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Original Research |

Relation of Nonsteroidal Anti-inflammatory Drugs to Serious Bleeding and Thromboembolism Risk in Patients With Atrial Fibrillation Receiving Antithrombotic Therapy: A Nationwide Cohort StudyRelation of NSAIDs to Serious Bleeding and Thromboembolism Rates in AF

Morten Lamberts, MD, PhD; Gregory Y.H. Lip, MD*; Morten Lock Hansen, MD, PhD; Jesper Lindhardsen, MD, PhD; Jonas Bjerring Olesen, MD, PhD; Jakob Raunsø, MD, PhD; Anne-Marie Schjerning Olsen, MD, PhD; Per Kragh Andersen, PhD, DMSc; Thomas Alexander Gerds, Dr Rer Nat; Emil L. Fosbøl, MD, PhD; Christian Torp-Pedersen, MD, DMSc*; and Gunnar H. Gislason, MD, PhD*
[+] Article, Author, and Disclosure Information

* Drs. Lip, Torp-Pedersen, and Gislason contributed equally to this work.


From Gentofte University Hospital, Hellerup, Denmark; University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom; University of Copenhagen, University Hospital of Copenhagen, Rigshospitalet, National Institute of Public Health, and University of Southern Denmark, Copenhagen, Denmark; and University of Aalborg, Aalborg, Denmark.

Financial Support: Dr. Gislason is supported by an unrestricted research scholarship from the Novo Nordisk Foundation.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1581.

Reproducible Research Statement:Study protocol: Not applicable. Statistical code: Methods for calculation of absolute risk are available from Dr. Lamberts (e-mail, mortenlamberts@gmail.com). Data set: Raw data are available from Statistics Denmark (www.dst.dk/en.aspx).

Requests for Single Reprints: Morten Lamberts, MD, PhD, Department of Cardiology, Gentofte University Hospital, Post 635, Niels Andersens Vej 65, 2900 Hellerup, Denmark; e-mail, mortenlamberts@gmail.com.

Current Author Addresses: Drs. Lamberts, Hansen, Lindhardsen, Olesen, Raunsø, Olsen, Fosbøl, and Gislason: Department of Cardiology, Gentofte University Hospital, Post 635, Niels Andersens Vej 65, 2900 Hellerup, Denmark.

Dr. Lip: Department of Medicine, City Hospital, University of Birmingham, Dudley Road, Birmingham B18 7QH, United Kingdom.

Dr. Andersen: University of Copenhagen, Oster Farimagsgade 5, Postboks 2099, 1014 Copenhagen, Denmark.

Dr. Gerds: Department of Public Health, Section of Biostatistics, University of Copenhagen, Oster Farimagsgade 5, Postboks 2099, Room 15-2-07, 1014 Copenhagen, Denmark.

Dr. Torp-Pedersen: Department of Health Science and Technology, Aalborg University, Niels Jernesvej 12, A5-208, 9220 Aalborg, Denmark.

Author Contributions: Conception and design: M. Lamberts, G.Y.H. Lip, M.L. Hansen, A.M.S. Olsen, E.L. Fosbøl, G.H. Gislason.

Analysis and interpretation of the data: M. Lamberts, G.Y.H. Lip, J. Lindhardsen, J.B. Olesen, J. Raunsø, A.M.S. Olsen, P.K. Andersen, T.A. Gerds, E.L. Fosbøl, G.H. Gislason.

Drafting of the article: M. Lamberts, G.Y.H. Lip, J. Lindhardsen, J. Raunsø, P.K. Andersen.

Critical revision of the article for important intellectual content: M. Lamberts, G.Y.H. Lip, M.L. Hansen, J. Lindhardsen, J.B. Olesen, J. Raunsø, A.M.S. Olsen, P.K. Andersen, E.L. Fosbøl, C. Torp-Pedersen, G.H. Gislason.

Final approval of the article: M. Lamberts, G.Y.H. Lip, J. Lindhardsen, J.B. Olesen, J. Raunsø, A.M.S. Olsen, P.K. Andersen, E.L. Fosbøl, G.H. Gislason.

