Original Investigation | Oct 22, 2012

Risk of Thromboembolism,
Recurrent Hemorrhage, and Death
After Warfarin Therapy Interruption
for Gastrointestinal Tract
Bleeding FREE
Daniel M. Witt, PharmD, FCCP, BCPS; Thomas Delate, PhD; David A. Garcia, MD; Nathan
P. Clark, PharmD; Elaine M. Hylek, MD; Walter Ageno, MD; Francesco Dentali, MD; Mark
A. Crowther, MD

Arch Intern Med. 2012;172(19):1484-1491.

doi:10.1001/archinternmed.2012.4261.

ABSTRACT
Background Patients who not only survive a warfarinassociated gastrointestinal tract bleeding (GIB) event but also
have an ongoing risk for thromboembolism present 2 clinical
dilemmas: whether and when to resume anticoagulation. The
objective of this study was to determine the incidence of
thrombosis, recurrent GIB, and death, as well as the time to
resumption of anticoagulant therapy, during the 90 days
following a GIB event.
Methods In this retrospective, cohort study using administrative
and clinical databases, patients experiencing GIB during

warfarin therapy were categorized according to whether they

resumed warfarin therapy after GIB and followed up for 90 days.
Variables describing the management and severity of the index
GIB were also collected. Kaplan-Meier curves were constructed
to estimate the survival function of thrombosis, recurrent GIB,
and death between the resumed warfarin therapy and did not
resume warfarin therapy groups, with Cox proportional hazards
modeling to adjust for potentially confounding factors.
Results There were 442 patients with warfarin-associated index
GIB included in the analyses. Following the index GIB, 260
patients (58.8%) resumed warfarin therapy. Warfarin therapy
resumption after the index GIB was associated with a lower
adjusted risk for thrombosis (hazard ratio [HR], 0.05; 95% CI,
0.01-0.58) and death (HR, 0.31; 95% CI, 0.15-0.62), without
significantly increasing the risk for recurrent GIB (HR, 1.32; 95%
CI, 0.50-3.57).
Conclusions The decision to not resume warfarin therapy in the
90 days following a GIB event is associated with increased risk
for thrombosis and death. For many patients who have
experienced warfarin-associated GIB, the benefits of resuming
anticoagulant therapy will outweigh the risks.
Gastrointestinal tract bleeding (GIB) affects an estimated 4.5%
of warfarin-treated patients annually and is associated with a
significant risk for death.1 A history of major bleeding is an
important predictor for future serious bleeding, suggesting that
patients with GIB might be considered for discontinuation of
warfarin therapy.2,3 However, interruption or permanent

discontinuation of warfarin therapy increases the risk of

thromboembolic complications.4 Thus, patients with warfarinassociated GIB present 2 clinical dilemmas: should warfarin
therapy be stopped and, if so, when should it be resumed?
Although some have suggested that anticoagulation can be
safely restarted relatively soon after a major bleeding event,
there is neither high-quality evidence nor consensus about the
ideal timing or risk of reanticoagulation. Indeed, surprisingly little
is known about warfarin therapy interruption and resumption
following GIB.2,5 An observational study of patients newly
initiated on anticoagulation therapy for venous thrombosis who
had major bleeding reported an association between resuming
anticoagulation and rebleeding.6 However, patients whose index
bleeding event occurred during long-term anticoagulation
therapy were not evaluated. Other studies examining the
resumption of anticoagulation therapy following major bleeding
have been limited by small numbers of patients, selection bias,
or both.2,5,7,8
In this study of warfarin-treated patients who experienced GIB,
we sought to determine the incidence of subsequent thrombosis,
recurrent GIB, and death as well as the time to resumption of
warfarin therapy during 90 days of follow-up. We evaluated
patient characteristics as well as the duration of warfarin therapy
interruption to identify factors associated with thromboembolism,
recurrent GIB, or death.

METHODS

We conducted a retrospective, cohort study using administrative

and clinical databases from Kaiser Permanente Colorado
(KPCO). Anticoagulation services at KPCO are provided by a
centralized Clinical Pharmacy Anticoagulation Service
(CPAS).9 We used integrated, electronic medical, pharmacy, and
laboratory record systems along with the CPAS database
(Dawn-AC; 4S Systems Ltd) to identify patients, treatments, and
outcomes for this study. Approval to conduct this study was
obtained from the KPCO institutional review board.
We used administrative coding data (see the eAppendix for a
complete listing of International Classification of Diseases, Ninth
Revision [ICD-9 ] codes) to identify adult KPCO members who
(1) were hospitalized or had an emergency department (ED)
encounter for GIB (index GIB) between January 1, 2005, and
December 31, 2008; (2) had an outpatient purchase of warfarin
and an international normalized ratio (INR) in the 60 days prior
to the index GIB; (3) had continuous KPCO membership in the
180 days prior to and 90 days after the index GIB (patients who
died within 90 days after the index GIB were included); and (4)
did not have a GIB diagnosis recorded during the 6 months prior
to the index GIB.
The primary outcomes of interest were thrombosis (stroke,
systemic embolism, and venous thromboembolism), recurrent
GIB, and death from any cause during the 90 days following
index GIB. Gastrointestinal tract bleeding (index and recurrent)
and thrombotic events were identified first through electronic
queries of inpatient and ED claims databases using ICD9 codes (see eAppendix) and then confirmed via manual

medical record review by study investigators (D.M.W. and

N.P.C.) using a standardized abstraction form. Validation of
study outcomes required objective evidence of either clinically
overt gastrointestinal tract hemorrhage (eg, visualization of
blood in stool, vomit, or gastric aspirate; positive guaiac test
result; evidence from endoscopy or colonoscopy) or thrombosis
(eg, positive computed tomographic scan, magnetic resonance
image, ventilation-perfusion scan, or ultrasonogram). Date and
cause of death were ascertained from death certificates and
medical record review. All records were independently reviewed
by 2 investigators (D.M.W. and N.P.C.), with disagreements
resolved by a third reviewer (E.M.H.).
The following variables describing the management and severity
of the index GIB were collected: presentation INR, warfarin
therapy interruption, plasma or blood transfusion, phytonadione
administration, intensive care unit (ICU) admission, length of
ED/inpatient stay, and warfarin therapy resumption. We also
recorded age, sex, warfarin indication, INR range, time from
warfarin therapy initiation to index GIB, aspirin and nonsteroidal
anti-inflammatory drug (NSAID) use before index GIB, lowmolecular-weight heparin use after index GIB, and proportion of
INR values in range during the 3 months before index GIB.
Information about comorbidities was collected using ICD9 codes. A validated aggregate measure of patient comorbidity,
the Chronic Disease Score (CDS), was calculated for each
patient using ambulatory prescription medication data recorded
before the index GIB.10,11 For patients with atrial fibrillation, the
CHADS2 score, a clinical prediction rule for estimating the risk of

