Restarting Anticoagulation and Outcomes After Major Gastrointestinal Bleeding in Atrial Fibrillation Waqas Qureshi, MD a, *, Chetan Mittal, MD b , Iani Patsias, MD b , Kiran Garikapati, MD b , Aishwarya Kuchipudi, MD b , Gagandeep Cheema, MD b , Mohammad Elbatta, MD b , Zaid Alirhayim, MD b , and Fatima Khalid, MD c Data regarding the outcomes of restarting anticoagulation in patients who develop gastro- intestinal 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. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:662e668) In patients with nonvalvular atrial fibrillation (AF), warfarin has been the anticoagulant agent of choice for the last 3 decades. 1 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. 2 GIB occurs in 5% to 15% of pa- tients on long-term anticoagulation. 3e5 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 interrup- tion has been shown to increase mortality and thrombo- embolism. 6 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. 7,8 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 so- cioeconomic strata, covering majority of Southeast Michi- gan, 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 anti- coagulation 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 pre- requisite. The database query was further narrowed using a Section of Cardiovascular Medicine and c Section of Nephrology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina; and b Department of Internal Medicine, Henry Ford Hospital/Wayne State University School of Medi- cine, Detroit, Michigan. Manuscript received September 23, 2013; revised manuscript received and accepted October 24, 2013. The authors acknowledge the support from the Department of Internal Medicine of Henry Ford Health System for providing funding for admin- istrative data collection. See page 667 for disclosure information. *Corresponding author: Tel: (336) 716-7427; fax: (336) 713-0163. E-mail address: [email protected](W. Qureshi). 0002-9149/13/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. www.ajconline.org http://dx.doi.org/10.1016/j.amjcard.2013.10.044
Transcript
Restarting Anticoagulation and Outcomes After MajorGastrointestinal Bleeding in Atrial Fibrillation
Data regarding the outcomes of restarting anticoagulation in patients who develop gastro-
aSection of CDepartment of InMedicine, WinstoMedicine, Henrycine, Detroit, Micmanuscript receive
The authors acMedicine of Henristrative data colle
See page 667*CorrespondinE-mail addres
0002-9149/13/$ -http://dx.doi.org/1
intestinal bleeding (GIB) while anticoagulated are sparse. We hypothesized that restartinganticoagulation in these patients is associated with better outcomes. This is a retrospectivecohort study that enrolled subjects who developedGIBwhile on anticoagulation from 2005 to2010. Atrial fibrillation was defined by history and electrocardiography on presentation. GIBwas defined as a decrease in hemoglobin by 2 g, visible bleeding, or positive endoscopicevaluation. Time-to-event adjusted analyses were performed to find an association ofrestarting warfarin and recurrent GIB, arterial thromboembolism, and mortality. Stratifiedanalysis 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 (HR0.67, 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, restartingwarfarin after 7 days was not associated with increased risk of GIB but was associated withdecreased risk of mortality and thromboembolism compared with resuming after 30 days ofinterruption. Decision to restart warfarin after an episode of major GIB is associated withimproved survival and decreased thromboembolismwithout increased risk ofGIB after 7 daysof interruption. � 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:662e668)
In patients with nonvalvular atrial fibrillation (AF),warfarin has been the anticoagulant agent of choice for thelast 3 decades.1 Elderly patients appear to have a greaterpropensity for complications of therapy such as GIB onone end or cerebrovascular events on the other end of thetherapeutic spectrum.2 GIB occurs in 5% to 15% of pa-tients on long-term anticoagulation.3e5 Literature is scarceabout the various outcomes in this specific population andcontroversy exists regarding various outcomes based ondurations of interruption of warfarin. Short-term interrup-tion has been shown to increase mortality and thrombo-embolism.6 It is important to understand the risks ofdevelopment of recurrent gastrointestinal hemorrhage,mortality, and thromboembolism in the context ofresuming warfarin in this particular group. Warfarin hasshown to not only improve cardiovascular mortality butalso quality of life.7,8 We hypothesized that warfarin
ardiovascular Medicine and cSection of Nephrology,ternal Medicine, Wake Forest University School ofn-Salem, North Carolina; and bDepartment of InternalFord Hospital/Wayne State University School of Medi-higan. Manuscript received September 23, 2013; revisedd and accepted October 24, 2013.knowledge the support from the Department of Internaly Ford Health System for providing funding for admin-ction.for disclosure information.g author: Tel: (336) 716-7427; fax: (336) 713-0163.s: [email protected] (W. Qureshi).
see front matter � 2014 Elsevier Inc. All rights reserved.0.1016/j.amjcard.2013.10.044
treatment prevents thromboembolism and has mortalitybenefit over the subjects who are not restarted on warfarin.Also, we investigated the various durations of interruptionand the risk of GIB, thromboembolism, and mortality.
