaelli F.
      • Paggi S.
      • et al.
      Anticoagulant or aspirin treatment does not affect the positive predictive value of an immunological fecal occult blood test in patients undergoing colorectal cancer screening: results from a nested in a cohort case-control study.
      Another study has shown no cross-reactivity between FOBTs and dabigatran.
      • Goss A.M.
      • van Ryn J.
      • Schurer J.
      • et al.
      Assessment of cross-reactivity in three different fecal occult blood test systems with dabigatran and dabigatran etexilate: identification of useful test methods.
      It is uncertain why MGIB appears sooner in dabigatran users with a malignant bleeding source than in those in whom cancer is not diagnosed. This observation is of scientific rather than clinical interest because bleeding always should be investigated methodically. We hypothesize that the observed difference may reflect the dissimilar anticoagulant pharmacology. The oral bioavailability of warfarin is essentially 100%,
      whereas that of dabigatran is approximately 7%.
      • Blech S.
      • Ebner T.
      • Ludwig-Schwellinger E.
      • et al.
      The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans.
      Dabigatran, ingested as an inactive prodrug, is converted to the active form by esterases as it passes through the GI tract.
      • Blech S.
      • Ebner T.
      • Ludwig-Schwellinger E.
      • et al.
      The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans.
      This results in progressively higher active dabigatran concentrations in the distal GI tract, which may act as a topical anticoagulant.
      • Eikelboom J.W.
      • Wallentin L.
      • Connolly S.J.
      • et al.
      Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) Trial.
      • Sherid M.
      • Sifuentes H.
      • Sulaiman S.
      • et al.
      Gastrointestinal bleeding with dabigatran, a comparative study with warfarin: a multicenter experience.
      • Desai J.
      • Granger C.B.
      • Weitz J.I.
      • et al.
      Novel oral anticoagulants in gastroenterology practice.
      • Blech S.
      • Ebner T.
      • Ludwig-Schwellinger E.
      • et al.
      The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans.
      Cancers such as CRC are highly vascular and friable, and typically bleed slowly but persistently.
      • James M.W.
      • Chen C.M.
      • Goddard W.P.
      • et al.
      Risk factors for gastrointestinal malignancy in patients with iron-deficiency anaemia.
      As such, they may be particularly susceptible to the topical and systemic effects of dabigatran. Earlier detection could result in better cancer-related outcomes.
      • Mandel J.S.
      • Church T.R.
      • Ederer F.
      • et al.
      Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood.
      • Mandel J.S.
      • Bond J.H.
      • Church T.R.
      • et al.
      Reducing mortality from colorectal cancer by screening for fecal occult blood.
      Topical dabigatran activity also may underlie the significant increase in MGIB from CRC in the dabigatran group compared with those on warfarin.
      Previous studies have suggested that warfarin-related GI bleeding results in significant morbidity and cost.
      • Ghate S.R.
      • Biskupiak J.
      • Ye X.
      • et al.
      All-cause and bleeding-related health care costs in warfarin-treated patients with atrial fibrillation.
      • Guerrouij M.
      • Uppal C.S.
      • Alklabi A.
      • et al.
      The clinical impact of bleeding during oral anticoagulant therapy: assessment of morbidity, mortality and post-bleed anticoagulant management.
      Our results confirm this observation and suggest that dabigatran treatment is associated with similar bleeding-related outcomes to warfarin treatment in patients bleeding from a cancer source and those in whom cancer was not diagnosed. Patients bleeding from cancer required a mean of approximately 10 nights in the hospital, and approximately one-fourth required intensive care, but 0 of 44 died as a direct result of the bleeding. It is hoped that the specific dabigatran reversal agent idarucizumab will improve bleeding outcomes in dabigatran-treated patients.
      • Pollack Jr., C.V.
      • Reilly P.A.
      • Eikelboom J.
      • et al.
      Idarucizumab for dabigatran reversal.
      In this retrospective review, we were limited by the quality of data collected during RE-LY. For example, as discussed in the Methods section, it is possible that a small fraction of patients in the comparator group bled from an undiagnosed cancer. Likewise, data regarding NSAID use at the time of MGIB events was not reliably available. We minimized the impact of these limitations by having 2 experienced gastroenterologists evaluate the source documents, and the high rate of concordance between these gastroenterologists and the RE-LY committee is reassuring. In addition, although there were 546 unique MGIB events in this study, there were only 34 cancer-related MGIB events with dabigatran and 10 with warfarin, so our power to detect differences between these groups was limited.
      In conclusion, our results suggest that approximately 1 in 12 MGIBs in AF patients taking warfarin or dabigatran is caused by an underlying cancer. This bleeding results in significant morbidity and resource consumption, which is similar in the 2 drug treatment groups. These findings have implications related to diagnosis and clinical management of patients receiving anticoagulation treatment.

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