stroke, was calculated by assigning 1 point for diagnoses of

congestive heart failure, hypertension, age 75 years or older,
and diabetes mellitus and 2 points for prior stroke or transient
ischemic attack.12
All patients were assigned to 1 of 2 groups defined by warfarin
therapy resumption after the index GIB (ie, resumed warfarin
therapy and did not resume warfarin therapy groups). When
warfarin therapy was not interrupted, patients were included in
the resumed warfarin therapy group. Categorical data were
reported as percentages, and continuous data were reported as
means (standard deviations)) and medians (interquartile ranges
[IQRs]). Comparisons between groups for categorical data were
made with the 2 or Fisher exact tests, whereas continuous data
were compared using 2-sample t tests or Wilcoxon rank sum
tests. Kaplan-Meier curves were constructed to estimate the
survival function of thrombosis, recurrent GIB, and death
between the resumed warfarin therapy and did not resume
warfarin therapy groups. Patients were censored at thrombosis,
recurrent GIB, death, or 90 days after index GIB, whichever
came first.
A propensity score13 for resumption of warfarin therapy after the
index GIB was estimated for each patient using logistic
regression (see theeAppendix for factors included in the
propensity score). Cox proportional hazards modeling was used
to adjust for potentially confounding factors in the assessment of
the association of warfarin resumption with time to thrombosis,
recurrent GIB, or death (see the eAppendix for factors included
in each model).

To limit the effect of the severity of the index GIB on death, post
hoc adjusted hazards modeling on time to death was performed,
in which patients who died within 1 week of the index GIB were
excluded. In addition, discrete time-varying and categorical
variables were constructed based on length of time patients
were off warfarin therapy after the index GIB to assess if there
was a time-dependent effect of warfarin therapy interruption on
the outcomes. Length of warfarin therapy interruption was
categorized as 0 days, 1 to 7 days, 8 to 14 days, 15 to 90 days,
and warfarin therapy not resumed. Individual post hoc adjusted
hazards models for time to recurrent GIB, thrombosis, and death
were constructed with the time-varying warfarin exposure
variable. Because warfarin therapy was not interrupted in all
cases, individual post hoc adjusted hazards models for time to
recurrent GIB, thrombosis, and death were constructed with
binary and time-varying warfarin exposure variables after
removing patients who did not interrupt warfarin therapy and had
an index GIB location of rectum-anus (n = 24) and then all
patients who did not interrupt warfarin therapy (n = 41). Post hoc
tests of association were performed with the categorical
exposure variables and study outcomes. Because adjusted
hazard modeling subanalyses using time-varying warfarin
exposure and/or removing patient groups who did not have
warfarin therapy interruption revealed similar results for the
thrombosis, recurrent GIB, and death outcomes, only results of
the initial analysis are reported.
Further analyses included comparisons of outcomes and patient
characteristics between patients who did and did not experience

a recurrent GIB and were and were not dead at the end of
follow-up, respectively. Statistical analyses were performed
using Intercooled STATA version 9.0 software (StataCorp). The
level was set at .05, and all tests were 2-sided.

RESULTS
Of 502 patients identified as having GIB using administrative
data, the index GIB was not confirmed during medical record
review in 57 patients, and 3 patients were not receiving warfarin.
Therefore, 442 patients with warfarin-associated index GIB were
included in the analyses (Table 1). The mean age was 74.2
years, 50.2% were male, and 46.4% used aspirin at some point
during the 90 days prior to the index GIB. Indications for warfarin
therapy included the following: prevention of atrial fibrillation
related stroke or systemic embolization (50.5%); treatment or
secondary prevention of venous thrombosis (24.4%); and
prevention of prosthetic heart valve thromboembolic
complications (9.5%). The median (IQR) INR on presentation
was 3.0 (2.3-4.3). Approximately one-third of patients (30.5%)
were initially treated in the ICU; 24.2% were evaluated and
discharged directly from the ED (Table 2). Following the index
GIB, 260 patients (58.8%) resumed warfarin therapy, including
41 patients whose warfarin therapy was never stopped. Median
(IQR) time to resumption of warfarin was 4 days (2-9 days).
Prosthetic heart valve indication for warfarin therapy (15.4% vs
1.1%; P < .001) and GIB localized to the rectum-anus
(representing predominately hemorrhoidal bleeds) (19.6% vs
7.1%; P < .001) were more common among the 260 patients
who resumed warfarin therapy compared with those who did

not, respectively. In contrast, compared with those resuming

warfarin therapy, older patients (mean age, 71.8 years [resumed
warfarin therapy] vs 77.7 years [did not resume warfarin
therapy]; P < .001) and patients for whom the GIB source was
not identified (16.9% [resumed warfarin therapy] vs 26.9% [did
not resume warfarin therapy]; P = .01) were less likely to resume
warfarin therapy (Table 1).
Table 1. Baseline Characteristics According to Warfarin Therapy
Status Following GIBa

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Table 2. Overall Outcomes Among Warfarin-Treated Patients

With GIBa

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During the 90-day follow-up period, 11 patients (2.5%)

experienced a thrombotic event (6 arterial [5 strokes and 1
systemic embolus] and 5 venous [3 pulmonary emboli and 2
deep vein thromboses]), and 3 of the strokes were fatal (Table
3). Of the 260 patients who resumed warfarin therapy following
the index GIB, 1 (0.4%) had a thrombotic event (deep vein

thrombosis) compared with 10 of 182 patients (5.5%) who did

not resume warfarin therapy (P < .001). Warfarin therapy
resumption after the index GIB was associated with a lower risk
for thrombosis (hazard ratio [HR], 0.05; 95% CI, 0.01-0.58) in a
multivariable analysis that controlled for the propensity score,
CDS, age, and sex (Figure, A). For patients resuming warfarin
therapy, thrombosis rates were similar regardless of the duration
of warfarin therapy interruption. Patients who either never
interrupted warfarin therapy or resumed therapy within 14 days
of the index GIB experienced no thromboses.
Time-to-outcome analysis according to resuming warfarin therapy status. A,
Thrombosis (P = .002, log-rank test); B, recurrent gastrointestinal tract bleeding (GIB)
(P = .10, log-rank test); C, death (P < .001, log-rank test); and D, death including only
patients who died at least 7 days after the index GIB (P < .001, log-rank test).
Figure.

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Table 3. Description of Thrombotic Events

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Of the 442 patients, 36 (8.4%) had recurrent GIB (Table 2).

