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Restarting Anticoagulation and Outcomes After Major Gastrointestinal Bleeding in Atrial Fibrillation

Published:November 25, 2013DOI:https://doi.org/10.1016/j.amjcard.2013.10.044
      Data regarding the outcomes of restarting anticoagulation in patients who develop gastrointestinal bleeding (GIB) while anticoagulated are sparse. We hypothesized that restarting anticoagulation in these patients is associated with better outcomes. This is a retrospective cohort study that enrolled subjects who developed GIB while on anticoagulation from 2005 to 2010. Atrial fibrillation was defined by history and electrocardiography on presentation. GIB was defined as a decrease in hemoglobin by 2 g, visible bleeding, or positive endoscopic evaluation. Time-to-event adjusted analyses were performed to find an association of restarting warfarin and recurrent GIB, arterial thromboembolism, and mortality. Stratified analysis by duration of interruption of warfarin was also performed. Overall, 1,329 patients (mean age 76 years, women 45%) developed major GIB. Warfarin was restarted in 653 cases (49.1%). Restarting warfarin was associated with decreased thromboembolism (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.54 to 0.93, p = 0.01) and reduced mortality (HR 0.67, 95% CI 0.56 to 0.81, p <0.0001) but not recurrent GIB (HR 1.18, 95% CI 0.94 to 1.10, p = 0.47). When the outcomes were stratified by duration of warfarin interruption, restarting warfarin after 7 days was not associated with increased risk of GIB but was associated with decreased risk of mortality and thromboembolism compared with resuming after 30 days of interruption. Decision to restart warfarin after an episode of major GIB is associated with improved survival and decreased thromboembolism without increased risk of GIB after 7 days of interruption.
      In patients with nonvalvular atrial fibrillation (AF), warfarin has been the anticoagulant agent of choice for the last 3 decades.
      • Mant J.W.
      Pro: ‘Warfarin should be the drug of choice for thromboprophylaxis in elderly patients with atrial fibrillation’. Why warfarin should really be the drug of choice for stroke prevention in elderly patients with atrial fibrillation.
      Elderly patients appear to have a greater propensity for complications of therapy such as GIB on one end or cerebrovascular events on the other end of the therapeutic spectrum.
      • Suehiro T.
      • Yakeishi Y.
      • Sakai F.
      • Matsuzaki K.
      • Sanefuji K.
      • Toyokawa T.
      • Shioshita K.
      • Sugie Y.
      • Okudaira Y.
      • Kano T.
      • Mine H.
      • Suetsugu K.
      • Suetsugu F.
      • Suehiro N.
      • Suhiro K.
      Gastrointestinal bleeding and blood transfusion in the elderly in Japan.
      GIB occurs in 5% to 15% of patients on long-term anticoagulation.
      • Lee J.K.
      • Kang H.W.
      • Kim S.G.
      • Kim J.S.
      • Jung H.C.
      Risks related with withholding and resuming anticoagulation in patients with non-variceal upper gastrointestinal bleeding while on warfarin therapy.
      • Fihn S.D.
      • McDonell M.
      • Martin D.
      • Henikoff J.
      • Vermes D.
      • Kent D.
      • White R.H.
      Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group.
      • Landefeld C.S.
      • Beyth R.J.
      Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention.
      Literature is scarce about the various outcomes in this specific population and controversy exists regarding various outcomes based on durations of interruption of warfarin. Short-term interruption has been shown to increase mortality and thromboembolism.
      • Raunso J.
      • Selmer C.
      • Olesen J.B.
      • Charlot M.G.
      • Olsen A.M.
      • Bretler D.M.
      • Nielsen J.D.
      • Dominguez H.
      • Gadsboll N.
      • Kober L.
      • Gislason G.H.
      • Torp-Pedersen C.
      • Hansen M.L.
      Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation.
      It is important to understand the risks of development of recurrent gastrointestinal hemorrhage, mortality, and thromboembolism in the context of resuming warfarin in this particular group. Warfarin has shown to not only improve cardiovascular mortality but also quality of life.
      • Smith P.
      Long-term anticoagulant treatment after acute myocardial infarction. The Warfarin Re-Infarction Study.
      • Das A.K.
      • Willcoxson P.D.
      • Corrado O.J.
      • West R.M.
      The impact of long-term warfarin on the quality of life of elderly people with atrial fibrillation.
      We hypothesized that warfarin treatment prevents thromboembolism and has mortality benefit over the subjects who are not restarted on warfarin. Also, we investigated the various durations of interruption and the risk of GIB, thromboembolism, and mortality.

