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Given the inhibition of platelet aggregation by non-steroidal antiinflammatory drugs (NSAIDs),1-3 bleed-

ing complications due to these agents can be expected.Both randomized controlled trials in healthy volunteers4

and case–control studies in patients5,6 indeed show in-creased frequencies of gastrointestinal bleeding related toNSAID use, also without the inclusion of aspirin (OR~3.5). This can be explained by the combined, reversibleinhibition of the cyclooxygenase-1 (COX-1) enzyme inboth platelets and the gastrointestinal mucosa1 by non-as-pirin NSAIDs; aspirin causes irreversible COX-1 inhibi-

tion. Other possible NSAID-related bleeding complicationshave rarely been investigated in prospective studies.7,8

In contrast, there is widespread knowledge of the bleed-ing complications of coumarin therapy. Coumarin deriva-tives are vitamin K antagonists and thus inhibit the synthe-sis of the vitamin K– dependent coagulation factors (II,VII, IX, X). This results in a 9.6% yearly incidence of hem-orrhages (with 0.6% fatal), as was shown in an overview of25 studies.8 Higher age and the duration and intensity of theanticoagulation are well known risk factors.9

Thus, the combined use of NSAIDs and coumarinderivatives may result in an even higher bleeding rate thanthe use of coumarin derivatives alone, since both plateletaggregation and coagulation factors are inhibited. Prospec-tive studies10-12 in coumarin users did not show suprathera-peutic anticoagulation (as measured by the international

Concomitant Coumarin–NSAID Therapy and Risk for Bleeding

Ellen AJ Knijff-Dutmer, Gelte A Schut, and Martin AFJ van de Laar

Drug Interactions

Author information provided at the end of the text.

Abstract presented as a poster during the Congress of the Ameri-can College of Rheumatology, November 2000, Philadelphia, PA,and abstract published in Arthritis Rheum 2000;43:S132.

OBJECTIVE: To investigate the risk of bleeding complications during the combined use of coumarin derivatives and nonsteroidalantiinflammatory drugs (NSAIDs) compared with the use of coumarin derivatives alone.

SUBJECTS AND METHODS: In this 1-year observational study, the local outpatient anticoagulation office detected all coumarin userswith bleeding complications. These patients were sent questionnaires regarding the type and consequences of the bleeding as wellas previous NSAID use. The local pharmacists detected patients with concomitant coumarin and NSAID prescriptions (but nobleeding). The relative risk for bleeding due to concomitant coumarin and NSAID use was estimated.

RESULTS: During 1 year, 738 hemorrhages were identified in 681 coumarin users. In 12.2% of these cases, an NSAID was involved.In contrast, in the whole population of coumarin users, 2.5% were prescribed an NSAID. Therefore, the relative risk of NSAID usewith regard to bleeding complications was 5.8 (95% CI 2.3 to 13.6).

CONCLUSIONS: NSAID use during coumarin therapy considerably increases the bleeding risk compared with coumarin therapyalone. Although in daily practice these medications are frequently prescribed concomitantly, our results underscore thecontraindication of concomitant use of NSAIDs and coumarin derivatives.

KEY WORDS: bleeding, coumarin derivatives, nonsteroidal antiinflammatory drugs.

Ann Pharmacother 2003;37:12-6.

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normalized ratio [INR]) after addition of NSAIDs; more-over, a case–control study13 in patients with very highINRs failed to show an increased frequency of NSAIDuse. In contrast, in some case reports,14,15 the initiation ofNSAID therapy in coumarin users did result in a higherINR and major hemorrhage. Thus, the actual risk of con-comitant coumarin and NSAID prescription is not clear.

The goal of this study was to investigate the risk ofbleeding complications due to the combination of NSAIDsand coumarin derivatives compared with the bleeding riskof coumarin derivatives alone.

