Risk of Bleeding with Exposure to Warfarin and Nonsteroidal Anti-Inflammatory Drugs:
A Systematic Review and Meta-Analysis
Oral anticoagulation (OAC) is used for thromboprophylaxis, but the downside is the
risk of bleeding; hence, clinical decision-making often has to balance the reduction
in thromboembolism against the potential for serious bleeding.[1] Indeed, many clinical risk factors have been described as contributing to bleeding
risk among OAC users.[2] The risks of antithrombotic therapy-related bleeding are multifactorial, and even
ethnicity may play a part.[3]
The use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) in combination
with OAC poses a risk of bleeding.[4]
[5]
[6]
[7]
[8]
[9] NSAIDs are also associated with thrombosis.[6]
[8]
[10]
[11]
[12]
[13]
[14] From a clinical perspective, the chronic use of NSAIDs with OAC tends to intersect
in patients with chronic osteoarthritis (OA) and atrial fibrillation (AF). The NSAID
class has therapeutic benefit for treating arthritic pain and inflammation, and providing
patients with important symptomatic relief and physical mobility. However, patients
can develop serious major bleeding, in particular gastrointestinal (GI) major bleeding,
when NSAIDs are combined with OAC.
Antiplatelet therapy (APT) or NSAID use in combination with warfarin are associated
with an increased risk of major bleeding and GI major bleeding.[4]
[6] The factor Xa inhibitors (apixaban, rivaroxaban) and direct thrombin inhibitor (dabigatran)
have a safer overall intracranial bleeding profile relative to therapeutically dosed
warfarin (international normalized ratio 2.0–3.0).[15]
[16]
[17] Apixaban has been shown to have less major bleeding and GI major bleeding relative
to warfarin.[17] Dabigatran and rivaroxaban are associated with increased GI major bleeding, and
relatively similar rates of major bleeding, relative to warfarin.[15]
[16] NSAID use in combination with apixaban is associated with an increased risk of major
bleeding, but not GI major bleeding.[9] NSAID use in combination with dabigatran is associated with an increased risk of
major bleeding and GI major bleeding.[8] Rivaroxaban with NSAIDs has shown a similar trend.[7] The general trends for major bleeding and GI major bleeding in combined NSAID and
OAC use are summarized in [Table 1]. In general, the use of NSAIDs in combination with the most commonly used OACs (apixaban,
rivaroxaban, dabigatran, or warfarin) is limited by the risk of major bleeding.
Table 1
General trends in bleeding, thrombosis among OACs with NSAIDs, and NSAIDs alone
|
Major bleeding
|
GI major bleeding
|
Thrombosis
|
Reference
|
|
OAC with NSAID compared with no NSAID
|
|
Apixaban + Any NSAID
|
⇑
|
⇔
|
⇔
|
12
|
|
Rivaroxaban + Any NSAID
|
⇑
|
⇑
|
–
|
2
|
|
Dabigatran + Any NSAID
|
⇑
|
⇑
|
⇑
|
3
|
|
Warfarin + Any NSAID
|
⇑
|
⇑
|
⇑
|
1
|
|
Warfarin + Selective COX-2 inhibitors
|
⇔
|
⇑
|
–
|
1, 16
|
|
Warfarin + Celecoxib
|
⇔
|
–
|
–
|
1
|
|
No OAC, NSAID alone compared with no NSAID
|
|
Any NSAID
|
⇑
|
⇑
|
⇑
|
1, 7
|
|
Selective COX-2 inhibitors
|
⇑
|
⇑
|
⇑
|
1, 7
|
|
Celecoxib
|
⇑
|
⇑
|
⇑
|
1, 7
|
Abbreviations: COX-2, cyclooxygenase enzyme 2; GI, gastrointestinal; NSAID, nonsteroidal
anti-inflammatory drug; OAC, oral anticoagulation.
Note: ⇑, significant increase. ⇔, no significant difference.
The clinical question remains: is there a safe course for using NSAIDs in combination
with OAC? Patients with AF on OAC and comorbid severe OA are limited in terms of pharmacologic
OA relief, which can impair physical mobility and quality of life. Celecoxib, a selective
COX-2 inhibitor NSAID, is effective for the symptomatic treatment of OA and improving
physical function,[18]
[19]
[20] and can be dosed once daily compared with multiple dosing for nonselective NSAIDs.
Celecoxib is understudied in regards to safety when used with OAC ([Table 1]).
In this issue of Thrombosis and Haemostasis, a meta-analysis by Zapata et al suggests that selective COX-2 inhibitors do not
have an elevated risk of major bleeding, but do for GI major bleeding, when used in
combination with warfarin, whereas nonselective NSAIDs were associated with an increased
risk of both major bleeding and GI major bleeding.[21] This analysis is consistent with a previous study regarding NSAID use with warfarin.[6] In a previous large cohort analysis of NSAID use with warfarin, celecoxib was the
only NSAID agent that did not demonstrate a significant increase in major bleeding
when combined with OAC; however, selective COX-2 inhibitors as a class were associated
with a significant increase in major bleeding and GI major bleeding. It is important
to caution that nonselective NSAIDs and selective COX-2 inhibitors alone are associated
with an increased bleeding and thrombotic risk compared with no NSAID use.[6]
[12] Celecoxib was shown to have similar rates of major adverse cardiovascular events
and GI bleeding risk compared with ibuprofen and naproxen in patients with OA.[8]
[9]
[13]
[14] Additional analysis of the selective COX-2 inhibitor celecoxib is needed to better
understand its safety when used in combination with OAC.
