EDITORIAL

Concomitant treatment with nonsteroidalanti-inflammatory drugs and vitamin K antagonists:critical appraisal of the recommendations issuedby the French Agency for Healthcare Product Safety

Bernard Bannwarth*Rheumatology Department, Pellegrin Hospital & Therapeutics Laboratory, EA 525, Victor Segalen University,33076 Bordeaux cedex, France

interaction / nonsteroidal anti-inflammatory drugs / vitamin K antagonists

Last January, the AFSSaPS (French Agency for Health-care Product Safety) revised the marketing license forvitamin K antagonists (VKA) and issued recommenda-tions [1] on “appropriate prescription” of these agents.Concern raised by the findings from two studiesprompted these steps. The first study, conducted in1998 by the Regional Pharmacovigilance Centers,found that bleeding events in patients on VKAsaccounted for 13% of admissions for adverse events oftreatments in France. This extrapolates to about 17,000admissions per year, the total number of admissions foradverse events of drugs in France being estimated at128,000 per year. The second study was done in neu-rosurgery departments during the summer of 2000 andshowed that nearly 8% of patients admitted for a brainhemorrhage were taking a VKA. Although most patientswere aware of the adverse effects of VKA, over half didnot know the symptoms of an impending brain hem-orrhage. These data are of direct relevance to rheuma-tologic practice because bleeding events in patients onVKA can be precipitated by the prescription of a non-steroidal anti-inflammatory drug (NSAID) or, lessoften, of a urate-lowering agent (allopurinol or ben-zbromarone).

INTERACTIONS BETWEEN NSAIDS AND VKAS

Most pharmacological studies were done with warfarin,a reference VKA widely used in the United States butlittle prescribed in France, where it is sold under theproprietary name Coumadinet. However, the findingsfrom these studies can be extended to all VKAs.

An NSAID can interact with a VKA at several levels[2]. Because both have a serum albumin binding greaterthan 95%, one can displace the other by competing forits binding sites. However, competition is not consis-tently observed in vivo [2]. Furthermore, any increasein plasma levels of free VKA, and therefore in antico-agulant activity, is short-lived because it induces anincrease in clearance of the drug [2]. In practice, phar-macokinetic interactions with VKAs are most likely tooccur with pyrazole derivatives, particularly as theseagents also inhibit the hepatic catabolism of the mostactive warfarin isomer, the S enantiomer [2]. Similarly,piroxicam potentiates the activity of acenocoumarol(Sintromt) by slowing the metabolism of its mosteffective enantiomer [3]. A recent study showed thatrofecoxib (25 mg/d) induced a mean 8% increase insteady-state warfarin activity by decreasing the metabo-lism of the R enantiomer [4] .

A pharmacodynamic interaction with conventionalNSAIDs may occur, since these consistently alter plate-let aggregation, albeit in varying degrees [2]. Aspirin isthe only NSAID that produces a consistent and sub

* Correspondance and reprints.E-mail address: bernard.bannwarth@thera.u-bordeaux 2.fr (B. Bannwarth).

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stantial increase in bleeding time. High doses of aspirinlower the prothrombin level [5]. A case-control studymilitates against a similar interaction with nonsalicylateNSAIDs [6]. Similarly, most studies found no signifi-cant prothrombin time increase after addition of anonsalicylate NSAID to warfarin [2, 7]. However, thenumbers of patients were small and, in most cases,treatment duration (with a VKA alone or a VKA plusan NSAID) was shorter than 1 week [2, 5, 7]. Theirnegative findings are unconvincing given the manyreports of bleeding events in patients given add-onNSAID therapy while on a VKA [2, 7]. Furthermore,the relative risk of gastrointestinal bleeding associatedwith conventional NSAIDs has been reported toincrease from about three to about 12–16 when a VKAwas given concomitantly, the difference being ascribedto the VKA promoting bleeding from NSAID-inducedulcers [8]. Although less alarming, the data from aretrospective cohort study of patients aged 65 years orolder also indicate a greater risk with the combination:the number of admissions for gastrointestinal bleedingwas 10.2 per 1000 patient-years with warfarin alone,i.e., 3.3-fold the baseline risk, and 26.3 per 1000patient-years with warfarin plus a nonsalicylate NSAID[9].

