Research
Original Investigation
Bleeding Risk of Patients With Acute Venous
Thromboembolism Taking Nonsteroidal
Anti-Inflammatory Drugs or Aspirin
Bruce L. Davidson, MD, MPH; Sara Verheijen, BS; Anthonie W. A. Lensing, MD, PhD; Martin Gebel, PhD;
Timothy A. Brighton, MBBS; Roger M. Lyons, MD; Jeffrey Rehm, MD; Martin H. Prins, MD, PhD
IMPORTANCE Combined anticoagulant and aspirin therapy is associated with increased
bleeding risk in patients with atrial fibrillation, but the bleeding risk of combined use of
anticoagulant and nonsteroidal anti-inflammatory drugs (NSAIDs) is poorly documented.
OBJECTIVE To estimate the bleeding risk of combined anticoagulant (rivaroxaban or
enoxaparin–vitamin K antagonist [VKA]) and NSAID or aspirin therapy in patients with venous
thromboembolism.
DESIGN, SETTING, AND PARTICIPANTS Prospective analysis of observational data from the
EINSTEIN deep vein thrombosis and pulmonary embolism clinical trials comparing
rivaroxaban with enoxaparin-VKA treatment, trials performed in hospitals and clinics in 8246
patients enrolled from 2007 to 2009.
EXPOSURE Bleeding event rates during exposure to NSAID and aspirin therapy were
compared to time without exposure.
MAIN OUTCOMES AND MEASURES Days of NSAID or aspirin use and nonuse, clinically relevant
bleeding event and major bleeding event rates by patient-years, and hazard ratios.
RESULTS During NSAID-anticoagulant concomitant treatment, clinically relevant bleeding
occurred with an event rate of 37.5 per 100 patient-years vs 16.6 per 100 patient-years during
anticoagulant use only (hazard ratio [HR], 1.77 [95% CI, 1.46-2.14]). Major bleeding during
NSAID-anticoagulant treatment occurred with an event rate of 6.5 per 100 patient-years,
compared to 2.0 per 100 patient-years during nonuse (HR, 2.37 [95% CI, 1.51-3.75]). For
aspirin-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an
event rate of 36.6 per 100 patient-years, compared to 16.9 per 100 patient-years during
aspirin nonuse (HR, 1.70 [95% CI, 1.38-2.11]). Major bleeding in aspirin-anticoagulant–treated
patients occurred with an event rate of 4.8 per 100 patient-years, compared to 2.2 per 100
patient-years during aspirin nonuse (HR, 1.50 [95% CI, 0.86-2.62]). Increases in risk for
clinically relevant and major bleeding were similar for rivaroxaban and enoxaparin-VKA
anticoagulation regimens.
CONCLUSIONS AND RELEVANCE Among patients with venous thromboembolism receiving
anticoagulant therapy, concomitant use of an NSAID or aspirin is associated with an increased
risk of clinically relevant and major bleeding.
JAMA Intern Med. 2014;174(6):947-953. doi:10.1001/jamainternmed.2014.946
Published online April 14, 2014.
Author Affiliations: Division of
Pulmonary and Critical Care
Medicine, University of Washington
School of Medicine, Seattle,
Washington (Davidson); University of
Amsterdam, the Netherlands
(Verheijen); Bayer Healthcare,
Wuppertal, Germany (Lensing,
Gebel); Academic Medical Centre,
Amsterdam, the Netherlands
(Lensing); Haematology Division,
Prince of Wales Hospital, Sydney,
Australia (Brighton); Cancer Care
Centers of South Texas/US Oncology,
San Antonio, Texas (Lyons);
Pulmonary Associates of
Fredericksburg, Fredericksburg,
Virginia (Rehm); Maastricht
University Medical Centre,
Maastricht, the Netherlands (Prins).
Corresponding Author: Bruce L.
Davidson, MD, MPH, 12209
Shorewood Dr SW, Burien, WA 98146
([email protected]).