Methods

This observational study (approved by the local Ethics Committee)was performed during 1 year (September 1, 1998, to August 31, 1999).It was comprised of the cohort of coumarin users in the city of Enschede(160 000 inhabitants), a dynamic population of about 4400, treated in theonly outpatient anticoagulation office. In Enschede, a well defined arealargely bordered upon Germany, there are 15 pharmacists supplying allmedication to the coumarin users; in addition, there is only 1 wellequipped hospital that rarely refers patients to other medical centers.Coumarin therapy is started in a total of 1500 patients every year, and isalso stopped in the same number every year. Thus, there are approxi-mately 125 patients initiating and 125 ceasing coumarin therapy everymonth; we assumed this number to be the same every month since a sea-sonal influence in coumarin therapy seems unlikely. Seventy-eight per-cent of patients receive long-term anticoagulation treatment (i.e., >6mo). There are 2 anticoagulation schedules: high-intensity (target INR3.0– 4.0; arterial thromboembolic disease, heart valve disease, after jointreplacement surgery) and low-intensity treatment (target INR 2.5–3.5;venous thromboembolic disease, atrial fibrillation), according to theDutch guidelines.16 All short-term patients and approximately two-thirdsof the long-term patients receive high-intensity treatment.

To obtain complete data regarding the incidence of hemorrhages, allpatients were instructed in a standardized manner to report all bleeding(major or minor) to the outpatient anticoagulation office. The office thenrecorded the age and gender of the patient, the type of coumarin (phen-procoumon or acenocoumarol), the indication for coumarin use, and thelocation of the bleeding. Moreover, from the hospital archive, every ad-mitted patient with coumarin therapy–related bleeding was identified;this was possible with the nationwide diagnosis registration system ap-plied in all Dutch hospitals. Thus, every month, all coumarin users withbleeding complications (both inpatients and outpatients) could be detect-ed. These patients were sent a questionnaire that could be completed bythemselves or by a proxy and then returned free of charge. Items on thequestionnaire focused on medication use (prescription or over-the-counter [OTC], esp. NSAIDs) in the month prior to the bleeding.NSAID use was defined as >1 dose in the previous month. Nonselectiveas well as COX-2–selective NSAIDs (only meloxicam and nabumetonein the Netherlands at that time) were included. Aspirin was recorded sep-arately and was not considered an NSAID in this study. Admitted pa-tients from whom medication data were available from the hospitalrecords and patients who returned the questionnaire were defined as re-sponders; nonresponders were all other patients with bleeding episodes.From the responders, the most recent INR before the hemorrhage wasrecorded. All data were recorded and analyzed anonymously.

In the same year, all 15 pharmacists in Enschede detected the patientswho were concomitantly prescribed both a coumarin derivative and anon-aspirin NSAID every month. Patients were recorded only once ev-ery month. Data concerning age, gender, and type of coumarin were col-lected anonymously. In contrast to the patients with bleeding, data onINR and OTC NSAID use were not available for patients without bleed-ing episodes.

STATISTICAL ANALYSIS

The incidences of coumarin-related bleeding and concomitant cou-marin/NSAID use were determined per month, not per year. The reason

for this was the fluctuation in number of coumarin users per year (but notper month), as described above.

To explore whether the responders were representative for the wholegroup of coumarin users with a bleeding complication, 1-sample t-testsand χ2 tests were performed. Statistical significance was set at p < 0.05.

The relative risk of bleeding was calculated per month for the com-bined use of coumarin and an NSAID versus the use of coumarin alone.For this purpose, data from the nonresponders were included, assumingtheir NSAID use to be equal to that of the responders. The numbers ofpatients without bleeding (with or without NSAID use) were calculatedfrom the above-described values. To control for the possible drawbackof missing OTC NSAID use in the patients without bleeding, a sensitivi-ty analysis was done with an arbitrarily chosen underestimation ofNSAID use of 50% in these patients.

Results

During the 1-year observational study, 738 coumarin-re-lated bleeding complications were recorded in 681 pa-tients. Every month, 38–73 bleedings were detected (mean57 patients; 1.3% of the 4400 coumarin users at risk). Themean age of the patients was 73 years (range 24–96).More men than women were involved. Coumarin therapy(phenprocoumon or acenocoumarol) was prescribed inmore than half of the patients for either atrial fibrillation orperipheral vascular disease (Table 1).