Methods
This is a retrospective cohort study that evaluated thepatients enrolled at the anticoagulation clinic of Henry FordHealth System with a large catchment area serving all so-cioeconomic strata, covering majority of Southeast Michi-gan, United States. Patients who developed major GIB(defined in the following) while taking warfarin and thenhad evidence of resolution of major GIB (defined as stabilityof hemoglobin levels with <1 g decrease of hemoglobin for48 hours) were included in the study. Patients who diedwithin the first 72 hours of GIB, hospice, postoperative orvalvular AF, patients in whom primary indication for anti-coagulation was any reason other than nonvalvular AF, andpatients in whom warfarin was not interrupted for at least48 hours were excluded.
Data were initially obtained from insurance claims ofwarfarin that were evaluated at Henry Ford Health Systemfrom January 2005 to December 2010. Patients who hadcommenced using warfarin for at least 1 year and with atleast 2 prescriptions of warfarin within 3 months of contactwith a physician were enrolled. In the absence of mortality,at least 2 years of available follow-up after that initialcontact in the electronic health record system was a pre-requisite. The database query was further narrowed using
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 hemo-globin <10 mg/dl after resolution of gastrointestinal bleed.CHADS2 ¼ Congestive heart failure, Hypertension, Age �75 years,
Diabetes mellitus, Stroke; HAS-BLED ¼ Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR,Elderly (age �65 years), Drugs/alcohol; INR ¼ international normalizedratio (detailed definitions are in the Supplementary material); TTR = timewithin therapeutic range.* Mean systolic blood pressure after resolution of GIB during the hospital
stay.
Arrhythmias and Conduction Disturbances/Outcomes in Anticoagulated Patients With AF and GIB 663
International Classification of Diseases, Ninth Revision,code 427.3, 427.31, and 427.32 for AF. They were thenevaluated for the indications of anticoagulation. Patientsother than those with nonvalvular AF as the primary reasonfor anticoagulation were excluded. The charts of these pa-tients were evaluated to identify major GIB that led todiscontinuation of warfarin therapy for at least 2 days.Eventually, 1,329 patients satisfied these criteria. Theywere reevaluated for accuracy by identifying either a his-tory of AF or atrial flutter in the anticoagulation clinic notesor AF or atrial flutter on the electrocardiogram. A detailedchart review of these patients was carried out by thephysician-investigators, and information on demographics,medication use, and other clinical variables was obtained.Index GIB was defined as information collected on the dayof GIB and subsequently at the time of resolution of indexGIB. Information for CHADS2 and HAS-BLED wascollected at the resolution of index GIB. The consortiumdiagram is available in the Supplementary material. IndexGIB was defined as a decrease in hemoglobin of �2 g/dland/or transfusion of �2 units of packed red blood cellswith at least one of the following: hematemesis, melena,hematochezia, bright red blood per rectum, blood in naso-gastric aspirate, or bleeding documented during an endo-scopic procedure. The study protocol was approved by theinstitutional review board.
Restarting warfarin was defined as prescription ofwarfarin with objective evidence of increase in internationalnormalized ratio to �2.0 with evidence of at least 2 days ofdiscontinuation of warfarin as observed by chart review.Patients who interrupted warfarin after 1 month of restartingwarfarin (54; 4.1%) were included in the group that restartedwarfarin. Patients who started warfarin after 6 months ofinterruption (39, 2.9%) were included in the group that didnot restart warfarin (warfarin cessation group). Patients whointerrupted warfarin within the first month (12; 0.9%) wereincluded in the warfarin cessation group.
Figure 1. (A) Kaplan-Meier survival analysis showing 1-year mortality in patients who were restarted on warfarin (restarted) versus those who were not (notrestarted). (B) Time-to-event analysis showing 90-day cumulative incidence of recurrent GIB in patients who were restarted on warfarin (restarted) versus thosewho 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).