947
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University Of New Mexico User on 06/25/2014
Research Original Investigation
Anticoagulants With NSAID or Aspirin
P
atients with acute deep vein thrombosis (DVT) or pulmonary embolism (PE) require anticoagulation to prevent recurrent venous thromboembolism. Although
anticoagulant treatment is highly effective, it is associated
with increased bleeding risk. Bleeding is most often trivial
but can be clinically relevant or even fatal. The incidence of
DVT and PE increases with age; thus, DVT and PE commonly
coexist with comorbid conditions such as atherosclerotic
vascular disease and arthritis. A substantial proportion of
these patients will receive anticoagulant therapy combined
with aspirin and/or nonsteroidal anti-inflammatory drugs
(NSAIDs).1,2 Combined anticoagulant therapy and aspirin use
has been associated with an approximate 1.5-fold to 2.5-fold
increased bleeding risk in patients with atrial fibrillation and
a bleeding risk increase ranging from none to 2.3-fold in
patients with ischemic heart disease and prosthetic heart
valves.3-13 Combined anticoagulant and NSAID therapy has
been evaluated to a very limited extent in those cardiac conditions, mainly in retrospective analyses, which showed risk
increases for major bleeding ranging from none to 3-fold.14-16
The bleeding risks for anticoagulation combined with either
aspirin or NSAID use have not been reported for patients
receiving anticoagulation treatment for DVT or PE. Therefore, we used the EINSTEIN DVT and PE17,18 study cohort to
compare the incidence of clinically relevant bleeding and
major bleeding in patients with venous thromboembolism
receiving study anticoagulant therapy combined with either
NSAID or aspirin compared to patients receiving anticoagulant therapy only.
Methods
The EINSTEIN DVT and PE program evaluated the efficacy and
safety of a 3-month, 6-month, or 12-month course of oral rivaroxaban vs subcutaneous enoxaparin overlapping with and
followed by international normalized ratio–adjusted vitamin
K antagonists (VKAs) (ie, warfarin or acenocoumarol) in patients with acute symptomatic DVT, PE, or both. The studies
were conducted in 39 countries at 336 sites. Patients were observed for the occurrence of suspected symptomatic DVT
and/or PE and overt bleeding, which had to be reported to the
central independent adjudication committee. Overt bleeding
events were classified as major if they were fatal, occurred at
a critical site, or were associated with a decrease in hemoglobin concentration of more than 2 g/dL (to convert to grams per
liter, multiply by 10) and/or the need for transfusion of at least
2 units of red blood cells. Clinically relevant nonmajor bleeding was defined as bleeding that was not major but associated
with medical intervention, an unscheduled contact with a physician, (temporary) cessation of study treatment, or discomfort for the patient such as pain or impairment of activities of
daily living. Together, these 2 bleeding subgroups comprised
clinically relevant bleeding. Use of NSAIDs and platelet aggregation inhibitors was discouraged. However, if indicated, aspirin up to 100 mg/d and clopidogrel up to 75 mg/d were advised dosages. Concomitant medications taken during the
study were collected at each site on an electronic case record
948
form, and source verification was done by a clinical research
associate. Concomitant medication was coded according to the
WHO Drug Dictionary, version 2005/Q3.19 The EINSTEIN study
patient data were obtained after written informed consent and
institutional review board approvals. Data from the EINSTEIN
studies’ databases had been entirely delinked from personal
health information when accessed for this observational study.
This study is consistent with the principles of the Declaration
of Helsinki.
The objective of the present analysis was to assess the effects of rivaroxaban or enoxaparin-VKA use combined with
NSAID or aspirin therapy on the risk of clinically relevant bleeding and major bleeding. Nonsteroidal anti-inflammatory drugs
were defined via the ATC (Anatomical Therapeutic Chemical)
code M01A (anti-inflammatory/antirheumatic products, nonsteroids). Drugs containing aspirin with or without other ingredients were included.
The use of NSAID or aspirin therapy was categorized as
either “with” or “without” for each day between the day of randomization and the end of the patient’s at-risk period, which
was defined as last intake of rivaroxaban or enoxaparin-VKA
plus 2 days, or the onset date of first clinically relevant bleeding, major bleeding, or recurrent DVT and/or PE if any of these
occurred. The NSAID or aspirin exposure period also included an additional period of 7 days added to the stop date
to reflect a possible continuing effect on subsequent outcome risk. Because the onset of a first clinically relevant nonmajor bleeding event was defined to end the risk period for that
type of bleeding but often did not end a patient’s use of NSAIDs
or aspirin and study medication, the risk periods for major
bleeding were generally slightly longer.