Compared with those who did not resume warfarin therapy, a
numerically higher proportion of patients resuming warfarin
therapy had recurrent GIB, but this difference was not

statistically significant (10.0% [resumed warfarin therapy] vs

5.5% [did not resume warfarin therapy]; P = .09). Multivariable
analysis that controlled for the propensity score, CDS, age, sex,
indication for warfarin use, prior heart failure diagnosis, location
of GIB, pre-GIB target INR, pre-GIB percentage of INRs in
range, reception of low-molecular-weight heparin, length of
ED/inpatient stay, and acute GIB treatment (blood transfusion)
also revealed that the risk for recurrent GIB associated with
warfarin therapy resumption was not increased significantly (HR,
1.32; 95% CI, 0.50-3.57) (Figure, B). Compared with all other
patients, the rate of recurrent GIB was significantly increased
when warfarin therapy was resumed between 1 and 7 days after
the index GIB (6.23% vs 12.4%, respectively; P = .03). Although
5 of the index GIB events were eventually fatal, no recurrent GIB
resulted in death. The median (IQR) time from warfarin therapy
resumption to recurrent GIB was 27 days (11-58 days). There
was no association between more aggressive management of
the index GIB (eg, ICU admission, use of blood products) and
recurrent GIB (all P > .05) (Table 4).
Table 4. Outcomes According to Recurrent GIB Statusa

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During the 90-day follow-up period, 52 patients (11.8%) died

(Table 5). The most common causes of death were related to
malignancy (28.8%), infection (19.2%), and cardiac disease
(17.3%). No deaths were attributed to recurrent GIB. Compared

with survivors, patients who died were older (P = .03) and had
higher CDS (P = .004). Patients with an index GIB localized to
the mouth-esophagus died less frequently, and those with an
index GIB with an unidentified bleeding source died more
frequently. Warfarin therapy resumption after the index GIB was
associated with a lower risk for death (HR, 0.31; 95% CI, 0.150.62) in multivariable analysis that controlled for the propensity
score, CDS, age, sex, location of GIB, ICU admission,
hypertension, prior stroke diagnosis, pre-GIB percent of INRs in
range, reception of low-molecular-weight heparin, length of
ED/inpatient stay, and acute GIB treatment (blood transfusion)
(Figure, C). This strong association persisted in a post hoc
analysis excluding all patients who died within 1 week of the
index GIB (Figure, D). The death rate during follow-up was
lowest when warfarin therapy was resumed between 15 and 90
days after the index GIB (2.3%, P = .04 compared with all other
patients).
Table 5. Patient Characteristics by Death Status at End of
Follow-upa

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COMMENT

Gastrointestinal tract bleeding is a common complication of

warfarin therapy. This retrospective cohort study evaluated 90day outcomes among warfarin-treated patients with GIB. The
results highlight the clinical dilemma of managing warfarin
therapy following a hospitalization or ED visit for GIB. Although
we observed a numerical increase in recurrent GIB associated
with not interrupting or resuming warfarin therapy in the 90 days
after the index GIB, this increase was not statistically significant.
However, a decision not to resume warfarin therapy was
associated with a significantly increased risk for both thrombosis
and death from any cause. Furthermore, while no GIB
recurrences were fatal, 3 patients with atrial fibrillation had fatal
strokes during warfarin therapy discontinuation following a GIB
event. While the increased risk of thrombosis and death
associated with any warfarin therapy interruption has been
reported previously in a Danish registry of patients with atrial
fibrillation,14 to our knowledge, ours is the first study to report this
observation in a cohort of patients receiving warfarin for diverse
indications specifically in the context of recent GIB. In our study,
the exact date and duration of warfarin therapy interruption and
adverse events were verified through medical record review,
whereas in the Danish study,14 the date of warfarin therapy
interruption was estimated from warfarin prescription claims
data, the reasons why patients interrupted therapy were
unknown, and adverse events were not confirmed by medical
record review.
The theoretical concern that abrupt warfarin therapy
discontinuation following GIB causes a temporary

hypercoagulable state may be relevant to the observed increase

in thrombosis in patients who did not resume warfarin
therapy,15 although no thrombotic events occurred within 7 days
of warfarin therapy interruption. It is difficult, if not impossible, to
determine the time course between thrombus formation and
subsequent clinical manifestations. However, the laboratory
evidence supporting the actual existence of rebound
hypercoagulability is inconsistent, and clinical trials have failed
to demonstrate increased thromboembolic risk associated with
abrupt anticoagulant withdrawal.15
Our observation that a decision not to resume warfarin therapy
is associated with higher overall mortality was unexpected and
not readily explained, given that only 3 of the 37 deaths in the
group not resuming warfarin therapy were attributed to
thrombosis. We attempted to control for possible confounding of
the warfarin therapy resumption indicator by including pertinent
factors in multivariable analysis and by performing propensity
score analysis; however, the association persisted. It is possible
that patients with a more serious index GIB (who would
presumably be more likely to die) were also less likely to resume
anticoagulation. However, the association between resuming
warfarin therapy and lower mortality persisted with modeling that
adjusted for ICU admission as well as blood transfusions
interventions that would be expected to be markers of a more
serious initial GIB. To further explore explanations for the
association between a decision not to resume warfarin therapy
and death, we reanalyzed the data after excluding patients who
died during the first week after the index GIB because these

patients would have had less opportunity to resume warfarin

therapy. Despite this, we found that the association remained
significant. We acknowledge that residual confounding was
likely present despite rigorous efforts at mitigation through
various analytical approaches. Therefore, the apparent increase
in nonthrombotic deaths when warfarin therapy was not
resumed may suggest that the treating physicians were reluctant
to resume warfarin therapy in sicker patients with a higher risk of
death in general.
Our results provide some guidance regarding the optimal timing
of warfarin therapy resumption following GIB, but clinical
judgment remains a critical factor in this difficult decision.
Resumption of warfarin therapy between days 1 and 7 following
a GIB event was associated with a higher risk of recurrent GIB
but lower risk of thrombosis. A better understanding of the
propensity for recurrent hemorrhage and its severity across the
spectrum of anatomic lesions would help to inform the decision
of optimal timing of anticoagulation resumption, an issue of
major importance for individuals at highest risk of
thromboembolism.
Our study is limited in that we used data from administrative
databases, and thus not all factors that affect clinical decision
making could be collected. However, the confirmation of
thrombosis, recurrent GIB, and death outcomes via medical
chart and death certificate review strengthens the validity of our
results. The observed results are biologically plausible because
the thrombotic events correlated with the indication for warfarin
therapypatients with atrial fibrillation experienced strokes or

systemic embolus, while patients with venous thromboembolism

had recurrent venous thromboembolism (Table 2). Despite
potential confounding, our study likely underestimates the
strength of the association between thrombosis and not
resuming warfarin therapy because patients at the highest risk
of thrombosis (eg, presence of mechanical heart valve, high
CHADS2 score) were probably less likely to remain off warfarin
therapy following GIB. Similarly, the strength of association
between recurrent GIB and resuming warfarin therapy may be
underestimated because patients perceived at high risk for
further GIB probably were less likely to resume warfarin therapy.
Accurate recording of baseline aspirin use status was facilitated
by the records maintained by CPAS. However, aspirin use status
was not routinely documented in index GIB discharge
summaries, and a sizeable proportion of patients did not resume
warfarin therapy and were thus not followed by CPAS after the
index GIB. Therefore, we were not able to accurately record
aspirin use following the index GIB and acknowledge that lack of
information on post-GIB aspirin use and its potential influence
on the risk of recurrent GIB, thrombosis, and death is a
limitation.
Our study shows that the decision to not resume warfarin
therapy in the 90 days following GIB is associated with
increased risk for thrombosis and death. Our analysis suggests
that, for many patients who have experienced GIB, the benefits
of resuming warfarin therapy will outweigh the risks. Further
research will be needed to identify the optimal duration of

warfarin interruption after a GIB event and the patients for whom
a more prolonged interruption can be justified.