      Methods

      This is a retrospective cohort study that evaluated the patients enrolled at the anticoagulation clinic of Henry Ford Health System with a large catchment area serving all socioeconomic strata, covering majority of Southeast Michigan, United States. Patients who developed major GIB (defined in the following) while taking warfarin and then had evidence of resolution of major GIB (defined as stability of hemoglobin levels with <1 g decrease of hemoglobin for 48 hours) were included in the study. Patients who died within the first 72 hours of GIB, hospice, postoperative or valvular AF, patients in whom primary indication for anticoagulation was any reason other than nonvalvular AF, and patients in whom warfarin was not interrupted for at least 48 hours were excluded.
      Data were initially obtained from insurance claims of warfarin that were evaluated at Henry Ford Health System from January 2005 to December 2010. Patients who had commenced using warfarin for at least 1 year and with at least 2 prescriptions of warfarin within 3 months of contact with a physician were enrolled. In the absence of mortality, at least 2 years of available follow-up after that initial contact in the electronic health record system was a prerequisite. The database query was further narrowed using International Classification of Diseases, Ninth Revision, code 427.3, 427.31, and 427.32 for AF. They were then evaluated for the indications of anticoagulation. Patients other than those with nonvalvular AF as the primary reason for anticoagulation were excluded. The charts of these patients were evaluated to identify major GIB that led to discontinuation of warfarin therapy for at least 2 days. Eventually, 1,329 patients satisfied these criteria. They were reevaluated for accuracy by identifying either a history of AF or atrial flutter in the anticoagulation clinic notes or AF or atrial flutter on the electrocardiogram. A detailed chart review of these patients was carried out by the physician-investigators, and information on demographics, medication use, and other clinical variables was obtained. Index GIB was defined as information collected on the day of GIB and subsequently at the time of resolution of index GIB. Information for CHADS2 and HAS-BLED was collected at the resolution of index GIB. The consortium diagram is available in the Supplementary material. Index GIB was defined as a decrease in hemoglobin of ≥2 g/dl and/or transfusion of ≥2 units of packed red blood cells with at least one of the following: hematemesis, melena, hematochezia, bright red blood per rectum, blood in nasogastric aspirate, or bleeding documented during an endoscopic procedure. The study protocol was approved by the institutional review board.
      Restarting warfarin was defined as prescription of warfarin with objective evidence of increase in international normalized ratio to ≥2.0 with evidence of at least 2 days of discontinuation of warfarin as observed by chart review. Patients who interrupted warfarin after 1 month of restarting warfarin (54; 4.1%) were included in the group that restarted warfarin. Patients who started warfarin after 6 months of interruption (39, 2.9%) were included in the group that did not restart warfarin (warfarin cessation group). Patients who interrupted warfarin within the first month (12; 0.9%) were included in the warfarin cessation group.
      Recurrent major GIB was defined as any of the following: (1) >2 g of hemoglobin decrease from the last known hemoglobin level warranting hospitalization, (2) need for blood transfusion of at least 2 units, and (3) visible bleeding by health personnel or endoscopic evidence of stigmata of recent bleeding in the form of visible bleeding or clot. We decided to analyze GIB within 90 days, as propensity for recurrent GIB should be short term. Also, 12% of the patients developed recurrent GIB and we only considered the index GIB.
      Thromboembolism was defined as venous thromboembolism (pulmonary embolism and deep venous thrombosis), arterial thromboembolism, or stroke or transient ischemic attack. Stroke or transient ischemic attack was defined as any of the following: (1) recent stroke on brain computed tomogram, (2) on brain magnetic resonance image, and (3) diagnosis of stroke or transient ischemic attack by a neurologist. This outcome was obtained over 1-year duration and only the first episode of thromboembolism was considered as an outcome. Mortality data were updated from the Social Security Death Index, death certificates, or hospital notes. Outcomes were evaluated by 2 blind reviewers (FK and ZA). These were then rechecked and conflicts resolved by consensus.
      Descriptive statistics were used to summarize the data. Continuous variables are expressed as mean ± SD and categorical variables are mentioned in percentages. They were analyzed using t test for continuous variables and Fisher's exact test or chi-square test for categorical variables, as appropriate. Univariate analyses and adjusted Cox proportional analyses were conducted to enunciate the association between restarting warfarin therapy and outcomes. These analyses were adjusted for age, gender, race, Charlson co-morbidity index, number of blood product transfusions, international normalized ratio on admission, and CHADS2 and HAS-BLED scores. Cumulative incidences were evaluated using Kaplan-Meier method. Time of interruption of warfarin along with restarting warfarin status was added as an interaction term in the Cox proportional hazards model to investigate the association of time in development of thromboembolism, mortality, and recurrent GIB. Because the interaction was significant, we divided the time of interruption of warfarin into 5 groups (<7, 7 to 15, 15 to 21, 21 to 30, and >30 days). Incidences were calculated by the formula: incidence per 100 person-years. Incidence rate ratios were calculated by the formula: incidence rate per 100 person-years of/incidence rate per 100 person-years in patients who interrupted warfarin for >30 days. Kaplan-Meier curves were produced to evaluate the differences in the cumulative incidences of recurrent GIB, mortality, and thromboembolism stratified by time duration of interruption of warfarin and cessation of warfarin use. All analyses were performed using PASW, version 18.0 (SPSS Inc., Chicago, Illinois), and JMP Pro 10.0 (SAS Institute, Cary, North Carolina). The study was analyzed on the basis of the initial group assigned to the patient (similar to intention-to-treat analysis) and p value of <0.05 was considered significant.

