A placebo-controlled study of interaction between nabumetone andacenocoumarol

A. Pardo,1 M. Garcıa-Losa,2 A. Fernandez-Pavon,3 S. del Castillo,1 T. Pascual-Garcıa,1 E. Garcıa-Mendez2

& R. Dal-Re2

1Department of Haematology, Prıncipe de Asturias Hospital, Alcala de Henares, Madrid, 2Medical Department, SmithKline Beecham Pharmaceuticals,Madrid and 3Department of Haematology, La Paz Hospital, Madrid, Spain

Aims The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients treatedwith oral anticoagulants is generally discouraged due to the risk of interactions thatcould increase the risk of bleeding complications. Available data suggest the NSAID,nabumetone, does not produce such an interaction. We investigated whethernabumetone would interact with acenocoumarol, an oral anticoagulant widely usedin some European countries.Methods A double-blind, randomized, placebo-controlled study was conductedevaluating nabumetone (1–2 g daily for up to 4 weeks) in osteoarthritis patientswith thromboembolic risk previously stabilized on acenocoumarol. The primaryefficacy end point was the proportion of patients whose International NormalizedRatio (INR) remained within established margins and whose acenocoumarol dosewas not changed. Fifty-six patients were randomized to receive nabumetone (n=27) or placebo (n=29).Results Eighteen patients in each group (67% for nabumetone and 62% for placebo)completed the study without showing INR or acenocoumarol dose changes, andwere considered as study successes. Nine patients (33%) with nabumetone and 11(38%) with placebo were considered study failures in the intention-to-treat analysis(one patient on nabumetone and four on placebo did not complete the study dueto reasons not related to INR and acenocoumarol dose changes). No significantdifferences were found between groups with regard to study successes. There weretwo minor bleeding complications, one in each group. Six patients per grouppresented with eight adverse experiences in each group.Conclusions Treatment with nabumetone did not alter INR levels compared withplacebo in patients stabilized on oral acenocoumarol who require NSAID therapy.These results suggest that nabumetone does not produce a clinically relevantinteraction with acenocoumarol. In orally anticoagulated patients without otherassociated risk factors, treatment with nabumetone for up to 4 weeks does notrequire increased monitoring of INR levels.

Keywords: acenocoumarol, interaction, nabumetone

risk of thromboembolic or bleeding complications [1]. ItIntroduction

is well known that the concomitant use of nonsteroidalanti-inflammatory drugs (NSAIDs) in these patients mayMaintenance of anticoagulation stability in patients under

treatment with oral anticoagulants (OACs) requires close modify the coagulation status through various mechan-isms: 1) Some NSAIDs enhance the hypoprothrombina-monitoring of coagulation parameters in order to prevent

unexpected shifts in anticoagulation and the subsequent emic effect of OACs through a pharmacokineticinteraction either by displacing OACs from their proteinbinding sites or by inhibiting their hepatic metabolism

Correspondence: Dr Manuel Garcıa-Losa, Departamento Medico, SmithKline[2]; 2) Most NSAIDs inhibit platelet function, thusBeecham Pharmaceuticals, Valle de la Fuenfrıa, 3, 28034 Madrid, Spain.

Received 9 June 1998, accepted 1 December 1998. increasing a patient’s bleeding liability [2]; 3) NSAIDs

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can induce direct gastrointestinal mucosal damage and (500 mg tablet−1) or matching placebo once daily for3–4 weeks. INR values were assessed at baseline andbleeding [3]. The global effect of these three mechanisms

is an increased risk of bleeding complications when every 7–10 days for 3 follow-up visits. All patients wereallowed to use orally administered 575 mg capsules ofOACs and NSAIDs are taken together.