The risk of disturbing the anticoagulant balanceachieved with a VKA seems greatest with aspirin andphenylbutazone but exists with all NSAIDs, includingselective COX-2 inhibitors [2, 4, 6, 10]. The strengthof this interaction is unpredictable because it variesacross individuals [4]. Its clinical expression alsodepends on patient-related factors: advanced age, frailty,presence of an organic lesion likely to bleed, arterialhypertension, and severe renal failure are risk factors forbleeding events [5, 7, 9].

MANAGEMENT

The AFSSaPS recommendations state that analgesics(acetaminophen/paracetamol) or glucocorticoidsshould be preferred over NSAIDs for treating painful orinflammatory rheumatic conditions in patients on VKAtherapy [1]. In addition to nonpharmacological mea-sures (e.g., physical treatments, technical aids, and reha-bilitation), many other drugs should have beensuggested as alternatives, including colchicine, opiates,symptomatic slow-acting drugs for osteoarthritis orchronic inflammatory joint disease, and even localadministration of nonsalicylate NSAIDs since the sys-

temic levels generated by this mode of delivery are toolow to induce interactions with VKAs [5, 11].

Nevertheless, the AFSSaPS recommendations statethat “any change in treatment (introduction, dosagechange, or discontinuation of a drug [other than theVKA]) should be followed 3 to 4 days later by determi-nation of the International Normalized Ratio [INR]”[1]. This is appropriate since a VKA can occasionallyinteract with a substance that usually carries no suchrisk, for instance acetaminophen [6, 12] or oxaceprol[13]. Of note, the INR is now the only laboratory testused to monitor VKA therapy, the prothrombin testhaving been discarded because of its lower reproduc-ibility [1]. The target INR value is 2.5 (therapeuticrange, 2–3), except in a few specific situations (somecases of mitral stenosis and mechanical prosthetic valves,for instance) that require a higher level of anticoagula-tion [1].

When the above-mentioned drugs induce unaccept-able side effects or fail to improve the rheumatic symp-toms, oral NSAIDs can be used, except for aspirin(≥3 g/d) and phenylbutazone. The AFSSaPS recom-mendations indicate that in this situation the INRshould be determined at shorter intervals, although nodetails are given [1]. In patients with stable INR values,it is standard practice to determine the INR at leastevery 4 weeks, in the absence of intercurrent events [1].Given that the INR should be determined 3 to 4 daysafter introduction of the NSAID, it seems reasonable touse the results of this first test as the basis for decidinghow often further determination should be performed.If the first INR after NSAID introduction is between 2and 3, the best interval is probably 1 or 2 weeks,according to patient-related factors. Conversely, if theINR moves outside the therapeutic range, requiring achange in the VKA dosage, further INR determinationsshould be done twice or three times a week until thevalue returns to the therapeutic range.

A second point on which the AFSSaPS recommenda-tions fail to provide guidance is the choice of theNSAID [1]. Selective COX-2 inhibitors do not alterprimary hemostasis and are less likely than conven-tional NSAIDs to cause gastrointestinal lesions [14].However, until concerns about their potential to inducethrombosis have been laid to rest [15], COX-2 inhibi-tors do not appear preferable to a conventional NSAIDin combination with misoprostol or omeprazole [16].In every case, the NSAID should be given in its smallesteffective dosage. Whenever possible, a drug with a shorthalf-life should be used.

452 B. Bannwarth

Finally, the AFSSaPS recommendations emphasizethe duty of physicians to inform their patients, particu-larly about the dangers of self-medication [1]. In par-ticular, patients should be warned that NSAIDs aresold as analgesics/antipyretics, sometimes as over-the-counter medications. Patients should also be told not tochange their VKA dosage without informing their phy-sician. Furthermore, a rheumatologist who starts apatient on NSAID therapy should inform the patient’sgeneral practitioner and other specialists of this changein treatment.

REFERENCES

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11 Heyneman CA, Lawless-Liday C, Wall GC. Oral versus topicalNSAIDs in rheumatic diseases. A comparison. Drugs 2000 ;60 : 555-74.

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