A person-time–based approach was used to characterize
the rate per 100 patient-years of a first clinically relevant bleeding event or major bleeding event while a patient was taking
NSAID or aspirin. Person-time was accumulated per patient
from the day of randomization until the end of the at-risk period. Patients who were sometimes taking and sometimes not
taking NSAIDs or aspirin during the at-risk period contributed person-time to both categories of exposure. Event rates
per 100 patient-years and corresponding 95% confidence intervals (CIs) were computed for the at-risk periods. The resulting point estimate and CI was then transformed into a rate
per 100 patient-years. Then, a single Cox regression model with
NSAID or aspirin use (no vs yes) as a time-dependent variable
was fitted to derive the hazard ratio (HR) and its corresponding 95% CI for rivaroxaban vs enoxaparin-VKA use. P values
for interaction between anticoagulant treatment and use or
nonuse of NSAID or aspirin medication were calculated. The
Cox regression model was stratified according to the study entry index event (ie, DVT only vs PE with or without DVT) to
address potential differences between these populations. Additional Cox regression models were fitted to generate HRs for
use vs nonuse of NSAIDs or aspirin overall and by treatment
group, including stratification for index event and intended
treatment duration, with adjustment for age (≥60 vs <60 years),
sex, and plasma creatinine clearance (<50 vs ≥50 mL/min/
1.73 m2; to convert to milliliters per second per square meter,
multiply by 0.0167).
JAMA Internal Medicine June 2014 Volume 174, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University Of New Mexico User on 06/25/2014
jamainternalmedicine.com
Anticoagulants With NSAID or Aspirin
Original Investigation Research
Table 1. Baseline Characteristics of Patients Using or Not Using Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
or Aspirin During the EINSTEIN Studies
Characteristic
No NSAID Use
(n = 6362)
Any NSAID Use
(n = 1884)
No Aspirin Use
(n = 7044)
Any Aspirin Use
(n = 1202)
Male sex, No. (%)
3558 (55.9)
942 (50.0)
3811 (54.1)
689 (57.3)
Age, mean (SD), y
58 (17)
55 (17)
56 (17)
64 (15)
Weight, mean (SD), kg
82 (18.6)
84 (19.7)
82 (18.7)
84 (19.9)
Creatinine clearance, mean (SD),
mL/min/1.73 m2
100 (41.2)
108 (48.1)
104 (43.5)
90 (38.0)
Malignancy, No. (%)
344 (5.4)
84 (4.5)
369 (5.2)
59 (4.9)
Cardiac disease, No. (%)
909 (14.3)
224 (11.9)
704 (10.0)
429 (35.7)
Index event, No.
DVT only
2743
632
3006
369
PE with or without DVT
3558
1237
3974
821
61
15
64
12
No confirmed index event
Results
The group that was used to evaluate safety in the EINSTEIN
DVT and PE studies comprised 8246 patients (54.6% male;
mean age, 57 years), with 4130 patients receiving rivaroxaban
and 4116 patients receiving enoxaparin-VKA, of whom 1884
(22.8%) and 1202 (14.6%), respectively, received concomitant
NSAID or aspirin therapy at any time during their study
treatment.17,18 A first clinically relevant bleeding event occurred in 388 rivaroxaban-treated patients (9.4%), compared
to 412 enoxaparin-VKA–treated patients (10.0%), whereas a first
major bleeding event occurred in 40 (1.0%) and 72 (1.7%) patients, respectively. Table 1 shows characteristics of patients
who took NSAIDS and took aspirin at any time, as well as patients who did not. Fewer than 45 patient-years altogether were
available for analysis for patients taking a study anticoagulant with nonaspirin antiplatelet therapy, with minimal bleeding among them, so bleeding incidences with these comedications were not further analyzed.
Bleeding and NSAIDs
Users of NSAIDs were more likely than nonusers to be women,
so all analyses were adjusted for sex. For the treatment groups
combined, 127 clinically relevant bleeding occurred during 339
patient-years of NSAID use (37.5 per 100 patient-years) and 673
events occurred during 4054 patient-years of nonuse of NSAIDs
(16.6 per 100 patient-years), for an adjusted HR of 1.77 (95% CI,
1.46-2.14). Major bleeding occurred in 24 patients during 369
patient-years of NSAID use (6.5 per 100 patient-years) and 88
events occurred during 4295 patient-years of nonuse of NSAIDs
(2.0 per 100 patient-years), for an adjusted HR of 2.37 (95% CI,
1.51-3.75).
In NSAID-rivaroxaban–treated patients, clinically relevant bleeding occurred with an event rate of 37.6 per 100 patient-years (95% CI, 29.0-48.1 per 100 patient-years), compared to 15.8 per 100 patient-years (95% CI, 14.1-17.6 per 100
patient-years) during NSAID nonuse (HR, 1.90 [95% CI, 1.452.49]) (Table 2 and Table 3). During NSAID use in enoxaparinVKA–treated patients, clinically relevant bleeding occurred with
an event rate of 37.3 per 100 patient-years (95% CI, 28.7-47.7
per 100 patient-years), compared to 17.4 per 100 patientjamainternalmedicine.com
Abbreviations: DVT, deep vein
thrombosis; PE, pulmonary
embolism.