ARTICLE INFORMATION
Correspondence: Daniel M. Witt, PharmD, FCCP, BCPS,
Clinical Pharmacy Anticoagulation Service, Kaiser Permanente
of Colorado, 16601 E Centretech Pkwy, Aurora, CO 80011
(dan.m.witt@kp.org).
Accepted for Publication: June 4, 2012.
Published Online: September 17, 2012.
doi:10.1001/archinternmed.2012.4261
Author Contributions: The principal investigator, Dr Witt, had
full access to all the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis. Study concept and design: Witt, Delate, Garcia, Clark,
and Dentali. Acquisition of data: Witt, Delate, Garcia, and
Clark. Analysis and interpretation of data: Witt, Delate, Garcia,
Hylek, Ageno, and Dentali. Drafting of the manuscript: Witt,
Delate, Garcia, and Dentali. Critical revision of the manuscript
for important intellectual content: Witt, Garcia, Clark, Hylek,
Ageno, and Dentali.Statistical analysis: Witt and
Delate. Obtained funding: Witt and Garcia. Administrative,
technical, and material support: Garcia and Clark. Study
supervision: Witt and Ageno.
Financial Disclosure: Dr Garcia has served as an advisor to
Boehringrer Ingelheim, Bristol-Meyers Squibb, Daiichi Sankyo,
and CSL Behring. Dr Hylek has served as an advisor to Bayer,

Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo,

Johnson and Johnson, and Pfizer and participated in clinical
symposia sponsored by Bayer, Boehringer Ingelheim, and
Bristol-Myers Squibb. Dr Crowther has served as an advisor to
Leo Pharma, Pfizer, Bayer, Boehringer Ingelheim, Alexion, CSL
Behring, and Artisan Pharma; has prepared educational
materials for Pfizer, Octapharm, and CSL Behring; has provided
expert testimony for Bayer; and holds a Career Investigator
award from the Heart and Stroke Foundation of Ontario and the
Leo Pharma Chair in Thromboembolism Research at McMaster
University. Dr Crowther's affiliated institution (McMaster
University) has received funding for research projects from
Boehringer Ingelheim, Octapharm, Pfizer, and Leo Pharma.
Funding/Support: CSL Behring LLC provided funding for the
study.
Role of the Sponsor: CSL Behring LLC was not involved in the
study design, collection, analysis, or interpretation of the data or
in preparation and submission of the manuscript for publication.
Additional Contributions: Aubrey E. Jones assisted with the
extraction of information from medical records.

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Copyright 2016 American Medical Association

original | 22 de octubre de 2012

Riesgo de tromboembolismo
recurrente, hemorragia y muerte
despus de la interrupcin de terapia
de warfarina para el sangrado del
tracto Gastrointestinal GRATIS
Daniel M. Witt, MD, FCCP, SBDC; Thomas Delate, PhD; David A. Garcia, MD; Nathan P.
Clark, MD; Elaine M. Hylek, MD; Walter Ageno, MD; Francesco dental, MD; Mark A.
Crowther, MD

Arch Intern Med. 2012; 172 (19): 1484 1491.

doi:10.1001/archinternmed.2012.4261.

RESUMEN
Fondo Pacientes que no slo sobreviven un tracto gastrointestinal
asociada a la warfarina hemorragias evento (GIB), pero tambin
tienen un riesgo permanente para el thromboembolism
presentan dilemas clnicos 2: si y cundo reanudar la
anticoagulacin. El objetivo de este estudio fue determinar la
incidencia de trombosis, GIB recurrente y la muerte, as como el
tiempo de reanudacin de la terapia anticoagulante, durante los
90 das despus de un evento GIB.
Mtodos En esta retrospectiva, estudio de cohorte utilizando
bases de datos administrativos y clnicos, pacientes que

experimentan los prisioneros durante la terapia de warfarina se

clasificaron segn si se reanuda la terapia de warfarina despus
de GIB y seguido por 90 das. Se recogieron tambin las
variables que describen la gestin y la gravedad del ndice GIB.
Se construyeron curvas de Kaplan-Meier para estimar la funcin
de supervivencia de trombosis recurrente GIB, y grupos de la
muerte entre la "terapia de warfarina se reanudaron" y "terapia
de warfarina no reasumi", con riesgos proporcionales de Cox
para ajustar potencialmente factores de confusin de modelado.
Resultados Hubo 442 pacientes con warfarina asociado ndice
GIB incluida en los anlisis. Siguiendo el ndice GIB, 260
pacientes (58,8%) reasumieron terapia de warfarina.
Reanudacin de la terapia de warfarina despus de que el
ndice de prisioneros fue asociado con un menor riesgo
ajustado para la trombosis (cociente de riesgo [HR], 0,05 IC
95%, 0,01 0,58) y muerte (HR, 0,31 IC 95%, 0.15-0.62), sin
aumentar significativamente el riesgo de recurrente GIB (HR,
1.32; 95% CI, 0,50-3.57).
Conclusiones La decisin de no reanudar la terapia de
warfarina en los 90 das despus de un evento GIB se asocia
con mayor riesgo de trombosis y muerte. Para muchos
pacientes que han experimentado la llave asociada a la
warfarina, los beneficios de la reanudacin de la terapia
anticoagulante superan los riesgos.
Tracto gastrointestinal sangrado (GIB) afecta a
aproximadamente el 4.5% de los pacientes tratados con
warfarina anualmente y se asocia con un riesgo significativo

para la muerte. 1 Una historia de hemorragia grave es un

predictor importante para el futuro sangrado grave, sugiriendo
que los pacientes con GIB podran considerarse para la
discontinuacin de la terapia de warfarina. 2 , 3 Sin embargo, la
interrupcin o discontinuacin permanente de la terapia de
warfarina aumenta el riesgo de complicaciones
tromboemblicas. 4 As, los pacientes con GIB de warfarina
asociada presentan dilemas clnicos 2: debe suspenderse la
terapia de warfarina y, por lo tanto, cuando debe ser reasumi?
Aunque algunos han sugerido que la anticoagulacin pueda
segura reiniciarse relativamente pronto despus de un evento
de sangrado mayor, hay evidencia de alta calidad ni un
consenso sobre el momento ideal o el riesgo de
reanticoagulation. De hecho, sorprendentemente poco es
conocido sobre la interrupcin de la terapia de warfarina y
reanudacin siguiente GIB. 2 , 5 Un estudio observacional de
pacientes recin iniciado terapia de anticoagulacin para
trombosis venosa que tuvieron sangrado mayor informado una
asociacin entre reanudar la anticoagulacin y resangrado. 6 Sin
embargo, no evaluaron a pacientes cuyo ndice sangrado
evento ocurri durante la anticoagulacin a largo plazo. Otros
estudios que examinan la reanudacin de la terapia de la
anticoagulacin despus de hemorragia grave han sido
limitadas por una pequea cantidad de pacientes, el sesgo de
seleccin o ambos. 2 , 5 , 7 , 8
En este estudio de pacientes tratados con warfarina que
experiment GIB, buscamos determinar la incidencia de
trombosis posterior, recurrente GIB y muerte as como el tiempo