Several studies suggest that nabumetone, a nonacidic dipyrone (magnesium metamizole), up to four per day,as analgesic rescue medication. Safety was assessed byNSAID, does not increase the risk of bleeding through

the mentioned mechanisms [2, 4–6]. When nabumetone routine haematology, biochemistry and urine laboratorytests performed at baseline and end-point visits, and bywas given to patients stabilized on chronic warfarin, the

International Normalized Ratio (INR) values did not recording of adverse events at all follow-up visits.Acenocoumarol and nabumetone compliance and con-differ significantly from those observed prior to initiating

nabumetone use [7]. Similarly, nabumetone did not comitant medication use (including dipyrone) wereevaluated at all follow-up visits. The primary efficacyproduce an interaction when given to patients under

stable anticoagulation with acenocoumarol an OAC endpoint was the proportion of patients whose INRremained within the specified margins and whoseclosely related to warfarin [8]: in this study only one of

16 patients showed an increase in the INR value, a acenocoumarol dose remained unchanged during thestudy and at study end.proportion similar to that observed in a series of patients

treated with acenocoumarol who had not received any Sample size was calculated assuming an expected similarefficacy of 90% in both treatment groups, and a clinicallyconcomitant NSAID (A. Fernandez-Pavon & A. Pardo,

unpublished data). meaningful difference higher than 20% between groups;for an alpha error of 0.05, a power of 80% for a one tailThe objective of this study was to assess whether

nabumetone compared with placebo interacts with the comparison, 28 patients per treatment group were needed[11]. All comparisons were made using the Fisher’sOAC acenocoumarol in patients previously stabilized on

acenocoumarol. exact test.

Methods Results

Fifty-six Caucasian outpatients (17 male) presenting toThis was a prospective, randomized, parallel group,placebo-controlled, double-blind trial carried out at two the Haematology Departments of two large general

hospitals in the Madrid, Spain area, were randomized tocentres in Spain. The study was approved by the ResearchEthics Committees of both participating centres. Male receive nabumetone (n=27) or placebo (n=29). No

significant differences were found between treatmentand female patients aged between 18 and 80 years oldunder stable oral anticoagulation with acenocoumarol groups in terms of demographic characteristics and sex

distribution (Table 2). The conditions for which aceno-were eligible to participate in the study. Stable anticoagul-ation was defined as no changes in both the INR and coumarol was prescribed are shown in Table 1.

Osteoarthitis conditions for which nabumetone wasacenocoumarol dose in the last three consecutive assess-ments prior to patient inclusion. Acenocoumarol dose prescribed are shown in Table 2. All randomized patients

taking at least one dose of study medication (n=56) werewas adjusted for each individual to maintain a level ofanticoagulation (INR) within specified margins [9] included in the intention-to-treat analysis. One patient

in the nabumetone group and four on placebo weredepending on the particular condition for which it wasindicated (Table 1) and/or common practice at the withdrawn from the study due to reasons not related to

INR and acenocoumarol dose changes.participating centres. In addition, patients were requiredto have a diagnosis of osteoarthritis requiring treatment Eighteen patients in each group successfully completed

the study without showing INR and acenocoumarol dosewith a NSAID. Exclusion criteria included previoustreatment with nabumetone, potentially fertile females, changes. Nine patients in the nabumetone group and 11

in the placebo group prematurely terminated theirallergy to NSAIDs, bleeding episodes or conditions within3 months prior to inclusion, other uncontrolled serious participation and were considered study failures in the

analysis (Table 3). Between-groups differences in successesconditions, concomitant treatment with drugs differentfrom acenocoumarol unless their dose had been stable for and failures were not statistically significant: 4.6% (95%

C.I. −29.7; 20.5).at least 3 months prior to inclusion, and concomitant useof other NSAIDs. Prior to beginning their participation There were no statistically significant differences

between the nabumetone and placebo groups, respect-in the study, written informed consent was obtained fromall patients. ively, in the mean number of rescue analgesic medication

capsules taken at visit 1 (8.3±8.8 and 9.2±8.3; 95% C.I.Patients were randomly allocated to receive theapproved [10] dose of 2–4 tablets of either nabumetone −5.55; 3.71), at visit 2 (8.1±10.1 and 10±10.3; 95%

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Lack of interaction of nabumetone with acenocoumarol

Table 1 Conditions for which oralanticoagulation was prescribed andrecommended INR ranges [9].