Table 2 shows the locations of all hemorrhages. Morethan 80% were located in the skin, nose, or conjunctiva.Hemorrhages with an incidence of <1% were included inthe "miscellaneous" group: hemarthros; hemoptysis; bleed-ing in muscle, abdominal wall, and genital tract; abdomi-nal malignancy; and aortic aneurysm. Fatal bleeding oc-curred in 5 cases (1.0%): 3 intracerebral hemorrhages, 1aortic aneurysm, and 1 hemorrhage in an abdominal ma-lignancy.

Four hundred fifty-four patients returned questionnaires.In addition, the hospital archive accounted for data on 34bleedings. Thus, 488 patients with bleeding episodes weretermed as "responders" (72%). There were no significantdifferences between the responders and the nonresponderswith respect to gender, type of coumarin, indication forcoumarin use, and location of the bleeding. However, theresponders were younger than the nonresponders (72 vs.76 y; p < 0.05).

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Table 1. Characteristics of Coumarin Users with a Bleeding Complication

Characteristic All Patients (n = 681)

Age, median (range) (y) 73 (24–96)

Gender, male:female (%) 57:43

Phenprocoumon:acenocoumarol (%) 62:38

Indication for coumarin therapy (%)atrial fibrillation 25peripheral vascular disease 26coronary disease 19prosthetic heart valve 10venous thrombosis/pulmonary embolus 10cerebrovascular disease 5joint prosthesis 4miscellaneous 1

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The INR in the patients with bleeding episodes (regis-tered 1 day to a few weeks before the bleeding) was notdifferent from the intended range: in the high-intensitygroup (target INR 3.0– 4.0), median recent INR was 3.5(range 1.3–32.2), and in the low-intensity group (targetINR 2.5–3.5), median recent INR was 3.0 (1.5–34.8).

In 83 (12.2%) of the bleeding complications, non-as-pirin NSAIDs were taken in addition to coumarin therapy.Mostly diclofenac was taken (>50%; in some cases, it wascombined with misoprostol); in addition, ibuprofen, in-domethacin, naproxen (all 10–12%), ketoprofen, piroxi-cam, and tiaprofenic acid (all 1–6%) were used. The typeof bleeding was not different in this group compared withthe non–NSAID -related bleedings; particularly, the fre-quency of gastrointestinal bleeding complications wascomparable in the 2 groups (8.0% and 7.0%, respectively;Table 3). In addition, the most recent INR did not differ be-tween NSAID and non–NSAID-related bleedings (median3.2 [1.5–7.1] vs. 3.3 [1.3–34.8]). Aspirin use was involvedin only 10 of the coumarin users with a bleeding complica-tion (all nonfatal; 1 located in the gastrointestinal tract); 1of these 10 patients was also receiving NSAID therapy.

Concomitant prescriptions of coumarin derivatives andNSAIDs were found 1322 times in 1 year: a mean monthlyincidence of 110, which represents 2.5% of all coumarinusers at risk. Diclofenac was the most prescribed NSAID(>50%; in some cases, it was combined with misoprostol),as in the coumarin users with a bleeding episode; in addi-tion, ibuprofen (almost 25%), nabumetone, indomethacin,naproxen, meloxicam (all 3–5%), piroxicam, ketoprofen,tiaprofenic acid, phenulbutazone, sulindac, flurbiprofen,aceclofenac, and azapropazone (all <2%) were found. Dur-ing coumarin therapy, the relative risk of bleeding permonth due to NSAID use in general was 5.8 (95% CI 2.3to 13.6). In the sensitivity analysis, assuming a theoretical50% underestimation of NSAID use (because of OTC use)in the patients without bleeding, the value 103 rises to 155

and 4240 diminishes to 4188 in Table 1. With these values,the relative risk would still be high at 3.8 (95% CI 1.5 to8.9). In the sensitivity analysis, assuming a theoretical 50%underestimation of NSAID use (because of OTC use) inthe patients without bleeding, the relative risk would stillbe high at 3.8 (95% CI 1.5 to 8.9).