Statistical expertise: J. Lindhardsen, P.K. Andersen, T.A. Gerds, G.H. Gislason.

Obtaining of funding: G.H. Gislason.

Administrative, technical, or logistic support: J. Lindhardsen, G.H. Gislason.

Collection and assembly of data: M. Lamberts, J. Lindhardsen, C. Torp-Pedersen, G.H. Gislason.


Ann Intern Med. 2014;161(10):690-698. doi:10.7326/M13-1581
Text Size: A A A

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are assumed to increase bleeding risk, but their actual relation to serious bleeding in patients with atrial fibrillation (AF) who are receiving antithrombotic medication is unknown.

Objective: To investigate the risk for serious bleeding and thromboembolism associated with ongoing NSAID and antithrombotic therapy.

Design: Observational cohort study.

Setting: Nationwide registries.

Patients: Danish patients with AF hospitalized between 1997 and 2011.

Measurements: Absolute risk for serious bleeding and thromboembolism with ongoing NSAID and antithrombotic therapy, assessed by using Cox models.

Results: Of 150 900 patients with AF (median age, 75 years [interquartile range, 65 to 83 years]; 47% female), 53 732 (35.6%) were prescribed an NSAID during a median follow-up of 6.2 years (interquartile range, 2.1 to 14.0 years). There were 17 187 (11.4%) and 19 561 (13.0%) occurrences of serious bleeding and thromboembolism, respectively. At 3 months, the absolute risk for serious bleeding within 14 days of NSAID exposure was 3.5 events per 1000 patients compared with 1.5 events per 1000 patients without NSAID exposure. The risk difference was 1.9 events per 1000 patients. In patients selected for oral anticoagulant therapy, the absolute risk difference was 2.5 events per 1000 patients. Use of NSAIDs was associated with increased absolute risks for serious bleeding and thromboembolism across all antithrombotic regimens and NSAID types. An NSAID dosage above the recommended minimum was associated with a substantially increased hazard ratio for bleeding.

Limitation: Observational design and unmeasured confounders.

Conclusion: Use of NSAIDs was associated with an independent risk for serious bleeding and thromboembolism in patients with AF. Short-term NSAID exposure was associated with increased bleeding risk. Physicians should exercise caution with NSAIDs in patients with AF.

Primary Funding Source: None.

Figures

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Figure 1.

Risks for serious bleeding and thromboembolism at 3 mo and 2 y, with and without 14 d of NSAID exposure.

Absolute risk differences were reported as NSAID exposure minus no NSAID exposure for each antithrombotic treatment group. The absolute risks were derived from Cox regression analysis, and 95% CIs were determined as quantiles of results in 200 bootstrap samples. “Single antiplatelet” denotes aspirin or clopidogrel. NSAID = nonsteroidal anti-inflammatory drug; OAC = oral anticoagulant.

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Figure 2.

Risks for serious bleeding and thromboembolism at 3 mo and 2 y, by predicted risk and concomitant NSAID use.

Vertical bars indicate 95% CIs, determined as quantiles of results in 200 bootstrap samples. CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75, Diabetes mellitus, Stroke, Vascular disease, Sex female; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile INRs, Elderly, Drug therapy/alcohol intake; NSAID = nonsteroidal anti-inflammatory drug.

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Appendix Figure.

Estimation of effect of unmeasured confounders.

“OREC” denotes the association between the confounder and NSAID use, and “RRCD” denotes the association between the confounder and the outcome. The blue line indicates the magnitude needed for an unmeasured confounder to render the results statistically insignificant at a given OREC and RRCD. The green line indicates the corresponding magnitude of an unmeaured confounder needed to nullify the results. The estimated HR for bleeding with NSAID therapy compared with no NSAID therapy (reference) is 2.27 (95% CI, 2.15 to 2.40). The blue line shows that an unmeasured confounder should be 6 times more prevalent among patients exposed to NSAIDs and be associated with a 6-fold increase in risk for bleeding to explain the effect of NSAID therapy compared with no NSAID therapy. HR = hazard ratio; NSAID = nonsteroidal anti-inflammatory drug.