SI conversion factor: To convert
creatinine clearance to milliliters per
second per square meter, multiply
by 0.0167.
years (95% CI, 15.7-19.4 per 100 patient-years) when NSAIDs
were not used (HR, 1.65 [95% CI, 1.26-2.17]).
In NSAID-rivaroxaban–treated patients, major bleeding occurred with an event rate of 4.7 per 100 patient-years (95% CI,
2.2-9.0 per 100 patient-years), compared to 1.4 per 100 patientyears (95% CI, 1.0-2.0 per 100 patient-years) during NSAID nonuse (HR, 2.56 [95% CI, 1.21-5.39]) (Table 2 and Table 3). In
NSAID-enoxaparin-VKA–treated patients, major bleeding occurred with an event rate of 8.4 per 100 patient-years (95% CI,
4.7-13.8 per 100 patient-years), compared to 2.7 per 100 patientyears (95% CI, 2.0-3.5 per 100 patient-years) during nonuse (HR,
2.28 [95% CI, 1.28-4.04]).
Gastrointestinal bleeding accounted for 18 of 127 clinically relevant bleeding events, with remaining bleeding events
divided between multiple sites. Among 1593 patients who used
NSAIDs but not antiplatelet agents, there were 110 clinically
relevant bleeding events (6.9%). In another 248 patients who
simultaneously took an antiplatelet agent, there were 17 clinically relevant bleeding events (6.9%). Very few patients received a COX-2 NSAID, and there were no major bleeding events
among them. Clinically relevant and major bleeding occurred with similar frequency at any time in patients taking
NSAID co-medication, rather than requiring a long period of
exposure before a bleeding event.
Bleeding and Aspirin
Compared to aspirin nonusers, aspirin users were older and
had a lower plasma creatinine clearance rate, variables for
which all analyses were adjusted. For the treatment groups
combined, 104 clinically relevant bleeding events occurred
during 284 patient-years of aspirin use (36.6 per 100 patientyears) and 696 events occurred during 4109 patient-years of
nonuse of aspirin (16.9 per 100 patient-years), for an adjusted HR of 1.70 (95% CI, 1.38-2.11). Fifteen major bleeding
events occurred during 310 patient-years of aspirin use (4.8
per 100 patient-years) and 97 major bleeding events
occurred during 4354 patient-years of nonuse of aspirin (2.2
per 100 patient-years), for an adjusted HR of 1.50 (95% CI,
0.86-2.62).
During rivaroxaban treatment, the event rate for clinically relevant bleeding with aspirin use was 34.9 per 100
patient-years, compared to 16.1 per 100 patient-years during
JAMA Internal Medicine June 2014 Volume 174, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University Of New Mexico User on 06/25/2014
949
Research Original Investigation
Anticoagulants With NSAID or Aspirin
Table 2. Event Rates for Clinically Relevant and Major Bleeding in Nonsteroidal Anti-Inflammatory Drug (NSAID) or Aspirin Users vs Nonusers
Rivaroxaban-Treated Patients
(n = 4130)
Outcome
Enoxaparin-VKA–Treated Patients
(n = 4116)
Patientyears
Events/
100 Patient-years
(95% CI)
57
163.5
34.9 (26.4-45.2)
331
2058.9
16.1 (14.4-17.9)
6
179.9
3.3 (1.2-7.3)
34
2181.0
1.6 (1.1-2.2)
64
170.1
37.6 (29.0-48.1)
324
2052.3
15.8 (14.1-17.6)
Events,
No.
Patientyears
Events/
100 Patient-years
(95% CI)
HR Rivaroxaban–
Enoxaparin- VKA
(95% CI)
47
120.1
39.1 (28.8-52.0)
0.99 (0.67-1.46)
365
2050.2
17.8 (16.0-19.7)
0.91 (0.78-1.06)
9
129.6
6.9 (3.2-13.2)
0.54 (0.19-1.51)
63
2172.6
2.9 (2.2-3.7)
0.54 (0.36-0.82)
63
168.8
37.3 (28.7-47.7)
1.04 (0.73-1.47)
349
2001.5
17.4 (15.7-19.4)
0.91 (0.79-1.06)
Events,
No.