      Results

      Overall, 1,329 patients (mean age 75 ± 11 years, women 47%) developed GIB during January 2005 to December 2010. There were 653 patients (49%) who were restarted on warfarin after a median duration of 50 days (interquartile range 21 to 78). The median CHADS2 and HAS-BLED scores were 3. Endoscopic evaluation was performed in 883 cases (66.4%). Chronic AF was present in 751 (52.6%), persistent AF in 345 (25.9%), and paroxysmal AF in 233 patients (17.5%). Caucasians, patients with concomitant upper and lower sources for GIB, diabetics, patients with renal disease, history of coronary artery disease, and history of falls were less likely to be restarted on warfarin (p <0.05; Table 1). Overall, there were greater co-morbidity burdens in the patients who were not restarted on warfarin. Major reasons for not restarting warfarin were physician preference (18%) and patient's inability to follow up with the anticoagulation clinic (19%).
      Table 1Baseline characteristics of the cohort
      VariableWarfarin Restartedp Value
      Yes (n = 653)No (n = 676)
      Age (yrs)74.8 ± 10.775.3 ± 10.70.43
      Men364 (55.7)336 (49.7)0.03
      White413 (63.2)437 (64.6)0.60
      Hyperlipidemia169 (25.9)196 (29.0)0.30
      Previous coronary artery disease54 (8.2)89 (13.1)0.005
      Smoker124 (19.0)158 (23.4)0.06
      Framingham risk score11.26 ± 8.1312.20 ± 8.60.04
      History of falls69 (10.6)124 (18.3)0.0001
      Cancer52 (7.9)65 (9.6)0.33
      INR at the time of gastrointestinal bleed2.873.060.22
      CHADS2 (median score)3 (2–4)3 (2–4)0.08
      Previous congestive heart failure156 (23.9)181 (26.7)0.23
      Hypertension575 (88.0)624 (95.6)0.06
      Diabetes mellitus211 (32.3)233 (34.5)0.42
      Thromboembolism190 (29.1)208 (30.7)0.1
      Peripheral vascular disease89 (13.6)96 (14.2)0.81
      HAS-BLED (median score)3 (1–4)3 (1–4)0.09
      Labile INR198 (30.3)218 (32.2)0.47
      Alcohol use43 (6.6)56 (8.2)0.25
      Abnormal renal function109 (16.7)146 (21.6)0.02
      Abnormal liver function25 (3.8)36 (4.4)0.23
      Previous major gastrointestinal bleed85 (13.0)99 (14.6)0.42
      TTR before gastrointestinal bleed57.5580.65
      Systolic blood pressure (mm Hg)
      Mean systolic blood pressure after resolution of GIB during the hospital stay.
      144.6 ± 28.9145.8 ± 21.80.80
      Medications on admission
       Aspirin154 (23.5)169 (25)0.56
       Nonsteroidal analgesic drug use33 (5.0)36 (4.9)0.90
       Antiplatelets15 (2.3)19 (2.8)0.60
       Proton pump inhibitor use79 (12.3)112 (16.5)0.02
       H2 blocker use24 (3.7)33 (4.8)0.28
      Location of the bleed
       Esophageal20 (3)23 (3.4)0.75
       Stomach and duodenum213 (32.6)216 (32.0)0.81
       Small intestine12 (1.8)12 (1.8)1.00
       Colon and rectum342 (52.3)359 (53.1)0.86
       Upper and lower15 (2.3)28 (4.1)0.06
       Obscure51 (7.8)38 (5.6)0.12
      Clinical presentation
       Occult24 (3.7)44 (6.5)0.02
       Hematochezia96 (14.7)105 (15.5)0.70
       Melena213 (32.7)225 (33.3)0.82
       Hematemesis86 (12.4)103 (15.2)0.30
       Blood in stools244 (37.4)264 (39.0)0.53
       Diagnosis on endoscopic evaluation13 (2.0)15 (2.2)0.85
       Nasogastric aspiration31 (4.7)49 (7.2)0.06
       Anemia on presentation85 (13.0)93 (13.7)0.74