664 The American Journal of Cardiology (www.ajconline.org)
Recurrent major GIB was defined as any of thefollowing: (1) >2 g of hemoglobin decrease from the lastknown hemoglobin level warranting hospitalization, (2)need for blood transfusion of at least 2 units, and (3) visiblebleeding by health personnel or endoscopic evidence ofstigmata of recent bleeding in the form of visible bleeding orclot. We decided to analyze GIB within 90 days, as pro-pensity for recurrent GIB should be short term. Also, 12%of the patients developed recurrent GIB and we onlyconsidered the index GIB.
Thromboembolism was defined as venous thromboem-bolism (pulmonary embolism and deep venous thrombosis),arterial thromboembolism, or stroke or transient ischemicattack. Stroke or transient ischemic attack was defined asany 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 aneurologist. This outcome was obtained over 1-year dura-tion and only the first episode of thromboembolism wasconsidered as an outcome. Mortality data were updated fromthe Social Security Death Index, death certificates, or hos-pital notes. Outcomes were evaluated by 2 blind reviewers(FK and ZA). These were then rechecked and conflictsresolved by consensus.
Descriptive statistics were used to summarize the data.Continuous variables are expressed as mean � SD andcategorical variables are mentioned in percentages. Theywere analyzed using t test for continuous variables andFisher’s exact test or chi-square test for categorical vari-ables, as appropriate. Univariate analyses and adjusted Cox
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 ofthromboembolism stratified by duration of interruption of warfarin.
Table 2Unadjusted and adjusted hazard ratios for restarting warfarin versus not restarting warfarin
Outcome Unadjusted Hazard Ratio (95% CI) p Value Adjusted Hazard Ratio (95% CI) p Value
Arrhythmias and Conduction Disturbances/Outcomes in Anticoagulated Patients With AF and GIB 665
proportional analyses were conducted to enunciate the as-sociation between restarting warfarin therapy and outcomes.These analyses were adjusted for age, gender, race, Charl-son co-morbidity index, number of blood product trans-fusions, international normalized ratio on admission, and
CHADS2 and HAS-BLED scores. Cumulative incidenceswere evaluated using Kaplan-Meier method. Time ofinterruption of warfarin along with restarting warfarin statuswas added as an interaction term in the Cox proportionalhazards model to investigate the association of time in
Table
3Adjustedhazard
ratio
sstratifi
edby
timeduratio
nof
interruptio
nof
warfarinforvariousoutcom
es
Outcome
WarfarinRestarted
Yes
No(n
¼67
6)
<7Days(n
¼62
)7e
15Days(n
¼51
)15e21
Days(n
¼58
)21e30
Days(n
¼53
)>30
Days(n
¼42
9)
Throm
boem
bolism
Events
97
1112
5113
1Incidence
11.6
(8.3e16
.2)
12.0
(8.2e17
.5)
18.1
(13.4e
24.5)
20.7
(15.5e
27.7)
20.4
(17.8e
23.5)
19.8
(18.1e
21.6)
IRR,pvalue
0.57
(0.28e
1.15),0.11
0.59
(0.27e
1.29),0.18
0.89
(0.46e
1.70
),0.73
1.01
(0.54e
1.90),0.97
Reference
NA
HR(95%
CI),pvalue
0.76
(0.37e
1.59),0.47
0.48
(0.20e
1.15),0.09
0.60
(0.30e
1.19
),0.14
1.00
(0.52e
1.94),>0.99
Reference
1.35
(0.97e
1.89
),0.07
Recurrent
GIB
Events
167
76
2529
Incidence
19.3
(14.6e
25.5)
10.8
(7.2e16
.3)
10.9
(7.2e16
.4)
9.9(6.3e15
.5)
9.9(8.0e12
.3)
5.4(4.5e6.6)
IRR,pvalue
1.95
(0.98e
3.89),0.06
1.09
(0.44e
2.71),0.85
1.09
(0.44e
2.72
),0.85
1.00
(0.38e
2.65),>0.99
Reference
NA
HR(95%
CI),pvalue
3.27
(1.82e
5.91),0.002
1.03
(0.45e
2.35),0.93
1.42
(0.65e
3.11
),0.37
1.50
(0.55e
4.04),0.42
Reference
1.27
(0.75 e
2.13
),0.37
Mortality
Events
1716
2021
113
276
HR(95%
CI),pvalue
0.56
(0.33e
0.93),0.03
0.56
(0.33e
0.98),0.04
0.56
(0.34e
0.90
),0.02
0.84
(0.52e
1.35),0.46
Reference
1.26
(1.01e
1.57
),0.04
CI¼
confi
denceinterval;HR¼
hazard
ratio
;IRR¼
incidencerate
ratio
;NA
¼notapplicable.