P
Valuea
Clinically relevant bleeding
Aspirin
No aspirin
.68
Major bleeding
Aspirin
No aspirin
.99
Clinically relevant bleeding
NSAID
No NSAID
.51
Major bleeding
NSAID
No NSAID
9
189.8
4.7 (2.2-9.0)
15
178.8
8.4 (4.7-13.8)
0.60 (0.26-1.37)
31
2171.1
1.4 (1.0-2.0)
57
2123.4
2.7 (2.0-3.5)
0.54 (0.35-0.83)
277
1908.0
14.5 (12.9-16.3)
308
1895.4
16.3 (14.5-18.2)
0.90 (0.76-1.06)
…
27
2012.1
1.3 (0.9-2.0)
48
2009.4
2.4 (1.8-3.2)
0.57 (0.35-0.90)
…
.82
Clinically relevant bleeding
Neither NSAID nor aspirin
Major bleeding
Neither NSAID nor aspirin
Abbreviations: Ellipses, no comparison made; HR, hazard ratio; VKA, vitamin K antagonist.
a
Interaction P value.
Table 3. Hazard Ratios for Clinically Relevant and Major Bleeding in Nonsteroidal Anti-Inflammatory Drug
(NSAID) or Aspirin Users vs Nonusers, Adjusted for Sex, Age, and Creatinine Clearance
Hazard Ratio (95% CI)
Variable
vs No NSAID
vs No Aspirin
vs Neithera
NSAID
Rivaroxaban
Clinically relevant bleeding
1.90 (1.45-2.49)
…
2.05 (1.56-2.70)
Major bleeding
2.56 (1.21-5.39)
…
2.62 (1.23-5.60)
Enoxaparin-VKA
Clinically relevant bleeding
1.65 (1.26-2.17)
…
1.75 (1.33-2.30)
Major bleeding
2.28 (1.28-4.04)
…
2.49 (1.39-4.48)
Aspirin
Rivaroxaban
Clinically relevant bleeding
…
1.81 (1.36-2.41)
1.96 (1.47-2.62)
Major bleeding
…
1.50 (0.63-3.61)
1.72 (0.70-4.20)
Enoxaparin-VKA
Clinically relevant bleeding
…
1.59 (1.17-2.17)
1.70 (1.24-2.33)
Major bleeding
…
1.50 (0.74-3.05)
1.79 (0.87-3.70)
Abbreviations: Ellipses,
no comparison made;
VKA, vitamin K antagonist.
a
aspirin nonuse (HR, 1.81 [95% CI, 1.36-2.41]) (Table 2 and
Table 3). For major bleeding during rivaroxaban treatment,
the event rate with aspirin use was 3.3 per 100 patient-years,
compared to 1.6 per 100 patient-years for aspirin nonuse
(HR, 1.50 [95% CI, 0.63-3.61]) (Table 2 and Table 3). During
enoxaparin-VKA treatment, the clinically relevant bleeding
rate during concomitant aspirin therapy was 39.1 per 100
patient-years, compared to 17.8 per 100 patient-years during
aspirin nonuse (HR, 1.59 [95% CI, 1.17-2.17]) (Table 2 and
Table 3). For major bleeding during enoxaparin-VKA treatment, the event rate was 6.9 per 100 patient-years, com950
Indicates patient-days taking
neither NSAID nor aspirin.
pared to 2.9 per 100 patient-years during aspirin nonuse (HR,
1.50 [95% CI, 0.74-3.05]) (Table 2 and Table 3). The
rivaroxaban–enoxaparin-VKA HRs for clinically relevant
bleeding and for major bleeding during aspirin use and aspirin nonuse were similar (Table 3). Twelve of 104 clinically
relevant bleeding events during aspirin treatment were gastrointestinal. Like the NSAID clinically relevant and major
bleeding events, the aspirin bleeding events were distributed
sparsely and relatively evenly over the duration of use; ie,
there was no apparent increased risk of bleeding with longer
duration of concomitant use.
JAMA Internal Medicine June 2014 Volume 174, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University Of New Mexico User on 06/25/2014
jamainternalmedicine.com
Anticoagulants With NSAID or Aspirin
Original Investigation Research
Table 4. Comparison of Numbers of Bleeding Events for Highest and Lowest Quartiles of Numbers of Days
of Exposure to Nonsteroidal Anti-Inflammatory Drugs and Aspirin for Rivaroxaban and Enoxaparin–Vitamin K
Antagonist (VKA) Patient Groups
Variable
Rivaroxaban
Enoxaparin-VKA
NSAID
Clinically relevant bleeding
Total bleeding events, No.
64
63
Highest quartile, >109 d, proportion (%)
13/215 (6.0)
13/219 (5.9)
Lowest quartile, ≤8 d, proportion (%)
28/277 (10.1)
29/250 (11.6)
Major bleeding
Total bleeding events, No.
9
16
Highest quartile, >109 d, proportion (%)
1/240 (0.4)
2/231 (0.9)
Lowest quartile, ≤8 d, proportion (%)
4/257 (1.6)
6/238 (2.5)
57
47
Aspirin
Clinically relevant bleeding
Total bleeding events, No.