de reanudacin de la terapia de warfarina durante 90 das de

seguimiento. Se evaluaron caractersticas de los pacientes, as
como la duracin de la interrupcin de la terapia de warfarina
para identificar factores asociados con el tromboembolismo,
GIB recurrente o muerte.

MTODOS
Se realiz un estudio de cohorte retrospectivo, utilizando bases
de datos administrativos y clnicos de Kaiser Permanente
Colorado (KPCO). Servicios de anticoagulacin en KPCO son
proporcionados por un servicio centralizado del anticoagulacin
de la farmacia clnica (CPAS). 9 Utilizamos integrados,
electrnicos mdica, farmacia y laboratorio de sistemas de
registro junto con la base de datos de CPA (amanecer-AC; 4S
Systems Ltd) para identificar a los pacientes, los tratamientos y
los resultados de este estudio. Aprobacin para llevar a cabo
este estudio se obtuvo de la Junta de revisin institucional
KPCO.
Se utilizaron datos administrativos de codificacin (ver la
eAppendix para una lista completa de los cdigos de la
clasificacin internacional de enfermedades, novena revisin
[ICD-9 ]) para identificar a los miembros adultos de KPCO que
(1) fueron hospitalizados o tenido una emergencia
departamento (ED) encuentro de GIB (ndice GIB) entre el 01
de enero de 2005 y 31 de diciembre de 2008; (2) tena una
compra del ambulatorio de warfarina y una razn normalizada
Internacional (INR) en los 60 das anteriores el ndice GIB; (3)
tena membresa KPCO en los 180 das antes y 90 das

despus el ndice GIB (pacientes que murieron dentro de 90

das despus de que se incluyeron el ndice GIB); y (4) no tuvo
un diagnstico GIB registrado durante los 6 meses previos el
ndice GIB.
La primaria resultados de inters fueron trombosis (ictus,
embolia sistmica y tromboembolismo venoso), GIB recurrente
y muerte por cualquier causa durante los 90 das siguientes
ndice GIB. Sangrado del tracto gastrointestinal (ndice y
recurrente) y eventos trombticos se identificaron primero a
travs de consultas electrnicas de pacientes hospitalizados y
ED reclama bases de datos mediante cdigos CIE-9 (ver
eAppendix) y luego confirmado mediante revisin manual del
registro mdico por los investigadores del estudio (D.M.W. y
N.P.C.) mediante un formulario estandarizado de la abstraccin.
Validacin de los resultados del estudio requiere evidencia
objetiva de hemorragia del tracto gastrointestinal clnicamente
evidente (por ejemplo, visualizacin de sangre en heces, vmito
o aspirado gstrico resultado de la prueba de guayaco positiva;
pruebas de endoscopia o colonoscopia) o trombosis (por
ejemplo, la exploracin tomogrfica computada positiva, imagen
de resonancia magntica, gammagrafa de ventilacin-perfusin
o ultrasonogram). Fecha y causa de la muerte fueron
comprobados de certificados de defuncin y revisin del registro
mdico. Todos los registros fueron revisados
independientemente por 2 investigadores (D.M.W. y N.P.C.), con
desacuerdos resueltos por un tercer revisor (E.M.H.).
el siguiente que describe la gestin y la
gravedad del ndice GIB: presentacin INR, interrupcin de la
Se recogieron variables de

terapia de warfarina, plasma o transfusiones, administracin de

este medicamento, admisin de la unidad de cuidados
intensivos (UCI), duracin de la hospitalizacin de ED y
reanudacin de la terapia de warfarina. Tambin se registraron
edad, sexo, indicacin de warfarina, el rango de INR, tiempo de
iniciacin de la terapia de warfarina ndice GIB, aspirina y
medicamento antiinflamatorio no esteroide (AINE) uso antes del
ndice GIB, uso de heparina de bajo peso molecular despus de
ndice GIB y proporcin de los valores INR en rango durante los
3 meses antes de ndice GIB. Se recopil informacin sobre
comorbilidades con cdigos CIE-9 . Una medida agregada
validada de comorbilidad del paciente, la puntuacin de
enfermedad crnica (CDS), se calcul para cada paciente
utilizando datos de medicacin de prescripcin ambulatoria
antes el ndice GIB. 10 , 11 Para los pacientes con fibrilacin
auricular, el CHADS 2 puntuacin, una regla de prediccin clnica
para estimar el riesgo de apopleja, fue calculada asignando 1
punto por diagnsticos de insuficiencia cardaca congestiva,
hipertensin, edad 75 aos o ms y mellitus de la diabetes y 2
puntos para el accidente cerebrovascular previo o accidente
isqumico transitorio. 12
Todos los pacientes fueron asignados a 1 de 2 grupos definidos
por la reanudacin de la terapia de warfarina despus el ndice
GIB (es decir, "no reanudar terapia del warfarin" grupos y
"terapia de warfarina continuacin"). Cuando la terapia de
warfarina no se interrumpi, se incluyeron pacientes en el grupo
de terapia de continuacin de la warfarina. Datos categricos
fueron divulgados como porcentajes, y continua de los datos se

informaron como medio (desviacin estndar)) y medianas

(rangos intercuartil [IQRs]). Se realizaron comparaciones entre
los grupos de datos categricos con el 2 o Fisher exacto
pruebas, mientras que los datos continuos se compararon
mediante pruebas de 2-sample t o Wilcoxon rank sum. Curvas
de Kaplan-Meier fueron construidas para estimar la funcin de
supervivencia de trombosis recurrente GIB y muerte entre la
terapia de continuacin de la warfarina y no volver a grupos de
terapia de warfarina. Pacientes fueron censurados a muerte de
trombosis recurrente GIB, o 90 das despus de ndice GIB, lo
que vino primero.
Una puntuacin de propensin 13 para la reanudacin de la
terapia de warfarina despus el ndice GIB se estim para cada
paciente mediante regresin logstica (ver laeAppendix de
factores incluidos en la puntuacin de propensin). Riesgos
proporcionales de Cox de modelado se utiliz para ajustar
potencialmente factores de confusin en la evaluacin de la
Asociacin de reanudacin de warfarina con el tiempo a la
trombosis, GIB recurrente o muerte (ver la eAppendix de
factores incluidos en cada modelo).
Para limitar el efecto de la gravedad del ndice GIB en muerte,
peligros ajustados post-hoc de modelado en tiempo a la muerte
fue realizado, en que los pacientes que murieron dentro de 1
semana del ndice GIB fueron excluidos. Adems, variables
discretas categricas y variables en el tiempo fueron
construidas basados en la longitud de tiempo que los pacientes
eran de terapia de warfarina despus el ndice GIB para evaluar
si hubo un efecto dependiente del tiempo de interrupcin de la

