EDITORIAL

Joint injections in patients on antiplateletor anticoagulant therapy: risk minimization

Valérie Lemaire1, Bernard Charbonnier2, Yves Gruel3, Philippe Goupille1*,Jean Pierre Valat11Department of rheumatology, CHU Trousseau, 37044 Tours cedex, France; 2Cardiology department, CHUTrousseau, 37044 Tours cedex, France; 3Hematology department, CHU Trousseau, 37044 Tours cedex, France

(Submitted for publication January 26, 2001; accepted in revised form July 25, 2001)

Aspiration and injection of joints and surroundingtissues is an everyday procedure for the practicing rheu-matologist. The risk of bleeding should be evaluated inpatients on antiplatelet and/or anticoagulant therapy,particularly if the procedure is to be repeated within afew days. Means of decreasing the bleeding risk shouldbe sought. Careful consideration should be given toalternative medications. Although data on bleeding riskminimization are scant in the rheumatological litera-ture, studies of spinal anesthesia have provided infor-mation that can be extrapolated to rheumatologypatients. We suggest a practical and prudent strategydeveloped on the basis of this information.

THE BLEEDING RISK

Antiplatelet agents

Antiplatelet agents are known to increase the risk ofintra- and postoperative bleeding. Few data are avail-able on the magnitude of this increase, however. In astudy of coronary artery bypass grafting, aspirin initia-tion before the procedure increased the risk of bleedingwithout decreasing the risk of thrombosis as comparedto aspirin initiation 6 hours after the procedure [1].With aspirin, ticlopidine, and clopidogrel, the bleeding

risk is independent from the dosage because these medi-cations irreversibly inhibit platelet aggregation, eitherby blocking the enzyme cyclooxygenase (aspirin) or bypreventing adenosine diphosphate from binding to itsplatelet receptors (thienopyridines). This effect persiststhroughout the lifespan of the platelet (7 to 10 days).With nonsteroidal anti-inflammatory drugs (NSAIDs),in contrast, reversible cyclooxygenase inhibition occurs,causing a dose-dependent increase in the bleeding risk.The duration of cyclooxygenase inhibition varies withthe time to clearance of the drug from the plasma [2, 3].

Epidural or spinal hematoma is exceedingly rare.However, the rate of occurrence among patients onantiplatelet therapy is unknown. Neither is any infor-mation available on the magnitude of the risk as com-pared with patients who are not on antiplatelet therapy.In a review of the literature published from 1906 to1994, Vandermeulen found only three cases ascribableto antiplatelet therapy [4]. One patient was on aspirin,one on ticlopidine, and one on indomethacin [5-7]. Afourth case, in a patient on ketorolac, was published in1997 [8]. No bleeding events were noted in a study of1500 pregnant women who received epidural anesthe-sia while under aspirin therapy [9] or in a study of 386patients who had epidural anesthesia while under anti-platelet therapy [10]. In patients at risk for bleeding,anesthesiologists prefer spinal anesthesia because intra-dural bleeding does not cause spinal cord compression.Furthermore, the needle diameter is smaller than forepidural anesthesia. However, the needle is removed* Correspondence and reprints.

Joint Bone Spine 2002 ; 69 : 8-11© 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved

S1297319X01003372/EDI

after injection of the anesthetic, so that repeat injec-tions cannot be performed [1].

Low-molecular-weight heparins (LMWHs)

A few cases of severe or fatal bleeding have been reportedin patients receiving appropriate dosages of LMWH.These patients had combinations of major risk factors,including obesity, chronic renal failure, congestive heartfailure, and malignant disease [11]. The risk of spinaland epidural hematoma seems far higher with LMWHthan with antiplatelet agents [1, 12]. Forty-three caseshave been reported in patients who were started onenoxaparin 30 mg bid before or immediately after sur-gery. Sixteen of these patients were taking a vitamin Kantagonist or an NSAID concomitantly. These casesprompted American anesthesiologists to issue a set ofrecommendations including postponement of antico-agulant therapy until 12 to 24 hours after the end ofsurgery [12, 13]. Samama and Lecompte have advo-cated discontinuation of prophylactic-dose LMWHtherapy 12 hours before any form of local or regionalanesthesia [3].

Oral vitamin K antagonists

To keep the risk of intra- and postoperative bleedingwithin reasonable limits, the INR should be within the1.5–2 range before the procedure [14].

BLEEDING RISK MINIMIZATION

The bleeding time is not a reliable predictor of thebleeding risk in patients on antiplatelet therapy: theincrease in bleeding time associated with aspirin therapyis not correlated with the risk of intra- and postopera-tive bleeding [15]. Ideally, drugs given to preventthrombosis should be discontinued if possible.Examples of situations in which these drugs can bestopped include prophylactic aspirin therapy in a patientwith no history of acute atherothrombotic events,chronic oral vitamin K antagonist therapy after a singlethrombotic event, and prophylactic LMWH therapy ina patient whose only risk factor for thrombosis is immo-bility. Joint aspiration and/or injection are rarely neededon an emergency basis. The safest approach is often towait 7 to 10 days, i.e., until complete disappearance ofthe effects of antiplatelet or antivitamin K antagonisttherapy. With antivitamin K antagonists, the INRshould be checked before the procedure.