Highest quartile, >182 d, proportion (%)
Lowest quartile, ≤8 d, proportion (%)
6/165 (3.6)
0/101
21/259 (8.1)
17/239 (7.1)
Major bleeding
Total bleeding events, No.
6
9
Highest quartile, >182 d, proportion (%)
1/182 (0.5)
0/114
Lowest quartile, ≤8 d, proportion (%)
2/246 (0.8)
2/231 (0.9)
Findings for Patients Taking Both NSAIDs and Aspirin
For major bleeding, there were only 37 patient-years of exposure altogether and 2 events among patients taking both
NSAIDs and aspirin. For clinically relevant bleeding, there were
33 patient-years of exposure altogether and 16 clinically relevant bleeding events. The point estimates of bleeding rates
per 100 patient-years were somewhat higher than for NSAID
and aspirin use individually, but the 95% CIs were wide and
overlapping. When the odds of bleeding while taking either
NSAIDs or aspirin was compared to the odds while taking neither (“neither” rows in Table 2 and Table 3), the point estimates for each comparison show a higher risk, but the CIs overlap with those of the co-medication being compared. To
investigate the timing of bleeding, we compared in Table 4 the
number of bleeding events of each category for each drug by
the quartile of days’ duration of taking either NSAIDs or aspirin. From 22% to 46% of major and clinically relevant bleeding events occurred within the first 8 days of either NSAID or
aspirin use for both anticoagulant treatment groups, and relatively fewer occurred in patients who had more than 109 (for
NSAID) or more than 182 (for aspirin) days of use concomitant with 1 of the study anticoagulants, but sporadic late bleeding did occur.
Discussion
Our study, for the first time to our knowledge, showed a
clinically important and statistically significant increase in
clinically relevant bleeding (ie, 1.8-fold) and major bleeding
(ie, 2.4-fold) in patients co-administered NSAIDs with anticoagulation. As has been previously shown for patients with
atrial fibrillation, ischemic heart disease, and prosthetic
jamainternalmedicine.com
heart valves,3-13 this study confirms the increased bleeding
risk with aspirin used together with anticoagulants in
patients treated for venous thromboembolism, although
unlike the finding for NSAIDs, this increased risk was less
pronounced and not significant for major bleeding. The
potential contribution of NSAIDs to bleeding in patients taking an anticoagulant has not been previously rigorously
quantified. Although aspirin and NSAID therapy were associated with an approximately 2-fold increase in gastrointestinal bleeding, this could not explain the overall increase in
clinically relevant bleeding.
In our study, 22% of patients took NSAIDs at some time,
although the protocol discouraged NSAID use. In a recently
published registry study of patients with atrial fibrillation
discharged from hospitals in Denmark, approximately 22%
also disclosed NSAID use.2 We wonder whether it is widely
appreciated that NSAIDs, available over the counter in most
places, put patients receiving anticoagulant therapy at
nearly double the risk of clinically important bleeding. We
found that a short duration of exposure to NSAIDs and aspirin confers similar risk to longer exposure. We could neither
confirm nor deny that COX-2 NSAIDs reduce risk and cannot
comment on NSAID dosage.
What are the clinical implications of our findings? The
doubled risk for bleeding should urge physicians to combine
anticoagulation with either NSAID or aspirin therapy with caution and only if genuinely indicated, with no similarly effective and safer alternative treatment available. If indicated, patients treated with VKAs should be monitored carefully to avoid
prolonged periods in the supratherapeutic zone, especially in
those with an a priori enhanced bleeding risk. For NSAID
therapy, we could not address whether the use of selective
COX-2 NSAIDs may be superior because our analysis was unJAMA Internal Medicine June 2014 Volume 174, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University Of New Mexico User on 06/25/2014
951
Research Original Investigation
Anticoagulants With NSAID or Aspirin
derpowered for this subgroup. The medical literature is limited to but 3 relevant retrospective studies that reported conflicting results.14-16 A recent comparison of rivaroxaban vs
placebo in patients with acute coronary syndrome reported a
bleeding HR of 3.8 for rivaroxaban-treated patients who took
both aspirin and a thienopyridine antiplatelet drug, as well as
rivaroxaban at either 2.5 or 5 mg twice daily.20 Such a treatment regimen differs distinctly from that taken by patients after DVT and PE.