Discussion

The data in this study clearly underscore the risk of bleed-ing complications during combined therapy of coumarinsand NSAIDs. The overall incidence of bleeding per monthwas 1.3%. This cannot easily be extrapolated to a yearlyincidence, since every year approximately 1500 patientsstart coumarin therapy while coumarin therapy is stoppedin a similar number of patients. However, with a rough es-timation, the total population of coumarin users at risk dur-ing 1 year can be calculated to be 4400 + (2 × 1500) =7400; therefore, the yearly incidence of bleedings with thisassumption would be 681 in 7400 patients, or 9.2%. Thisis in accordance with the 9.6% yearly incidence, asdemonstrated earlier9; in addition, the 1.0% incidence offatal bleedings in our study approaches the incidence of0.6% in the same publication.

Most of the hemorrhages can be regarded as minor;most were located in the skin, nose, and conjunctiva. Thegastrointestinal tract was the location of only 7% of allhemorrhages. In contrast, previous studies on NSAID -re-lated bleeding focus mainly on the gastrointestinal tract.Several case–control studies5,6,17,18 in patients with uppergastrointestinal bleeding showed high odds ratios for theuse of NSAIDs, even without including aspirin. Few dataare available on other than gastrointestinal bleedings due toNSAIDs: 1 case–control study7 in patients with hematuriademonstrated a high odds ratio for previous NSAID use,but another case–control study8 on cerebrovascular hemor-rhage did not find an association with NSAID use. In con-

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EAJ Knijff-Dutmer et al.

Table 2. Type and Frequency of Hemorrhages in CoumarinUsers, Responders vs. Nonresponders

Frequency

All Pts. R NR(n = 681) (n = 488) (n = 193)

Type n % % %

Hematoma 240 35 31 46

Epistaxis 197 29 30 26

Conjunctiva 110 16 16 16

Hematuria 49 7 7 7

Gastrointestinal 48 7 8 4

Intracerebral 10 1 2 1

Postoperative 10 1 2 0

Miscellaneousa 17 4 4 0

NR = nonresponders; R = responders.aHemorrhages with a frequency of <1% are included in the "miscel-laneous" group.

Table 3. Type and Frequency of Hemorrhages inResponders, NSAID Users vs. non-NSAID Users

Frequency

Without NSAID With NSAID(n = 405) (n = 83)

Type n % n %

Hematoma 119 29 31 37

Epistaxis 124 31 23 28

Conjunctiva 69 17 10 12

Hematuria 28 7 7 8

Gastrointestinal 34 8 7 8

Intracerebral 8 2 1 1

Postoperative 8 2 2 3

Miscellaneousa 15 4 2 3

Fatal 4 1 1 1

NSAID = nonsteroidal antiinflammatory drug.aHemorrhages with a frequency of <1% are included in the "miscel-laneous" group.

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trast, our study shows that, with NSAID use, the frequencyof bleeding increases at all locations and not only in thegastrointestinal tract. This is in accordance with the ob-served interference with platelet function by NSAIDs.1,2

The NSAID inhibition of the COX enzyme causes lesserproduction of thromboxane and thus decreases platelet ag-gregation. This possibly leads to hemorrhage in a largenumber of organ systems, not only in the digestive tract.

The responders in our study were considerably youngerthan the nonresponders. Although no differences in gender,type of coumarin, and indication for coumarin therapywere found, it is possible that the age difference is respon-sible for some discrepancies in NSAID use. One Dutchstudy19 showed that NSAID use rises with age; 3 other re-ports indicated the NSAID use among the elderly to be10.7% (people >65 y, US),20 8.4% (people >75 y, Italy),21

and 19.6% (people >75 y, Denmark).22 Thus, if there were adifference at all, the NSAID use in the older nonresponderswould presumably rather be higher than lower comparedwith the younger responders. This would then increase therelative risk of bleeding with concomitant coumarin andNSAID use compared with the use of coumarins alone.