      Setting of presentation
       Clinic47 (7.2)62 (9.2)0.20
       Emergency room112 (17.2)254 (37.6)0.0001
       Hospital494 (75.6)360 (53.2)0.0001
       Intensive care unit admission123 (18.8)139 (19.1)0.45
      Management
       No blood transfusion235 (36.0)264 (39.1)0.27
       No fresh frozen plasma336 (51.5)377 (55.7)0.12
       No vitamin K474 (72.6)482 (71.3)0.68
      Length of stay (days)4.7 ± 4.64.5 ± 4.00.27
      Data are presented as mean ± SD, percentage, or n (%).
      Previous coronary artery disease defined as a history of acute coronary syndrome or revascularization; hyperlipidemia defined as total cholesterol >200 mg/dl or lipid-lowering medication use; anemia defined as hemoglobin <10 mg/dl after resolution of gastrointestinal bleed.
      CHADS2 = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (age ≥65 years), Drugs/alcohol; INR = international normalized ratio (detailed definitions are in the Supplementary material); TTR = time within therapeutic range.
      Mean systolic blood pressure after resolution of GIB during the hospital stay.
      In total, 463 deaths occurred over a period of 2 years. Restarting warfarin was independently associated with decreased mortality (adjusted hazard ratio 0.66, 95% confidence interval 0.55 to 0.80, p <0.0001) compared with warfarin cessation group. The survival analysis is shown in Figure 1. There were 4 thromboembolism-related deaths all in the patients in whom warfarin was stopped, whereas, there was only 1 death attributable to massive gastrointestinal hemorrhage in the patients who resumed warfarin. There was no significant difference in survival by the duration of interruption of warfarin <30 days; however, as the interruption duration became longer, the survival approached toward the group that did not resume warfarin (Figure 2).
      Figure thumbnail gr1
      Figure 1(A) Kaplan-Meier survival analysis showing 1-year mortality in patients who were restarted on warfarin (restarted) versus those who were not (not restarted). (B) Time-to-event analysis showing 90-day cumulative incidence of recurrent GIB in patients who were restarted on warfarin (restarted) versus those who were not (not restarted). (C) Time-to-event analysis showing 1-year cumulative incidence of thromboembolism in patients who were restarted on warfarin (restarted) versus those who were not (not restarted).
      Figure thumbnail gr2
      Figure 2(A) Kaplan-Meier survival analysis showing 1-year mortality stratified by duration of interruption of warfarin. (B) Time-to-event analysis showing 90-day cumulative incidence of recurrent GIB stratified by duration of interruption of warfarin. (C) Time-to-event analysis showing 1-year cumulative incidence of thromboembolism stratified by duration of interruption of warfarin.