Some methodological aspects and possible limitations of
our study warrant comment. First, this study was a post hoc
analysis. However, the use of concomitant medication with
NSAID and aspirin therapy was prospectively collected,
intensively monitored, and centrally coded. Bleeding events
were prospectively collected as well and were reported using
standardized forms. In addition, bleeding events were adjudicated centrally using internationally accepted criteria
without knowledge of treatment assignment and use of concomitant medication. Second, use of concomitant NSAIDs or
aspirin occurred in patients with differing demographic
characteristics and comorbid conditions between users and
nonusers. Although the HRs from users vs nonusers were
adjusted for confounders, the true additive effect on bleeding of NSAID and aspirin therapy to comorbid illness would
optimally be addressed in a randomized trial. Third, the par-
ARTICLE INFORMATION
Accepted for Publication: February 18, 2014.
Published Online: April 14, 2014.
doi:10.1001/jamainternmed.2014.946.
Author Contributions: Drs Davidson and Gebel had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Davidson, Lensing,
Gebel, Prins.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Davidson, Verheijen,
Lensing, Brighton, Lyons, Prins.
Critical revision of the manuscript for important
intellectual content: Davidson, Lensing, Gebel,
Brighton, Lyons, Rehm, Prins.
Statistical analysis: Davidson, Lensing, Gebel, Prins.
Administrative, technical, or material support:
Davidson, Lensing, Prins.
Study supervision: Davidson, Lensing.
Conflict of Interest Disclosures: Drs Davidson and
Prins were paid by Bayer for steering committee
and related work for the EINSTEIN studies. Drs
Brighton, Lyons, and Rehm, site principal
investigators in the EINSTEIN studies, were paid for
time and costs of patient recruitment and
follow-up, and Dr Rehm has been a paid speaker for
a sponsor, Janssen Pharmaceuticals. All attended
EINSTEIN-related meetings with travel-related
costs paid by Bayer. No other disclosures are
reported.
Funding/Support: Drs Lensing and Gebel are paid
employees of Bayer and devoted salaried time to
this work; the other authors were unsupported.
Role of the Sponsors: Bayer Healthcare reviewed
the manuscript, but Bayer Healthcare and Janssen
Pharmaceuticals had no role in the design and
952
ticipating physicians were discouraged from using NSAID
and aspirin therapy and instructed to use the lowest possible
dose if such medications were indicated. Moreover, the EINSTEIN study protocols required that patients with a clearly
increased bleeding risk be excluded from participation, and
physicians might have been selective in prescribing or continuing NSAIDs and aspirin in those patients with an estimated lower bleeding risk. Thus, the observed bleeding incidences in our studies likely reflect underestimates compared
to what would be encountered in community practice and
the HR estimates for bleeding that we found in our reduced
bleeding risk population may be underestimates for the
overall population of patients with DVT and PE who are
receiving anticoagulation treatment.
Conclusions
Combined anticoagulant and NSAID or aspirin therapy is associated with an increased risk of clinically relevant bleeding. The increase was similar in rivaroxaban-treated and enoxaparin-VKA–treated patients. Physicians should inform patients
about the potential for increased bleeding with these readily
available commonly used drugs and advise patients to curtail
their casual use.
conduct of the study; collection, management,
analysis, and interpretation of the data; preparation
of the manuscript; and decision to submit the
manuscript for publication. Bayer Healthcare and
Janssen Pharmaceuticals sponsored the 2 EINSTEIN
clinical trials, collected and maintained the data,
and performed the analyses that the authors
requested. The sponsors’ other roles are described
in the original EINSTEIN publications.
Previous Presentation: This study was presented
at the 24th Congress of the International Society on
Thrombosis and Haemostasis; July 2, 2013;
Amsterdam, the Netherlands.
REFERENCES
1. Levine MN, Raskob G, Beyth RJ, Kearon C,
Schulman S. Hemorrhagic complications of
anticoagulant treatment: the Seventh ACCP
Conference on Antithrombotic and Thrombolytic
Therapy. Chest. 2004;126(3)(suppl):287S-310S.
2. Olesen JB, Lip GYH, Lindhardsen J, et al. Risks of
thromboembolism and bleeding with
thromboprophylaxis in patients with atrial
fibrillation: a net clinical benefit analysis using a ‘real
world’ nationwide cohort study. Thromb Haemost.
2011;106(4):739-749.
3. Hansen ML, Sørensen R, Clausen MT, et al. Risk of
bleeding with single, dual, or triple therapy with
warfarin, aspirin, and clopidogrel in patients with
atrial fibrillation. Arch Intern Med. 2010;170(16):
1433-1441.
4. Lechat P, Lardoux H, Mallet A, et al; FFAACS
(Fluindione, Fibrillation Auriculaire, Aspirin et
Contraste Spontané) Investigators. Anticoagulant
(fluindione)-aspirin combination in patients with
high-risk atrial fibrillation. Cerebrovasc Dis.