666 The American Journal of Cardiology (www.ajconline.org)
development of thromboembolism, mortality, and recurrentGIB. Because the interaction was significant, we divided thetime of interruption of warfarin into 5 groups (<7, 7 to 15,15 to 21, 21 to 30, and >30 days). Incidences were calcu-lated by the formula: incidence per 100 person-years. Inci-dence rate ratios were calculated by the formula: incidencerate 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 differ-ences in the cumulative incidences of recurrent GIB, mor-tality, and thromboembolism stratified by time duration ofinterruption of warfarin and cessation of warfarin use. Allanalyses were performed using PASW, version 18.0 (SPSSInc., Chicago, Illinois), and JMP Pro 10.0 (SAS Institute,Cary, North Carolina). The study was analyzed on the basisof the initial group assigned to the patient (similar tointention-to-treat analysis) and p value of <0.05 wasconsidered significant.
Results
Overall, 1,329 patients (mean age 75 � 11 years, women47%) developed GIB during January 2005 to December2010. There were 653 patients (49%) who were restarted onwarfarin after a median duration of 50 days (interquartilerange 21 to 78). The median CHADS2 and HAS-BLEDscores were 3. Endoscopic evaluation was performed in 883cases (66.4%). Chronic AF was present in 751 (52.6%),persistent AF in 345 (25.9%), and paroxysmal AF in 233patients (17.5%). Caucasians, patients with concomitantupper and lower sources for GIB, diabetics, patients withrenal disease, history of coronary artery disease, and historyof falls were less likely to be restarted on warfarin (p <0.05;Table 1). Overall, there were greater co-morbidity burdensin the patients who were not restarted on warfarin. Majorreasons for not restarting warfarin were physician preference(18%) and patient’s inability to follow up with the anti-coagulation clinic (19%).
In total, 463 deaths occurred over a period of 2 years.Restarting warfarin was independently associated withdecreased mortality (adjusted hazard ratio 0.66, 95% con-fidence interval 0.55 to 0.80, p <0.0001) compared withwarfarin cessation group. The survival analysis is shown inFigure 1. There were 4 thromboembolism-related deaths allin the patients in whom warfarin was stopped, whereas,there was only 1 death attributable to massive gastrointes-tinal hemorrhage in the patients who resumed warfarin.There was no significant difference in survival by theduration of interruption of warfarin <30 days; however, asthe interruption duration became longer, the survivalapproached toward the group that did not resume warfarin(Figure 2).
There were 90 patients who developed recurrent majorGIB within 90 days of index GIB (Table 2). The freedomfrom 90-day recurrent GIB is shown in Figure 1. Cumula-tive incidences of GIB based on duration of interruption ofwarfarin are given in Figure 2, which shows that the groupthat restarted warfarin within the first 7 days has greater riskof recurrent GIB; however, the cumulative incidences of therest of the groups are very similar to the group that restartedwarfarin after 30 days. Table 3 demonstrates the incidences
Arrhythmias and Conduction Disturbances/Outcomes in Anticoagulated Patients With AF and GIB 667
of patients stratified by days of interruption of warfarin. Italso shows the incidence rate ratios compared with thegroup that was restarted on warfarin after 30 days of inter-ruption of warfarin. The incidence rate ratios of 7- to 15-day, 15- to 21-day, and 21- to 30-day groups are notsignificantly different for recurrent GIB from the incidencerate ratio of patients who restarted warfarin after 30 days ofinterruption (Table 3).
There were 221 patients (16.6%) who developed athromboembolic episode within 1 year of interruption ofwarfarin. The risk was reduced in patients who wererestarted on warfarin (hazard ratio 0.71, 95% confidenceinterval 0.54 to 0.93, p ¼ 0.01; Table 2). The freedom from1-year thromboembolism is shown in Figure 1. Cumulativeincidences of thromboembolic events based on duration ofinterruption of warfarin are given in Figure 2, which showsthat there is a trend in decrease in the risk of thromboem-bolic events if anticoagulation was started earlier. Table 3demonstrates the incidences of patients stratified by days ofinterruption of warfarin. It also lists the incidence rate ratioscompared with the group that was restarted on warfarin after30 days of interruption of warfarin. There is a trend towardreduced incidence the earlier the warfarin therapy is rein-stituted (Table 3).