terapia de warfarina en los resultados. Longitud de la

interrupcin de la terapia de warfarina se categoriz como 0
das, 1 a 7 das, 8 a 14 das, 15 a 90 das y la terapia de
warfarina no. Post-hoc del individuo ajusta modelos de riesgos
para tiempo a GIB recurrente, trombosis, y muerte fueron
construidos con la variable de exposicin de warfarina varan
con el tiempo. Porque terapia de warfarina no se interrumpi en
todos los casos, se construyeron modelos de riesgos ajustados
post-hoc individuales de tiempo recurrente GIB, trombosis y
muerte con variables de exposicin warfarina binarias y
variables en el tiempo despus de retirar a los pacientes que no
interrumpir la terapia de warfarina y tenan un ndice de
ubicacin de la llave del recto-ano (n = 24) y luego todos los
pacientes que no interrumpir la terapia de warfarina (n = 41). Se
realizaron las pruebas post-hoc de la asociacin con las
variables de exposicin categricas y los resultados del estudio.
Porque ajustar subanlisis de modelacin de riesgo usando
variables en el tiempo exposicin de warfarina o eliminacin de
grupos de pacientes que no tienen interrupcin de la terapia de
warfarina revel resultados similares para la trombosis,
recurrente GIB y los resultados de muerte, slo los resultados
del anlisis inicial se presentan.
Los anlisis adicionales incluyeron comparaciones de los
resultados y caractersticas de los pacientes entre pacientes
que hicieran y no experiment un GIB recurrente y eran y no
eran muertos al final de la carta recordativa, respectivamente.
Anlisis estadsticos se realizaron utilizando el software de

Intercooled STATA versin 9.0 (StataCorp). El nivel fue fijado

en.05 y todas las pruebas fueron 2 cara.

RESULTADOS
De 502 pacientes identificados como teniendo GIB utilizando
datos administrativos, el ndice de GIB no fue confirmado
durante la revisin del registro mdico en 57 pacientes y 3
pacientes no reciban warfarina. Por lo tanto, en los anlisis se
incluyeron 442 pacientes con warfarina asociado ndice GIB
(tabla 1). La edad media fue de 74,2 aos 50,2% eran hombres
y 46.4% utiliza aspirina en algn momento durante los 90 das
anteriores el ndice GIB. Indicaciones para la terapia de
warfarina fueron las siguientes: prevencin de accidente
cerebrovascular relacionado con fibrilacin atrial o embolizacin
sistmica (50,5%); tratamiento o prevencin secundaria de
trombosis venosa (24,4%); y prevencin de corazn prosttica
de la vlvula de complicaciones tromboemblicas (9,5%). La
mediana (IQR) INR en la presentacin fue de 3.0 (2.3-4.3).
Aproximadamente un tercio de los pacientes (30,5%) fueron
tratados inicialmente en la UCI; 24,2% fueron evaluadas y
descargado directamente del ED (tabla 2). Siguiendo el ndice
GIB, 260 pacientes (58,8%) reasumieron terapia de warfarina,
incluyendo a 41 pacientes cuya terapia de warfarina nunca fue
detenida. Mediana (IQR) tiempo para la reanudacin de la
warfarina fue 4 das (das 2-9). Indicacin de vlvula cardaca
protsica para la terapia de warfarina (15.4% vs 1,1%; P < 001)
y GIB localizada en el recto-ano (representando
predominantemente hemorragias hemorroidales) (19,6% vs
7,1%; P < 001) fueron ms frecuentes entre los 260 pacientes

que reanudaron la terapia de warfarina en comparacin con

aquellos que no, respectivamente. En contraste, en
comparacin con los reanudar terapia de warfarina, pacientes
de edad avanzada (media edad, 71,8 aos [terapia de warfarina
continuacin] vs 77,7 aos [terapia de warfarina no
reasumieron]; P < 001) y los pacientes para los cuales no fue
identificada la fuente GIB (16,9% [terapia de warfarina
continuacin] vs 26,9% [terapia de warfarina no reasumieron]; P
=.01) tenan menos probabilidades de reanudar la terapia de
warfarina (tabla 1 ).
Tabla 1. Caractersticas basales segn estado de la terapia de
warfarina despus de GIBun

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Tabla 2. Los resultados globales en los pacientes tratados con

warfarina con GIBun

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Durante el perodo de 90 das de seguimiento, 11 pacientes

(2,5%) experimentaron un evento trombtico (6 arterial [5
accidentes cerebrovasculares y embolia sistmica 1] y 5 venosa

[3 embolia pulmonar y trombosis venosa profunda 2]), y 3 de los

trazos eran fatales (tabla 3). De los 260 pacientes que
reasumieron terapia de warfarina despus el ndice GIB, 1
(0,4%) tuvieron un evento trombtico (trombosis venosa
profunda) en comparacin con 10 de los 182 pacientes (5,5%)
que no reanudar la terapia de warfarina (P < 001. Reanudacin
de la terapia de warfarina despus de que el ndice GIB se
asoci con un menor riesgo de trombosis (cociente de riesgo
[HR], 0,05 IC 95%, 0,01 0,58) en un anlisis multivariable que
controlaba para la propensin puntuacin, CDS, edad y sexo
(figura, A). Para los pacientes reanudar terapia de warfarina, las
tasas de trombosis fueron similares independientemente de la
duracin de la interrupcin de la terapia de warfarina. Los
pacientes que nunca interrupcin la terapia de warfarina o
reanudaron la terapia dentro de 14 das del ndice GIB no
experimentaron trombosis.
Anlisis de tiempo-resultado segn reasumir estado de terapia de warfarina.
Una, trombosis (P =.002, log-rank test); B tracto gastrointestinal recurrente sangrado
(GIB) (P =.10, log-rank test); C, muerte (P < 001, log-rank test); y D, muerte
incluyendo slo los pacientes que murieron por lo menos 7 das despus el ndice GIB
(P < 001, prueba de log-rank).
Figura.

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Tabla 3. Descripcin de eventos trombticos

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De los 442 pacientes, 36 (8,4%) tenan recurrente GIB (tabla 2).

