Is it safe to prescribe NSAIDs with dabigatran etexilate and
Prepared for NHS healthcare professionals by the HAT Committee of the UK Clinical Pharmacy Association
Date Prepared: April 2010
The combination of aspirin and anticoagulant therapy is associated wit h a clinically meaningful and
significantly increased risk of major extrac ranial bleeding events, a large proportion from the upper
GI tract . How safe therefore are the concurrent use of aspirin and NSA IDs with dabigatran or
rivaroxaban, bearing in mind that the cohort of patients undergoing elective hip or knee
replacement surgery are likely to be older?
The SP C for dabigatran etexilat e states that due to t he risk of haemorrhage, caution should be
exercised with concurrent NSA ID use, especially those with elimination half-lives of more than 12
hours or if the patient has additional risk factors for bleeding. The rivaroxaban SPC advises care
with co-prescribing of NSAIDs, but notes that no clinically relevant prolongation of bleeding time
was observed after concomitant administration of rivaroxaban and 500 mg naproxen .
In the two major phase III orthopaedic clinical trials with dabigatran etexilate (RENOVA TE and
REMODEL ), the concomitant use of aspirin at doses less than 160mg and short acting NSA IDs
with half lives less than 12 hours were permitted. NSAIDs were administered to 55. 2% and 63.7%
of patients respectively whilst aspirin was used by 4.1% and 3. 3% of patients respectively.
Unfortunately, information regarding the specific NSA IDs, dosing regimens and duration of therapy
Results from t hese studies suggest that the concomit ant use of aspirin did not appear to influence
the occurrence of major bleeding events in any treatment group . There was one major bleed in
each treatment group in patients concomitantly taking aspirin; during REMODE L (1 patient on
220mg dabigatran and >160mg as pirin, 1 patient on enoxaparin) and RENOVA TE (1 patient on
With regards t o rivaroxaban, pooled analysis from RECORD 1-4 , revealed that approximately
70% of patients reported concomitant use (at least once) of NSA IDs and 9% reported concomitant
use of platelet aggregation inhibitors or aspirin in both groups
The major and clinically relevant non-major bleeding rate ratio for NSAID use versus non -use was
greater with rivaroxaban at 1. 28 (95% CI 0.94 -1. 73) compared to 0.9 with enoxaparin (95% CI
0.63 - 1.28). In addition, the major and clinically relevant non-major bleeding rate ratio for
antiplatelet use versus non-use was 1.11 (95% CI 0.55-2.25) with rivaroxaban and 1.13 (95% CI
0.47-2.75) with enoxaparin. Therefore, although the RECORD 1–4 analysis showed that the
concomitant use of NSAIDs or antiplatelet agents was associated with a small increase in bleeding
risk, the magnitude of the increase was similar in patients treated with rivaroxaban 10mg once
daily and the enoxaparin treatment regimens studied.
It is important to remember that different criteria were used to assess bleeding events in the
RECORD (rivaroxaban) and RE -MODEL/RE -NOVA TE (dabigatran) studies and so it is not
possible to directly compare safety profiles.
From the National Electronic Library for Medicines. www.nelm.nhs.uk 1
At UCLH, rivaroxaban is our formulary choice for oral thromboprophylaxis post elective hip and
knee replacement surgery. Acknowledging the limited data available and the fact that these are
still early days for clinical practice, we have translated the above information into our guidelines as
o If possible, avoid the use of NSA ID for post-op analgesia.
o If NSA ID therapy is deemed essential, then an agent with a shorter half -life and with a lower
GI and cardiovascular side-effect profile would be preferable (e. g. ibuprofen).
o Routine GI prophylaxis with ranitidine or a PPI is not warranted, unless the patient is
considered at higher GI risk from NSAID therapy per se.
Manufacturers advise caution when using NSAIDs in patients taking rivaroxaban or dabigatran
because of a potentially increased risk of bleeding, but the combination is not cont ra-indicated.
There are limited published data on bleeding risk with these combinations. The evidence
available has been reviewed, but it does not allow risks with the two agents to be compared
Knowledge of potential bleeding risks enables clinic ians to develop practical guidelines to limit
the risk, such as those developed at UCLH.
Published data are limited. Clinicians should review the evidence and develop their own
organisational guidance to reduce patient risk.
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(1) Bhatt DL et al. ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the
Gastroint estinal Risks of Antiplatelet Therapy and NSA ID Use: A Report of the American
College of Cardiology Foundation Task Force on Clinical Expert Cons ensus Documents.
JACC 2008. 52(18): 1502-1517
(2) Boehringer Ingelheim Limited. Pradaxa 110mg and 75mg hard capsules: summary of product
characteristics via www.medicines.org.uk Last updated on the eMC: 25/11/2009.
(3) Eriksson BI, Dahl OE et al. Dabigat ran etexilate versus enoxaparin for prevention of venous
thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.
RE-NOVA TE. Lancet 2007; 370:949-956
(4) Eriksson BI, Dahl OE et al. Oral dabigatran etexilate vs. subcut aneous enoxaparin for the
prevention of venous thromboembolism after total knee replacement: the RE -MODEL
randomized trial. J. Throm Haemost. 2007; 5: 2178-2185
(5) Personal communication: N. Mathieson. Medical Information. Boehringer Ingelheim 5.1.09
(6) Eriksson BI et al. A Pooled Analysis of Four Pivot al Studies of Rivaroxaban for the Prevention
of V enous Thromboembolism after Ort hopaedic Surgery: Effects of Specified Co-medications.
Abstract 1986 presented at the American Society of Hemat ology (AS H) 50th Annual Meeting
and Exposition, San Francisco, CA, USA; December 6–9, 2008.
(7) Bayer plc. Xarelto 10mg: summary of product characteristics via www.medicines.org. uk
Last updated on the eMC: 21/05/2009.
Prepared and checked by
Haemostasis, Anticoagulation & Thrombosis (HA T) Committee, UK Clinical Pharmacy Associati on.
Quality assurance assisted by UKMi.
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