2001;12(3):245-252.
5. Shireman TI, Howard PA, Kresowik TF, Ellerbeck
EF. Combined anticoagulant-antiplatelet use and
major bleeding events in elderly atrial fibrillation
patients. Stroke. 2004;35(10):2362-2367.
6. Lane DA, Kamphuisen PW, Minini P, Büller HR,
Lip GY. Bleeding risk in patients with atrial
fibrillation: the AMADEUS study. Chest.
2011;140(1):146-155.
7. Turpie AG, Gent M, Laupacis A, et al. A
comparison of aspirin with placebo in patients
treated with warfarin after heart-valve
replacement. N Engl J Med. 1993;329(8):524-529.
8. Altman R, Rouvier J, Gurfinkel E, Scazziota A,
Turpie AG. Comparison of high-dose with low-dose
aspirin in patients with mechanical heart valve
replacement treated with oral anticoagulant.
Circulation. 1996;94(9):2113-2116.
9. Meschengieser SS, Fondevila CG, Frontroth J,
Santarelli MT, Lazzari MA. Low-intensity oral
anticoagulation plus low-dose aspirin versus
high-intensity oral anticoagulation alone:
a randomized trial in patients with mechanical
prosthetic heart valves. J Thorac Cardiovasc Surg.
1997;113(5):910-916.
10. Laffort P, Roudaut R, Roques X, et al. Early and
long-term (one-year) effects of the association of
aspirin and oral anticoagulant on thrombi and
morbidity after replacement of the mitral valve with
the St. Jude medical prosthesis: a clinical and
transesophageal echocardiographic study. J Am Coll
Cardiol. 2000;35(3):739-746.
11. Coumadin Aspirin Reinfarction Study (CARS)
Investigators. Randomised double-blind trial of
fixed low-dose warfarin with aspirin after
myocardial infarction. Lancet.
1997;350(9075):389-396.
JAMA Internal Medicine June 2014 Volume 174, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University Of New Mexico User on 06/25/2014
jamainternalmedicine.com
Anticoagulants With NSAID or Aspirin
Original Investigation Research
12. Hurlen M, Smith P, Arnesen H. Effects of
warfarin, aspirin and the two combined, on
mortality and thromboembolic morbidity after
myocardial infarction: the WARIS-II
(Warfarin-Aspirin Reinfarction Study) design. Scand
Cardiovasc J. 2000;34(2):168-171.
13. van Es RF, Jonker JJ, Verheugt FW, Deckers JW,
Grobbee DE; Antithrombotics in the Secondary
Prevention of Events in Coronary Thrombosis-2
(ASPECT-2) Research Group. Aspirin and coumadin
after acute coronary syndromes (the ASPECT-2
study): a randomised controlled trial. Lancet.
2002;360(9327):109-113.
14. Shorr RI, Ray WA, Daugherty JR, Griffin MR.
Concurrent use of nonsteroidal anti-inflammatory
jamainternalmedicine.com
drugs and oral anticoagulants places elderly persons
at high risk for hemorrhagic peptic ulcer disease.
Arch Intern Med. 1993;153(14):1665-1670.
15. Battistella M, Mamdami MM, Juurlink DN,
Rabeneck L, Laupacis A. Risk of upper
gastrointestinal hemorrhage in warfarin users
treated with nonselective NSAIDs or COX-2
inhibitors. Arch Intern Med. 2005;165(2):189-192.
16. Chung L, Chakravarty EF, Kearns P, Wang C,
Bush TM. Bleeding complications in patients on
celecoxib and warfarin. J Clin Pharm Ther. 2005;30
(5):471-477.
17. Bauersachs R, Berkowitz SD, Brenner B, et al;
EINSTEIN Investigators. Oral rivaroxaban for
symptomatic venous thromboembolism. N Engl J
Med. 2010;363(26):2499-2510.
18. Büller HR, Prins MH, Lensin AW, et al;
EINSTEIN–PE Investigators. Oral rivaroxaban for the
treatment of symptomatic pulmonary embolism.
N Engl J Med. 2012;366(14):1287-1297.
19. WHO Drug Dictionary. Version 2005/Q3.
Uppsala, Sweden: Uppsala Monitoring Centre;
2005.
20. Mega JL, Braunwald E, Wiviott SD, et al; ATLAS
ACS 2–TIMI 51 Investigators. Rivaroxaban in patients
with a recent acute coronary syndrome. N Engl J
Med. 2012;366(1):9-19.
JAMA Internal Medicine June 2014 Volume 174, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University Of New Mexico User on 06/25/2014
953