En comparacin con quienes no reanudar la terapia de
warfarina, numricamente mayor proporcin de pacientes
reanudar terapia de warfarina tena recurrente GIB, pero esta
diferencia no fue estadsticamente significativa (10.0% [terapia
de warfarina continuacin] vs 5,5% [terapia de warfarina no
reasumieron]; P =.09. Anlisis multivariable que controlaba para
la propensin puntuacin, CDS, edad, sexo, indicacin para el
uso de warfarina, diagnstico previo de insuficiencia cardaca,
ubicacin del GIB, GIB la blanco INR, el porcentaje de pre-GIB
de INRs en gama, recepcin de heparina de bajo peso
molecular, longitud de ED de hospitalizacin y tratamiento
agudo de GIB (transfusin de sangre) tambin revel que el
riesgo para GIB recurrente asociado con reanudacin de la
terapia de warfarina no aument significativamente (HR , 1.32;
IC del 95%, 0,50-3.57) (figura, B). Comparado con el resto de
los pacientes, la tasa de GIB recurrente fue significativamente
mayores terapia de warfarina fue reasumida entre 1 y 7 das
despus el ndice GIB (6.23% vs 12,4%, respectivamente; P =
03. Aunque 5 de los eventos GIB ndice fueron eventualmente
fatal, no GIB recurrente dio lugar a muerte. La mediana (IQR)
de reanudacin de la terapia de warfarina a GIB recurrente fue
de 27 das (das 11-58). No haba ninguna asociacin entre el
manejo ms agresivo del ndice GIB (por ejemplo, ICU
admisin, uso de productos de la sangre) y recurrente GIB
(todos P >.05) (tabla 4 ).

Tabla 4. Los resultados segn estado recurrente GIBun

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Durante el perodo de seguimiento de 90 das, 52 pacientes

(11.8%) murieron (tabla 5). Las causas ms comunes de
muerte se relaciona con malignidad (28,8%), infeccin (19,2%)
y enfermedad cardiaca (17,3%). No hay muertes fueron
atribuidas a GIB recurrente. En comparacin con los
sobrevivientes, los pacientes que murieron fueron mayores (P =
03) y CDS ms alto (P =.004. Pacientes con un ndice GIB
localizada en el boca-esfago murieron con menos frecuencia,
y aquellos con un ndice GIB con una fuente de sangrado no
identificado murieron con ms frecuencia. Reanudacin de la
terapia de warfarina despus de que el ndice de GIB fue
asociado con un menor riesgo de muerte (HR, 0.31; 95% CI,
0.62 0.15) en anlisis multivariable que controlaba para la
puntuacin de propensin, CDS, edad, sexo, ubicacin del GIB,
admisin de ICU, hipertensin, diagnstico de accidente
cerebrovascular previo, pre-GIB por ciento del INRs en gama,
recepcin de heparina de bajo peso molecular, longitud de ED
de hospitalizacin y tratamiento agudo de GIB (transfusin de
sangre) (figura , C). Esta fuerte asociacin persisti en un
anlisis post-hoc excluidos todos los pacientes que murieron
dentro de 1 semana del ndice GIB (figura, D). La tasa de
mortalidad durante el seguimiento fue menor cuando la terapia
de warfarina fue reasumida entre 15 y 90 das despus el ndice

GIB (2,3%, P =.04 en comparacin con el resto de los

pacientes).
Tabla 5. Caractersticas de los pacientes por estado de la
muerte al final de la carta recordativaun

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COMENTARIO
Gastrointestinal tracto sangrado es una complicacin frecuente
de la terapia de warfarina. Este estudio de cohorte retrospectivo
evalu los resultados de 90 das entre los pacientes tratados
con warfarina con GIB. Los resultados destacan el dilema
clnico de la administracin de siguiente de la terapia de
warfarina una hospitalizacin o ED visita GIB. Aunque se
observ un aumento numrico en GIB recurrente asociada a no
interrumpir o reanudar la terapia de warfarina en los 90 das
despus el ndice GIB, este aumento no fue estadsticamente
significativo. Sin embargo, una decisin de no reanudar la
terapia de warfarina se asoci con un aumento significativo del
riesgo de trombosis y muerte por cualquier causa. Adems,
mientras que ningunas repeticiones GIB eran fatales, 3
pacientes con fibrilacin auricular tenan golpes fatales durante
la discontinuacin de la terapia de warfarina despus de un
evento GIB. Mientras que el mayor riesgo de trombosis y

muerte asociada a cualquier interrupcin de la terapia de

warfarina se ha divulgado previamente en un registro dans de
pacientes con fibrilacin auricular,14 a nuestro conocimiento,
nuestro es el primer estudio que informe esta observacin en
una cohorte de pacientes que reciben warfarina para las
indicaciones diversas especficamente en el contexto del
reciente GIB. En nuestro estudio, la fecha exacta y la duracin
de la interrupcin de la terapia de warfarina y los eventos
adversos fueron verificados a travs de la revisin del registro
mdico, mientras que en el estudio dans,14 la fecha de
interrupcin de la terapia de warfarina se estim a partir de
datos de siniestros de prescripcin de warfarina, las razones
por qu pacientes interrupcin la terapia eran desconocidas, y
los eventos adversos no fueron confirmados por revisin de
registro mdica.
La terica preocupacin que discontinuacin de terapia de
warfarina abrupto GIB siguiente causa temporal estado
hipercoagulable puede ser relevante para el incremento
observado en la trombosis en pacientes que no reanudar la
terapia de warfarina, 15 aunque no eventos trombticos se
produjeron dentro de los 7 das de la interrupcin de la terapia
de warfarina. Es difcil, si no imposible, determinar el curso del
tiempo entre la formacin del trombo y las manifestaciones
clnicas posteriores. Sin embargo, las pruebas de laboratorio
que apoyan la existencia real de "hipercoagulabilidad de rebote"
son inconsistente, y ensayos clnicos no han podido demostrar
mayor riesgo tromboemblico asociado con retiro precipitado
anticoagulante. 15

Nuestra observacin de que una decisin de no reanudar la

terapia de warfarina se asocia con mayor mortalidad fue
inesperada y no fcilmente explicado, teniendo en cuenta que
slo 3 de las 37 muertes en el grupo de no reanudar la terapia
de warfarina fueron atribuidos a la trombosis. Intentamos
controlar posibles factores de confusin del indicador de
reanudacin de la terapia de warfarina al incluir factores
pertinentes en el anlisis multivariable y realizando anlisis de
puntaje de propensin; sin embargo, persisti la asociacin. Es
posible que pacientes con un ndice ms grave GIB (que
presumiblemente seran ms propensos a morir) tambin eran
menos propensos a reanudar la anticoagulacin. Sin embargo,
la asociacin entre reanudar la terapia de warfarina y una
menor mortalidad persisti con modelado que ajustar para
admisin de ICU, as como transfusiones de sangre,
intervenciones que se esperara para ser marcadores de un GIB
inicial ms grave. Para profundizar en las explicaciones para la
asociacin entre una decisin de no reanudar la terapia de
warfarina y la muerte, reanaliz los datos despus de excluir los
pacientes que murieron durante la primera semana despus del
ndice GIB porque estos pacientes hubiera tenido menos
oportunidad de reanudar la terapia de warfarina. A pesar de
esto, encontramos que la Asociacin segua siendo
significativa. Reconocemos que el factor de confusin residual
era probable presente a pesar de esfuerzos rigurosos de
mitigacin a travs de diversos enfoques analticos. Por lo tanto,
el aparente incremento en muertes de nonthrombotic cuando la
terapia de warfarina no se reanud puede sugerir que el
tratamiento los mdicos eran reacios a reanudar la terapia de