Careful medication review is necessary to identify other bleeding risk agents, such
as APT (e.g., aspirin, clopidogrel, ticagrelor), as well as multiple NSAID use, to
avoid “stacking” bleeding risk. Review of the past medical history to gauge bleeding
risk also helps to identify contraindications to NSAID use with OAC. Past medical
history of major bleeding, GI mucosal disease, cirrhosis, or renal failure are major
precautions to NSAID use all together. A proactive management strategy with appropriate
use of dynamic bleeding risk assessment, mitigation of modifiable bleeding risk factors,
and follow-up of high-risk patients was associated with lowered bleeding events and
improved anticoagulation uptake among patients with AF, when compared with usual care.[22]
If patients with comorbid AF and OA, receiving OAC, are relatively otherwise healthy
without bleed risk “stacking,” then close clinical follow-up and patient counseling
may warrant safe NSAID use on a pro re nata basis. A clinical approach to NSAIDs and
OAC is proposed in [Table 2]. Adjunctive analgesic therapies for OA include weight loss, physical therapy, acetaminophen,
transdermal lidocaine, transdermal NSAIDs, and tramadol. Opioids are generally not
recommended. Consultation with orthopaedics surgery for definitive arthroplasty is
warranted in severe cases of OA. Duloxetine is recommended as a safe adjunctive therapy
for chronic lumbar back pain. In summary, a comprehensive multimodal strategy for
treating OA pain in patients with AF on OAC is recommended. Review with cardiology,
rheumatology, hematology, or nephrology are also important considerations on a case-by-case
basis before initiating an NSAID in patients receiving OAC.
Table 2
Proposal for clinical assessment of NSAIDs in patients receiving OAC
|
• Assess indication for NSAID use
• Is there a safe alternative to NSAID use?
• Does NSAID use require expert consultation?
• Review bleeding risk
a. Medical history
i. Advanced age
ii. Previous major or minor bleeding events
iii. Gastric mucosal disease (e.g., ulcer, H. pylori, varices, AVMs)
iv. CKD, ESRD on HD
v. Malignancy
vi. Cirrhosis
vii. Alcohol use
viii. ICH, CNS disease
ix. Coagulopathy
x. Thrombocytopenia
b. Medications
i. Oral anticoagulation (e.g., warfarin, dabigatran, rivaroxaban, apixaban)
ii. NSAID use (e.g., ibuprofen, naproxen, meloxicam, diclofenac)
iii. Antiplatelet agents (e.g., aspirin, clopidogrel, ticagrelor)
iv. Herbal supplements
• Review thrombotic risk
a. Medical history
i. AF, MI, PCI, CABG, PAD
ii. Ischemic stroke or TIA
iii. DVT/PE
iv. Smoking
v. Obesity
vi. Immobility
vii. Pending surgery
viii. Hypercoagulable state
b. Medications (e.g., OCPs, testosterone)
• Review other NSAID risks
a. CHF, renal dysfunction, electrolyte abnormalities
• Do the benefits outweigh the risks of using concomitant NSAID?
• Recommend avoiding NSAIDs with warfarin, dabigatran, and rivaroxaban
• Consider the use of PRN celecoxib (lowest dose, shortest duration) with apixaban
• Patient counseling and close follow-up
• Monitor for bleeding and thrombotic risks, discontinue NSAID if risk > benefit
|
Abbreviations: AF, atrial fibrillation; AVM, arteriovenous malformation; CABG, coronary
artery bypass graft; CHF, congestive heart failure; CKD, chronic kidney disease; CNS,
central nervous system; DVT/PE, deep vein thrombosis/pulmonary embolism; ESRD, end-stage
renal disease; HD, hemodialysis; ICH, intracranial hemorrhage; MI, myocardial infarction;
NSAID, nonsteroidal anti-inflammatory drug; OAC, oral anticoagulation; OCPs, oral
contraceptives; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention;
PRN, pro re nata; TIA, transient ischemic attack.
Importantly, NSAIDs are also used on a short-term basis for their antipyretic effects.
It is important to opt for acetaminophen in place of NSAIDs for patients with a febrile
illness who are on OAC. NSAID-related renal dysfunction is also an important consideration,
especially in regards to the pharmacokinetics of OACs that depend on the creatinine
clearance (renal elimination: apixaban 27%, rivaroxaban 66%, dabigatran 80%).
Further clinical investigation into the relationship between NSAID and OAC use, specifically
the selective COX-2 inhibitor celecoxib at low dose, may help define a relatively
safe strategy for their combined use in select situations to address the therapeutic
goals of patients with comorbid OA and AF, among other related chronic conditions
in which NSAIDs and OAC intersect.