Condition Nabumetone Placebo[recommended INR ranges] n (%) n (%)

AF [1.5–2.5* or 2–3†] 6 (22) 6 (21)AF+cardiac pathology [2–3] 6 (22) 6 (21)DVT [2–3] — 1 (3)Acute myocardial infarction [2–3] — 1 (3)Cardiac pathology—no prosthesis [2–4] 4 (15) 8 (28)Cardiac valvular prosthesis [2.5–4] 11 (41) 4 (14)DVT+PT [2–3] — 2 (7)AF+DVT [2–3] — 1 (3)

AF=Atrial fibrillation. PT=Pulmonary thromboembolism. DVT=Deep vein thrombosis.*Simple AF. †Embolic AF.

Table 2 Demographic characteristics andconditions for which nabumetone wasprescribed.

Nabumetone (n=27) Placebo (n=29)(%) [range] (%) [range]

Sex Male/Female 11 (40.7)/16 (59.3) 6 (20.7)/23 (79.3)Age (years) Mean {s.d.} 60.1 {8.9} [44–74] 65.1 {7.6} [49–79]Height (cm) Mean {s.d.} 160 {9.1} [142–179] 158 {9.3} [144–181]Weight (kg) Mean {s.d.} 72.0 {12.1} 73.7 {14.3}

[52.0–107.5] [47.5–114.5]Spondyloarthritis* 12 (39) 6 (20)Knee osteoarthritis* 9 (29) 8 (27)Generalized osteoarthritis* 3 (10) 8 (27)Shoulder osteoarthritis* 2 (6) 4 (13)Other osteoarthritis* 5 (16) 4 (13)

*Some patients presented with more than one condition.

Table 3 Patients withdrawn during thestudy period and successes at study end. Nabumetone (n=27) Placebo (n=29)

Up to visit 1 Withdrawn (failure*) 1 1Withdrawn (other) 0 1

Visit 1 to visit 2 Withdrawn (failure*) 2 1Withdrawn (other) 1 1

Visit 2 to visit 3 Withdrawn (failure*) 5 5Withdrawn (other) 0 2

Visit 3 Successes 18 18

*Failure: patients with INR and acenocoumarol dose changes.

C.I. −7.79; 3.87) and at visit 3 (9.3±9.6 and 13.3±12.1; not requiring corrective treatment and not leading toimmediate patient’s withdrawal.95% C.I. −10.55; 2.46).

There was not a statistically significant difference eitherbetween mean (±s.d.) baseline acenocoumarol dose (mg)

Discussionin both groups: 1.4 (±2.22) (95% C.I. −5.86; 3.06), orbetween mean (±s.d.) baseline INR values in both Nabumetone is a nonacidic NSAID, which unlike other

NSAIDs [2], does not inhibit platelet aggregation signifi-groups: 0.38 (±0.17) (95% C.I. 0.03; 0.073).Six patients in each group reported eight adverse cantly [12]. In a comparative study between aspirin,

nabumetone (1 g day−1), placebo and no treatment, theexperiences per group. Only one patient per group waswithdrawn due to adverse experiences (a biliary colic and incidence of gastrointestinal microscopic haemorrhage

was not significantly different between the nabumetone,an acute myocardial infarction). There were no clinicallysignificant abnormal laboratory values during the study. placebo and no treatment groups [5].

Although it has been shown in in vitro studies that, dueThere was one minor bleeding complication per group

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Madrid, Spain. We are indebted to Pilar de la Ossa and Juana Sanzto its protein binding affinity, 6-MNA, the activefor their technical support, and to Felipe Rodrıguez-Alcantara,metabolite of nabumetone, is able to displace otherMD, for his comments on statistical analysis.protein-bound drugs from their binding sites [6], clinical

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