Discussion
This study provides incidences of thromboembolism,mortality, and recurrent GIB in patients who developed GIBwhile on anticoagulation for nonvalvular AF. The study alsodemonstrated that lower risks of thromboembolism andmortality were associated with resuming anticoagulation.There were also no significant differences in risk of GIBbetween resuming warfarin after 1 week of interruption ofwarfarin compared with restarting warfarin after 1 month;however, risk of recurrent GIB was significantly greater ifwarfarin was resumed within the first week of major GIB.
We found that as many as 1/2 of the patients that interruptwarfarin during a major GIB did not resume taking warfarin.The study is not large enough to be generalizable to the rest ofthe country; however, the cohort had adequate diversity toprovide an idea of this practice gap. Moreover, we also foundthat majority of the deaths and thromboembolic eventsoccurred in the patients who did not restart warfarin within amonth. Interrupting warfarin may lead to an increase in short-term risk of thromboembolism.6 This may have clinical im-plications especially if further research shows that earlyresumption of warfarin leads to better outcomes. For thepurpose of our study, we equated the term cessation withinterruption of >6 months and did not analyze them bycauses. However, we noticed that majority of the cessationoccurred due to inability to follow up with anticoagulationclinic or physician refusal of continuing anticoagulation dueto the documentation of previous GIB (37%). These findingswere markedly different from the findings of the AtrialFibrillation Follow-up Investigation of RhythmManagementtrial, in which physician refusal to continue warfarin andpatient’s refusal accounted for 19% of the cases.9
Several previous studies have evaluated the treatmentinterruptions in surgical patients but are limited by the smallnumber of events.10e14 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 ourpatients. Patients who are at a greater risk of GIB are also atgreater risk of thromboembolic events as the risk scoressuch as HAS-BLED and CHADS2 share many commonvariables. Another interesting finding was that, there, theincidence of thromboembolic events and deaths withinthe first 90 days of interruption of warfarin was greater thanthe incidences afterward. However, the risks for these eventsstayed higher in the group that did not restart warfarinsuggesting that there might be other factors that might beplaying a role in these events. Whether this occurredbecause of “rebound hypercoagulability” or “catch up” ofevents is not clear and is a matter of controversy.15e18 Ourfinding of decreased mortality may be explained by theanticoagulation effects of warfarin.19
To investigate the optimal duration of restarting warfarinafter an episode of major GIB, we attempted to evaluate thedifferent durations of interruption of warfarin with respect tothe reference group of patients who resumed taking warfarinafter 1 month. We found that patients who resumed takingwarfarin in the first week were at a greater risk of recurrentGIB; however, the rest of the groups did not show significantdifferences. In contrast, lower risk of mortality and thrombo-embolism was associated with earlier re-initiation of warfarin.Although there are many other variables that physicians takeinto account while making a decision of resuming warfarin inthese patients, we have provided the risks versus benefits ofthese treatment decisions thatmight have clinical implications.
Our study faces the limitations that any study based oninsurance claims and retrospective data does. Although wetried to narrow down our exposure variable, there was somecrossover that occurred. However, we used an analysissimilar to intention-to-treat analysis to minimize the con-founding. We also were not able to enunciate all the factorsthat affect the clinical decision making. However, confir-mation of thromboembolism, recurrent GIB, and mortalityby way of medical chart review strengthens the validity ofour data. The study is also susceptible to detection bias andmay have underestimated the events of thromboembolism inthe group that did not resume warfarin as there was lesshealth-care contact. Also, patients who were perceived atgreatest risk of GIB were probably not restarted on warfarin,and hence, the association of resuming warfarin with GIBmight be underestimated. There might be also a componentof survivorship bias as we only used the data for patientswho were alive for at least 2 days after index major GIB.However, we wanted to avoid making conclusions aboutpatients who were so ill that they did not survive their first48 hours, which might have led to further underestimationof our results, as many of them did not resume takingwarfarin. Also, as apparent in the baseline characteristics ofthe 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 theanalysis; however, there was still a difference in mortalitythat was unexplained by just selection bias.
Disclosures
The authors have no conflicts of interest to disclose.
668 The American Journal of Cardiology (www.ajconline.org)
Supplementary Data
Supplementary data related with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.amjcard.2013.10.044.
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