Prospective studies on combined aspirin/coumarin usereveal a higher bleeding risk compared with the use of cou-marin alone.23,24 However, there are no previous prospec-tive data on the bleeding risk of combined non-aspirinNSAID/coumarin use. Only 1 retrospective study25 indicat-ed a threefold higher incidence of bleeding gastrointestinalulcers in elderly people with combined NSAID/coumarinuse compared with those with coumarin use alone. Thissupports the data found in our study.

The frequency of concomitant prescriptions of NSAIDsin coumarin users has long been unclear, but in our study itwas shown to be 2.5% every month. One Dutch cross-sec-tional study26 in elderly people (mean age 80 y) indicatedthat 1.4% used an NSAID/coumarin combination. Thus,the frequency of 2.5% concomitant NSAID prescriptionsin coumarin users of all ages (but with a mean age of 72 y),found in our study seems to be in accordance with thesescarce data. In comparison with the overall NSAID use inthe general Dutch population (8.6%),19 the percentage inour study may be viewed as low. However, we considerthis percentage to be high in view of the assumed in-creased bleeding risk. It reflects clinical practice, in whichit is often difficult to withhold either coumarin or NSAIDtherapy from the patient’s regimen.

The design of our study has some drawbacks. A ran-domized controlled trial probably would have answeredour question more adequately, but it was considered uneth-ical to deliberately expose coumarin users to increasedbleeding risks. Therefore, an observational design waschosen, leading to limited data in the nonbleeders. Particu-larly, data on intensity of anticoagulation, dose and dura-tion of both coumarin and NSAID use, and concomitantdisease and/or medication were lacking due to the studydesign. Multivariate analysis incorporating these risk fac-tors would have been able to value the importance ofNSAID use in relation to them. In only the coumarin users

with bleeding was the intensity of anticoagulation treat-ment recorded, which seemed to play a modest role: themedian INR immediately before the bleeding was not sub-stantially different from the target INR. However, giventhe wide range of INRs, some with very high values, theINR may have been an important factor in a subpopula-tion. Of note, the INR was not influenced by the concomi-tant use of NSAIDs, which supports the results of formerprospective studies,10-12 but not the findings of some casereports.14,15

Our method could not detect OTC NSAID use in cou-marin users without bleeding complications. A Finnishstudy27 found that 461 of 10 477 patients (4.4%) used anOTC NSAID 2 days prior to an interview; 0.7% of theOTC NSAID users were also receiving coumarin therapy.Due to the Dutch healthcare system, OTC use of NSAIDsis limited; in addition, the relative risk with a large theoret-ical 50% underestimation of NSAID use in the patientswithout bleeding was still high. Thus, the lack of informa-tion on OTC NSAID use probably did not bias the overallresults.

Summary

This study shows the additional risk of NSAID therapyfor various bleeding complications in coumarin users. Al-though these medications are frequently prescribed con-comitantly in daily practice, our results emphasize the con-traindication of coumarin derivatives and NSAIDs.

Ellen AJ Knijff-Dutmer MD, Rheumatologist, Department ofRheumatology, Medisch Spectrum Twente, Enschede, the Nether-landsGelte A Schut PharmD Pharmacist, Stroinkslanden Pharmacy, En-schedeMartin AFJ van de Laar MD, Rheumatologist, Department ofRheumatology, Medisch Spectrum Twente Reprints: Ellen AJ Knijff-Dutmer MD, Department of Rheumatolo-gy, Medisch Spectrum Twente, PO Box 50,000, 7500 KA Enschede,the Netherlands, FAX 31 53 487 3106, E-mail eajknijff@hotmail.com

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1. Vane JR, Botting RM. New insights into the mode of action of anti-in-flammatory drugs. Inflamm Res 1995;44:1-10.

2. Schafer AI. Effects of nonsteroidal anti-inflammatory therapy onplatelets. Am J Med 1999;106(5B):25S-36S.

3. van Hecken A, Schwartz JI, Depre M, De Lepeire I, Dallob A, TanakaW, et al. Comparative inhibitory activity of rofecoxib, meloxicam, di-clofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthyvolunteers. J Clin Pharmacol 2000;40:1109-20.

4. McAlindon ME, Cook GA, Elliott SL, Hawkey CJ, Yeomans ND. Gas-tric microbleeding following single and repeated dosing with naproxen.Aliment Pharmacol Ther 1995;9:655-9.