      There were 90 patients who developed recurrent major GIB within 90 days of index GIB (Table 2). The freedom from 90-day recurrent GIB is shown in Figure 1. Cumulative incidences of GIB based on duration of interruption of warfarin are given in Figure 2, which shows that the group that restarted warfarin within the first 7 days has greater risk of recurrent GIB; however, the cumulative incidences of the rest of the groups are very similar to the group that restarted warfarin after 30 days. Table 3 demonstrates the incidences of patients stratified by days of interruption of warfarin. It also shows the incidence rate ratios compared with the group that was restarted on warfarin after 30 days of interruption of warfarin. The incidence rate ratios of 7- to 15-day, 15- to 21-day, and 21- to 30-day groups are not significantly different for recurrent GIB from the incidence rate ratio of patients who restarted warfarin after 30 days of interruption (Table 3).
      Table 2Unadjusted and adjusted hazard ratios for restarting warfarin versus not restarting warfarin
      OutcomeUnadjusted Hazard Ratio (95% CI)p ValueAdjusted Hazard Ratio (95% CI)p Value
      Thromboembolism0.75 (0.58–0.98)0.030.71 (0.54–0.93)0.01
      Recurrent gastrointestinal bleed1.20 (0.78–1.86)0.401.18 (0.94–1.10)0.47
      Mortality0.72 (0.60–0.86)<0.00010.67 (0.56–0.81)<0.0001
      CI = confidence interval.
      Table 3Adjusted hazard ratios stratified by time duration of interruption of warfarin for various outcomes
      OutcomeWarfarin Restarted
      YesNo (n = 676)
      <7 Days (n = 62)7–15 Days (n = 51)15–21 Days (n = 58)21–30 Days (n = 53)>30 Days (n = 429)
      Thromboembolism
       Events97111251131
       Incidence11.6 (8.3–16.2)12.0 (8.2–17.5)18.1 (13.4–24.5)20.7 (15.5–27.7)20.4 (17.8–23.5)19.8 (18.1–21.6)
       IRR, p value0.57 (0.28–1.15), 0.110.59 (0.27–1.29), 0.180.89 (0.46–1.70), 0.731.01 (0.54–1.90), 0.97ReferenceNA
       HR (95% CI), p value0.76 (0.37–1.59), 0.470.48 (0.20–1.15), 0.090.60 (0.30–1.19), 0.141.00 (0.52–1.94), >0.99Reference1.35 (0.97–1.89), 0.07
      Recurrent GIB
       Events167762529
       Incidence19.3 (14.6–25.5)10.8 (7.2–16.3)10.9 (7.2–16.4)9.9 (6.3–15.5)9.9 (8.0–12.3)5.4 (4.5–6.6)
       IRR, p value1.95 (0.98–3.89), 0.061.09 (0.44–2.71), 0.851.09 (0.44–2.72), 0.851.00 (0.38–2.65), >0.99ReferenceNA
       HR (95% CI), p value3.27 (1.82–5.91), 0.0021.03 (0.45–2.35), 0.931.42 (0.65–3.11), 0.371.50 (0.55–4.04), 0.42Reference1.27 (0.75–2.13), 0.37
      Mortality
       Events17162021113276
       HR (95% CI), p value0.56 (0.33–0.93), 0.030.56 (0.33–0.98), 0.040.56 (0.34–0.90), 0.020.84 (0.52–1.35), 0.46Reference1.26 (1.01–1.57), 0.04
      CI = confidence interval; HR = hazard ratio; IRR = incidence rate ratio; NA = not applicable.
      There were 221 patients (16.6%) who developed a thromboembolic episode within 1 year of interruption of warfarin. The risk was reduced in patients who were restarted on warfarin (hazard ratio 0.71, 95% confidence interval 0.54 to 0.93, p = 0.01; Table 2). The freedom from 1-year thromboembolism is shown in Figure 1. Cumulative incidences of thromboembolic events based on duration of interruption of warfarin are given in Figure 2, which shows that there is a trend in decrease in the risk of thromboembolic events if anticoagulation was started earlier. Table 3 demonstrates the incidences of patients stratified by days of interruption of warfarin. It also lists the incidence rate ratios compared with the group that was restarted on warfarin after 30 days of interruption of warfarin. There is a trend toward reduced incidence the earlier the warfarin therapy is reinstituted (Table 3).