warfarina en los pacientes ms enfermos con mayor riesgo de

muerte en general.
Nuestros resultados proporcionan una orientacin sobre el
momento ptimo de la reanudacin de la terapia de warfarina
despus de GIB, pero juicio clnico sigue siendo un factor crtico
en esta difcil decisin. Reanudacin de la terapia de warfarina
entre los das 1 y 7 despus de un evento GIB se asoci con un
mayor riesgo de GIB recurrente pero menor riesgo de
trombosis. Una mejor comprensin de la propensin a la
hemorragia recurrente y su severidad a travs del espectro de
lesiones anatmicas ayudara a informar la decisin del
momento ptimo de anticoagulacin reanudacin, un tema de
gran importancia para individuos en alto riesgo de
tromboembolismo.
Nuestro estudio es limitado en que se utilizaron datos de bases
de datos administrativas y as no todos los factores que afectan
la toma de decisin clnica podran ser recogidos. Sin embargo,
la confirmacin de trombosis, GIB recurrente y los resultados de
la muerte a travs de la carta mdica y revisin del certificado
de muerte consolida la validez de nuestros resultados. Los
resultados observados son biolgicamente plausibles porque
los eventos trombticos se correlacionaron con la indicacin
para la terapia de warfarina: pacientes con fibrilacin auricular
experimentaron golpes o embolia sistmica, mientras que los
pacientes con tromboembolismo tromboembolismo venoso
recurrente (tabla 2). A pesar de la confusin potencial, nuestro
estudio probablemente subestima la fuerza de la asociacin
entre trombosis y no reanudar la terapia de warfarina porque los

pacientes en mayor riesgo de trombosis (por ejemplo, presencia

de vlvula mecnica del corazn, alta CHADSpuntuacin2 ) fueron
probablemente menos propensas a permanecer fuera de
terapia de warfarina despus de la llave. Del mismo modo, la
fuerza de asociacin entre recurrente GIB y reanudar la terapia
de warfarina se puede subestimar porque pacientes percepcin
un alto riesgo de ms prisioneros probablemente tenan menos
probabilidades de reanudar la terapia de warfarina. Registro
exacto de referencia estado de uso de aspirina fue facilitada por
los registros mantenidos por CPAS. Sin embargo, estado de uso
de aspirina no fue documentada rutinariamente en los
resmenes de descarga ndice GIB, y una proporcin
considerable de pacientes no reanudar la terapia de warfarina y
as no fueron seguidas por CPAS despus el ndice GIB. Por lo
tanto, no fuimos capaces de exactamente registrar el uso de
aspirina tras el ndice GIB y reconocer que la falta de
informacin sobre el uso de aspirina despus GIB y su potencial
influencia sobre el riesgo de GIB recurrente, trombosis, y la
muerte es una limitacin.
Nuestro estudio muestra que la decisin de no reanudar la
terapia de warfarina en los 90 das que siguiente GIB se asocia
con mayor riesgo de trombosis y muerte. Nuestro anlisis
sugiere que, para muchos pacientes que han experimentado
GIB, los beneficios de la reanudacin de la terapia de warfarina
superan los riesgos. Se necesitan investigaciones adicionales
para determinar la duracin ptima de la interrupcin de la
warfarina despus de un evento de prisioneros y los pacientes

para quienes ms haba prolongada interrupcin pueden

justificarse.

INFORMACIN DEL ARTCULO

Correspondencia: Daniel M. Witt, MD, FCCP, SBDC, servicio
de anticoagulacin de farmacia clnica, Kaiser Permanente
Colorado, 16601 E Centretech Pkwy, Aurora, co 80011
(dan.m.witt@kp.org ).
Aceptado para su publicacin : 04 de junio de 2012.
Publicado en lnea: 17 de septiembre de 2012.
doi:10.1001/archinternmed.2012.4261
Las contribuciones del autor: El investigador principal, Dr.
Witt, tuvo acceso completo a todos los datos en el estudio y
asume la responsabilidad de la integridad de los datos y la
exactitud de los anlisis de los datos. Diseo y concepto de
estudio: Witt, Delate, Garcia, Clark y dental. Adquisicin de
datos: Witt, Delate, Garcia y Clark. Anlisis e interpretacin de
datos: Witt, Delate, Garcia, Hylek, Ageno y dental. Redaccin
del manuscrito: Witt, Delate, Garcia y dental. Revisin crtica del
manuscrito de contenido intelectual importante: Witt, Garcia,
Clark, Hylek, Ageno y dental. Anlisis estadstico: Witt y Delate.
Obtener financiacin: Witt y Garca. Apoyo administrativo,
tcnico y material: Garca y Clark. Supervisin de estudio: Witt y
Ageno.
Divulgacin de informacin financiera: El Dr. Garcia ha
servido como asesor Boehringrer Ingelheim, Bristol-Meyers
Squibb, Daiichi Sankyo y CSL Behring. Dr. Hylek ha servido

como asesor de Bayer, Boehringer Ingelheim, Bristol-Myers

Squibb, Daiichi Sankyo, Johnson y Johnson y Pfizer y particip
en simposios clnicos patrocinados por Bayer, Boehringer
Ingelheim y Bristol-Myers Squibb. El Dr. Crowther ha servido
como asesor de Leo Pharma, Pfizer, Bayer, Boehringer
Ingelheim, Alexion, CSL Behring y artesanal Pharma; ha
elaborado materiales educativos para Pfizer, Octapharm y CSL
Behring; ha proporcionado testimonio experto de Bayer; y tiene
una carrera de investigador de pleno y carrera Fundacin de
Ontario y el Leo Pharma Chair en la investigacin de
tromboembolismo en la Universidad de McMaster. Institucin
afiliada del Dr. Crowther (McMaster University) ha recibido
financiacin para proyectos de investigacin de Boehringer
Ingelheim, Pfizer, Octapharm y Leo Pharma.
Financiacin y soporte: CSL Behring LLC proporcion fondos
para el estudio.
Papel de patrocinador: CSL Behring LLC no estaba
involucrada en el diseo del estudio, coleccin, anlisis o
interpretacin de los datos o en la preparacin y presentacin
del manuscrito para su publicacin.
Contribuciones adicionales: Aubrey E. Jones colabor con la
extraccin de informacin de registros mdicos.

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