5. Bartle WR, Gupta AK, Lazor J. Nonsteroidal anti-inflammatory drugsand gastrointestinal bleeding. A case–control study. Arch Intern Med1986;146:2365-7.

6. Holvoet J, Terriere L, Van Hee W, Verbist L, Fierens E, Hautekeete ML.Relation of upper gastrointestinal bleeding to non-steroidal anti-inflam-matory drugs and aspirin: a case–control study. Gut 1991;32:730-4.

7. Kraus SE, Siroky MB, Babayan RK, Krane RJ. Hematuria and the use ofnonsteroidal anti-inflammatory drugs. J Urol 1984;132:288-90.

8. Thrift AG, McNeil JJ, Forbes A, Donnan GA. Risk of primary intracere-bral haemorrhage associated with aspirin and non-steroidal anti-inflam-matory drugs: case–control study. BMJ 1999;318:759-64.

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9. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epi-demiology, prediction, and prevention. Am J Med 1993;95:315-28.

10. Michot F, Ajdacic K, Glaus L. A double-blind clinical trial to determineif an interaction exists between diclofenac sodium and the oral anticoag-ulant acenocoumarol (Nicoumalone). J Int Med Res 1975;3:153-7.

11. Mieszcak C, Winther K. Lack of interaction of ketoprofen with warfarin.Eur J Clin Pharmacol 1993;44:205-6.

12. Pardo A, Garcia-Losa M, Fernandez-Pavon A, del Castillo S, Pascual-Garcia T, Garcia-Mendez E, et al. A placebo-controlled study of interac-tion between nabumetone and acenocoumarol. Br J Clin Pharmacol1999;47:1-4.

13. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acet-aminophen and other risk factors for excessive warfarin anticoagulation.JAMA 1998;279:657-62.

14. Chan TYK. Prolongation of prothrombin time with the use of in-domethacin and warfarin. Br J Clin Pract 1997;51:177-8.

15. Dennis VC, Thomas BK, Hanlon JE. Potentiation of oral anticoagulationand hemarthrosis associated with nabumetone. Pharmacotherapy 2000;20:234-9.

16. Trombotest. In: Van Leusden HAIM, ed. Diagnostisch Kompas. Uitg,the Netherlands: College voor Zorgverzekeringen, 1999:631-2.

17. Carson JL, Strom BL, Soper KA, West SL, Morse L. The association ofnonsteroidal anti-inflammatory drugs with upper gastrointestinal tractbleeding. Arch Intern Med 1987;147:85-8.

18. Kaufman DW, Kelly JP, Sheehan JE, Laszlo A, Wiholm BE, AlfredssonL, et al. Nonsteroidal anti-inflammatory drug use in relation to major up-per gastrointestinal bleeding. Clin Pharmacol Ther 1993;53:485-94.

19. Leufkens HG, Ameling CB, Hekster YA, Bakker A. Utilization patternsof nonsteroidal anti-inflammatory drugs in an open Dutch population.Pharm Weekbl Sci 1990;12:97-103.

20. Chrischilles EA, Lemke JH, Wallace RB, Drube GA. Prevalence andcharacteristics of multiple drug use in an elderly study group. J Am Geri-atr Soc 1990;38:979-84.

21. Nobili A, Tettamanti M, Frattura L, Spagnoli A, Ferraro L, Marrazzo E,et al. Drug use by the elderly in Italy. Ann Pharmacother 1997;31:416-22.

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23. Chesebro JH, Fuster V, Elveback LR, McGoon DC, Pluth JR, Puga FJ, etal. Trial of combined warfarin plus dipyridamole or aspirin therapy inprosthetic heart valve replacement: danger of aspirin compared withdipyridamole. Am J Cardiol 1983;51:1537-41.

24. Hurlen M, Erikssen J, Smith P, Arnesen H, Rollag A. Comparison ofbleeding complications of warfarin and warfarin plus acetylsalicylicacid: a study in 3166 outpatients. J Int Med 1994;236:299-304.

25. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Concurrent use of nons-teroidal anti-inflammatory drugs and oral anticoagulants places elderlypersons at high risk for hemorrhagic peptic ulcer disease. Arch InternMed 1993;153:1665-70.

26. Gill K, Hermans J, Vermeij P. Multiple drug use by the elderly in need ofcare and nursing and possibility of reducing this practice. Ned TijdschrGeneeskd. 1996;140:1076-80. Dutch.

27. Sihvo S, Klaukka T, Martikainen J, Hemminki E. Frequency of dailyover-the-counter drug use and potential clinically significant over-the-counter-prescription drug interactions in the Finnish adult population.Eur J Clin Pharmacol 2000;56:495-9.

EXTRACTO

PROPÓSITO: Investigar el riesgo de complicaciones de sangrado duranteel uso combinado de los derivados de coumarin y los antiinflamatoriosno esteroidales (AINE), comparado al uso de los derivados de coumarinsolos.

SUJETOS Y MÉTODOS: En este estudio de un año de duración, los pacientesambulatorios de una oficina de anticoagulación fueron observados paracomplicaciones de sangrado. A estos pacientes se les envió cuestionariossobre el tipo y la consecuencia del sangrado y el uso previo de AINE.Los farmacéuticos del área identificaron aquellos pacientes que usabanderivados de coumarin y AINE concomitantemente sin problemas desangrado. Se estimó con estos datos el riesgo relativo de sangrado por eluso combinado de derivados de coumarin y AINE.

RESULTADOS: Durante el período de un año, se identificaron 738hemorragias en 681 usuarios de coumarin. Se detectó el uso combinadode AINE en 12.2% de estos casos. En contraste, entre la totalidad de lapoblación de usuarios de coumarin, el 2.5% recibió prescripción por unAINE. Por lo tanto, el riesgo relativo del uso de AINE con relación a lascomplicaciones de sangrado fue de 5.8% (intervalo de confianza 95%2.3–13.6).

CONCLUSIONES: El uso de AINE durante la terapia con derivados decoumarin aumenta considerablemente el riesgo de sangrado. Aunque enla práctica ambos fármacos se combinan frecuentemente, nuestroshallazgos apoyan la contraindicación al uso concomitante de ambos.

Mitchell Nazario

RÉSUMÉ

OBJECTIF: Comparer le risque de complications hémorragiques survenantlors de l’association thérapeutique de dérivés coumariniques et d’anti-inflammatoires non-stéroidiens (AINS) par rapport au risque de cescomplications lorsque qu’une monothérapie aux dérivés coumariniquesest utilisée.

SUJETS ET MÉTHODES: Dans le cadre d’une étude descriptive d’une duréed’un an effectuée chez la clientèle d’une clinique d’anticoagulothérapie,les chercheurs ont colligé tous les cas de complications hémorragiquessurvenus chez les utilisateurs de dérivés coumariniques. Ces patients ontreçu un questionnaire ayant pour objet de préciser le type decomplication et les conséquences du saignement ainsi que touteutilisation d’AINS. Le pharmacien de pratique privée dépistait lespatients recevant des ordonnances précisant l’utilisation concomitante dedérivés coumariniques et d’AINS (mais sans évidence de saignement).Le risque relatif de saignement imputable à cette association a étéestimé.

RESULTATS: Sur cette période d’un an, 783 hémorragies ont été identifiéeschez 681 personnes anticoagulées. Les AINS étaient impliqués dans12.2% de ces cas. Cependant, au sein de toute la population recevant desdérivés coumariniques, seulement 2.5% recevaient des AINS. Parconséquent, le risque relatif de complication hémorragique relié àl’utilisation additionnelle d’AINS est de 5.8 (IC 95%: 2.3–13.6).

CONCLUSIONS: L’utilisation d’AINS durant l’anticoagulation avec desdérivés coumariniques augmente considérablement le risque desaignement. Bien qu’en pratique ces médicaments soient souventprescrits concomitamment, ces résultats soulignent la contre-indication àl’utilisation combinée de coumariniques et d’AINS.

Marc Parent

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