WHAT TO DO IN RHEUMATOLOGICAL PRACTICE

Joints

Antiplatelet agentsThere are no recommendations for special precautionsin patients receiving a joint injection [16]. The risk ofhematoma at the injection site is unknown. The adverseconsequences of injection site hematomas are minor.

LMWHMejjad and Favre have suggested that 10 to 14 hoursshould be allowed to elapse between the last LMWHinjection and joint aspiration and/or injection [16].Our experience suggests that the procedure should bedone immediately before the next LMWH injection,i.e., during the activity trough. LMWH reaches itsactivity peak 3 hours after the injection and has ahalf-life of 3–4 hours.

Oral vitamin K antagonistsUntil now, standard practice involved replacing theoral vitamin K antagonist by an LMWH and perform-ing the joint injection when the prothrombin time wasat least 65%, after omitting the morning dose ofLMWH [16]. However, this approach is open to criti-cism. In a study of 32 joint or soft tissue injections in 25patients on vitamin K antagonist therapy with an INRvalue lower than 4.5, Thumboo and O’Duffy did notrecord any bleeding events [17]. Although the numberof patients is small, this study is valuable for medicole-gal reference and invites an evaluation of the risk ofhemarthrosis as compared to the risk of thrombosisassociated with changes in anticoagulant therapy. Fur-thermore, curative LMWH therapy requires only oneinjection per day. Consequently, there is no need toomit an injection. The safety of omitting an LMWHinjection has not been established. These new therapeu-tic strategies are not associated with an increased risk ofspontaneous bleeding [18]. In patients who are receiv-ing twice-daily LMWH therapy, switching to a once-a-day regimen and performing the joint procedure justbefore the next LMWH injection is the safest approach.

Spine

In a review of the literature published between 1966and 1995, Wulf [19] found 51 cases of spinal hematomaoccurring in the wake of epidural anesthesia. Risk fac-tors included difficult or traumatic catheter insertion in21 cases, heparin therapy in 18, a coagulopathy in 14,ankylosing spondylitis in five, thrombocytopenia in

Antiplatelets, anticoagulants and joint injections 9

five, aspirin or NSAID therapy in three and LMWHtherapy in two. The overall risk was estimated at about1/190,000 epidural anesthesias [19]. The outcome ofspinal hematoma is favorable in only 50% of cases evenwhen decompressive surgery is performed within 12hours after onset of the clinical symptoms [20].

Antiplatelet agentsBecause repeating an epidural injection after 48 hours isassociated with a higher risk of hematoma, we believethat antiplatelet agent discontinuation 7 to 10 daysbefore the hospital admission is appropriate, even invery low-risk patients. The risk and procedure are iden-tical for periradicular injections. We do not recom-mend antiplatelet therapy discontinuation before facetjoint injections because development of a hematoma isextremely rare at this site and carries little risk of adverseeffects.

LMWHBed rest alone does not warrant prophylactic LMWHtherapy in nonsurgical patients. When LMWH therapyis required, it is unwise to add an NSAID that has a longhalf-life. The epidural injection should be performedimmediately before the LMWH injection.

Vitamin K antagonistsAll spinal injections are contraindicated.

SUBSTITUTING MEDICATIONS

Antiplatelet therapy should not be stopped in a patientwith a history within the last 3 to 5 months of ischemicstroke, myocardial infarction, or angina. In patientswith atrial fibrillation or peripheral arterial disease, thepotential adverse effects of treatment discontinuationfor 2 weeks are unknown. The wisest course is toreplace the antiplatelet agent by the NSAID flurbipro-fen (Cebutidt). This drug has been shown to exertpotent antiplatelet activity in patients with cardiovas-cular disease. An important advantage of flurbiprofen isthat its effects are reversible within a few hours becauseit inhibits platelet cyclooxygenase without causing irre-versible acetylation of the enzyme (the mechanismunderlying the effects of aspirin). The dosage is 100 mg(two 50-mg tablets) once daily. The effect disappearscompletely within 24 hours, and consequently the jointor spinal injection can be performed immediately beforethe next dose [21, 22].

In patients with a mechanical heart valve prosthesis ora history of thrombosis within the last month, wereplace the vitamin K antagonist by curative-dose

LMWH. It has been shown that LMWH is equivalentto heparin immediately after valve replacement surgery,provided the anti-Xa activity is kept between 0.5 and1 antiXaU/mL, for 2 weeks [23]. In patients with amechanical valve prosthesis, LMWH has been usedduring pregnancy [24] and when severe bleedingrequired discontinuation of vitamin K antagonisttherapy [25]. It should be borne in mind, however, thatLMWH has not been approved in this indication andthat the treatment of patients with mechanical valveprostheses continues to raise significant challenges.