      Discussion

      This study provides incidences of thromboembolism, mortality, and recurrent GIB in patients who developed GIB while on anticoagulation for nonvalvular AF. The study also demonstrated that lower risks of thromboembolism and mortality were associated with resuming anticoagulation. There were also no significant differences in risk of GIB between resuming warfarin after 1 week of interruption of warfarin compared with restarting warfarin after 1 month; however, risk of recurrent GIB was significantly greater if warfarin was resumed within the first week of major GIB.
      We found that as many as 1/2 of the patients that interrupt warfarin during a major GIB did not resume taking warfarin. The study is not large enough to be generalizable to the rest of the country; however, the cohort had adequate diversity to provide an idea of this practice gap. Moreover, we also found that majority of the deaths and thromboembolic events occurred in the patients who did not restart warfarin within a month. Interrupting warfarin may lead to an increase in short-term risk of thromboembolism.
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      • Gislason G.H.
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      • Hansen M.L.
      Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation.
      This may have clinical implications especially if further research shows that early resumption of warfarin leads to better outcomes. For the purpose of our study, we equated the term cessation with interruption of >6 months and did not analyze them by causes. However, we noticed that majority of the cessation occurred due to inability to follow up with anticoagulation clinic or physician refusal of continuing anticoagulation due to the documentation of previous GIB (37%). These findings were markedly different from the findings of the Atrial Fibrillation Follow-up Investigation of Rhythm Management trial, in which physician refusal to continue warfarin and patient's refusal accounted for 19% of the cases.
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      Occurrence and characteristics of stroke events in the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM) study.
      Several previous studies have evaluated the treatment interruptions in surgical patients but are limited by the small number of events.
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      We had comparable sample size but found that our cohort experienced greater number of events. This is perhaps due to the higher co-morbidity burden in our patients. Patients who are at a greater risk of GIB are also at greater risk of thromboembolic events as the risk scores such as HAS-BLED and CHADS2 share many common variables. Another interesting finding was that, there, the incidence of thromboembolic events and deaths within the first 90 days of interruption of warfarin was greater than the incidences afterward. However, the risks for these events stayed higher in the group that did not restart warfarin suggesting that there might be other factors that might be playing a role in these events. Whether this occurred because of “rebound hypercoagulability” or “catch up” of events is not clear and is a matter of controversy.
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      Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit.
      To investigate the optimal duration of restarting warfarin after an episode of major GIB, we attempted to evaluate the different durations of interruption of warfarin with respect to the reference group of patients who resumed taking warfarin after 1 month. We found that patients who resumed taking warfarin in the first week were at a greater risk of recurrent GIB; however, the rest of the groups did not show significant differences. In contrast, lower risk of mortality and thromboembolism was associated with earlier re-initiation of warfarin. Although there are many other variables that physicians take into account while making a decision of resuming warfarin in these patients, we have provided the risks versus benefits of these treatment decisions that might have clinical implications.
      Our study faces the limitations that any study based on insurance claims and retrospective data does. Although we tried to narrow down our exposure variable, there was some crossover that occurred. However, we used an analysis similar to intention-to-treat analysis to minimize the confounding. We also were not able to enunciate all the factors that affect the clinical decision making. However, confirmation of thromboembolism, recurrent GIB, and mortality by way of medical chart review strengthens the validity of our data. The study is also susceptible to detection bias and may have underestimated the events of thromboembolism in the group that did not resume warfarin as there was less health-care contact. Also, patients who were perceived at greatest risk of GIB were probably not restarted on warfarin, and hence, the association of resuming warfarin with GIB might be underestimated. There might be also a component of survivorship bias as we only used the data for patients who were alive for at least 2 days after index major GIB. However, we wanted to avoid making conclusions about patients who were so ill that they did not survive their first 48 hours, which might have led to further underestimation of our results, as many of them did not resume taking warfarin. Also, as apparent in the baseline characteristics of the cohort, the patients restarted on warfarin had fewer co-morbidities, which might have led to improved outcomes. We performed various methods to adjust for this in the analysis; however, there was still a difference in mortality that was unexplained by just selection bias.

      Disclosures

      The authors have no conflicts of interest to disclose.

      Supplementary Data

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