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Comments

Submit a Comment/Letter
Be aware of NSAID in atrial fibrillation
Posted on November 19, 2014
Gauranga Dhar
Bangladesh Institute of Family Medicine and Research
Conflict of Interest: None Declared
Atrial fibrillation (AF) is not uncommon. About one third of patients seeking medical help for irregular heartbeats are diagnosed as AF. Mandatory drugs for AF are the drugs for rate and rhythm control and anticoagulants. On the other hand use of different NSAIDs is also wide spread. Both selective and non-selective COX inhibitors, some are available as over the counter drugs and many are prescribed by the physicians. This study probably the first of this kind will be a good alert for physician during prescription of NSAID to a patient with AF specifically who are on anticoagulant
Warfarin-Acetaminophen Adverse interaction
Posted on November 20, 2014
Arthur H Friedlander , DMD
Veterans Affairs Los Angeles/UCLA Oral and Maxillofacial Surgery
Conflict of Interest: None Declared
The authors of a recent paper in this journal (Lamberts M, et al. Relation of nonsteroidal anti-inflammatory drugs to serious bleeding and thromboembolism in patients with atrial fibrillation receiving antithrombic therapy. Ann Intern Med 2014; 161: 690-698) noted that in patients with atrial fibrillation the concomitant administration of warfarin and an NSAID resulted in an increased risk of serious bleeding and thromboembolism. They concluded that their data supported previous recommendations that use of NSAIDs be discouraged and that administration of acetaminophen be considered. In our review of the literature however, we have retrieved a number of studies which delineate an adverse drug-drug reaction between warfarin and acetaminophen as evidenced by marked increases in the INR value although these have rarely been associated with adverse clinical outcome.1,2
Most akin to our clinical practice which involves management of postoperative acute surgical pain is the classic study by Hylek which demonstrated that taking four regular strength (325 mg) tablets of acetaminophen per day for longer than one week significantly increased the risk of markedly elevating the INR value.3 The warfarin-acetaminophen interaction may arise because of pharmacokinetic interaction at the level of cytochrome P 450 (CYP) 2 C9 resulting in decreased metabolism of warfarin4, a toxic acetaminophen metabolite inhibiting enzymes in the vitamin K cycle required for the liver’s production of coagulation factors5 or because of hepatotoxicity resulting from excessive ingestion of the analgesic agent. Lamberts et al. study pointedly identifies the need for collaborative healthcare provider management of these very labile patients even in the ambulatory setting and intensive patient education regarding their use of over-the-counter medications.


References
1) Mahe I, Bertrand N, Drouet L, Bal Dit Sollier C, Simoneau G, Mazoyer E, et al. Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study. Haematologica 2006; 91: 1621-1627.
2) Parra D, Beckey NP, Stevens GR. The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy. Pharmacotherapy 2007; 27: 675-683.
3) Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998; 279: 657-662.
4) Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717-719.
5) Thijssen HH, Soute BA, Vervoort LM, Claessens JG. Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle. Thromb Haemost 2004; 92: 797-802.
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Summary for Patients

Nonsteroidal Anti-inflammatory Drugs and Serious Bleeding and Thromboembolism in Patients With Atrial Fibrillation

The full report is titled “Relation of Nonsteroidal Anti-inflammatory Drugs to Serious Bleeding and Thromboembolism Rates in Patients With Atrial Fibrillation Receiving Antithrombotic Therapy. A Nationwide Cohort Study.” It is in the 18 November 2014 issue of Annals of Internal Medicine (volume 161, pages 690-698). The authors are M. Lamberts, G.Y.H. Lip, M.L. Hansen, J. Lindhardsen, J.B. Olesen, J. Raunsø, A.M.S. Olsen, P.K. Andersen, T.A. Gerds, E.L. Fosbøl, C. Torp-Pedersen, and G.H. Gislason.

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