In patients receiving vitamin K antagonist therapy forother conditions, we use prophylactic-dose LMWH[26]. The MEDENOX study indicates that a singledaily subcutaneous injection of 40 mg enoxaparin issatisfactory [27]. The joint or spinal injection should beperformed in the morning.

CONCLUSION

Joint aspiration and joint injection are simple and safe:bleeding is uncommon and does not cause serioussymptoms. In contrast, epidural injections in patientson vitamin K antagonist or antiplatelet therapy cancause bleeding events responsible for devastating impair-ments, although this is exceedingly rare. Rheumatolo-gists, cardiologists, and hematologists should worktogether to develop a consensus on the best practicalmanagement of these common situations.

REFERENCES

1 Goldman S, Copeland J, Moritz T, Henderson W, Zadina K,Ovitt KB, et al. Starting aspirin therapy after operation. Effectson early graft patency. Circulation 1991 ; 2 : 520-6.

2 Patrono C, Coller B, Dalen JE, Fuster V, Gent M, Marker LA,et al. Platelet-active drugs: the relationships among dose, effec-tiveness and side effects. Chest 1998 ; 114 (Suppl) : 470-88.

3 Samama M, Lecompte T. Est-il possible de réaliser uneanesthésie locorégionale rachidienne chez un patient traité avecun ou plusieurs antithrombotiques? STV 1999 ; 9 : 661-70.

4 Vandermeulen EP, Van Haken H, Vermylen J. Anticoagulantsand spinal subarachnoid anesthesia. Anesth Analg 1994 ; 79 :1165-77.

5 Mayumi T, Dohi S. Spinal subarachnoid hematoma after lum-bar puncture in a patient receiving antiplatelet therapy. AnesthAnalg 1983 ; 62 : 777-9.

6 Greensite F, Katz J. Spinal subdural hematoma associated withattempted epidural anesthesia and subsequent spinal anesthesia.Anesth Analg 1980 ; 59 : 72-3.

7 Williams KN, Jackowski A, Evans PJ. Epidural hematomarequiring surgical decompression following repeated cervicalepidural steroid injections for chronic pain. Pain 1990 ; 42 :197-9.

8 Gerancher JC, Waterer R, Middleton J. Transient paraparesisafter postdural puncture spinal hematoma in a patient receivingketorolac. Anesthesiology 1997 ; 86 : 490-4.

10 V. Lemaire et al.

9 Clasp: a randomised trial of low dose aspirin for the preventionand treatment of pre-eclampsia among 9364 pregnant women.CLASP (Collaborative Low-dose Aspirin Study in Pregnancy)Collaborative group. Lancet 1994 ; 343 : 619-29.

10 Horlocker TT, Wedel DJ, Schroeder DR, Rose SH, Elliot BA,Mc Gregor DG, et al. Preoperative antiplatelet therapy does notincrease the risk of spinal hematoma associated with regionalanesthesia. Anesth Analg 1995 ; 80 : 303-9.

11 Grateau G, Chauvenet L, Oudard S, Bachmeyer C, Capron L,Horellou MH, et al. Complications hémorragiques sévères soushéparine de bas poids moléculaire. À propos de 2 cas. Rev MedInterne 1997 ; 5 : 411-5.

12 Wysowski DK, Talarico L, Bacsanyi J, Botstein P. Spinal andepidural hematoma and low molecular heparin. N Engl J Med1998 ; 338 : 1174.

13 Horlocker TT, Wedel DJ. Spinal and epidural blockade andperioperative low molecular weight heparin: smooth sailing onthe Titanic. Anesth Analg 1998 ; 86 : 1153-6.

14 Derlon A, Fiessinger JN. Utilisation des antivitamines K enpratique médicale. courante. STV 1993 ; 8 : 15-21.

15 Lind SE. The bleeding time does not predict surgical bleeding.Blood 1991 ; 12 : 2547-52.

16 Mejjad O, Favre S. Anticoagulants et antiagrégantsplaquettaires : l’infiltration est-elle possible, et comment? LettRhumatol 1997 ; 237 : 12-3.

17 Thumboo J, O’Duffy JD. A prospective study of the safety ofjoint and soft tissue aspirations and injections in patients takingwarfarin sodium. Arthritis Rheum 1998 ; 41 : 736-9.

18 Charbonnier B, Fiessinger JN, Banga JD, Wenzel E,D’Azemar P, Sagnard L. Comparison of a once daily with atwice daily subcutaneous weight heparin regimen in the treat-ment of deep vein thrombosis. Thromb Haemost 1998 ; 79 :897-901.

19 Wulf H. Epidural anesthesia and spinal haematoma. Can JAnesth 1996 ; 43 : 1260-71.

20 Modig J. Spinal or epidural anesthesia with low molecularweight heparin for thromboprophylaxis requires careful postop-erative neurological observation. Acta Anaesth Scand 1992 ;36 : 603-4.

21 Pincus KT, Spruill J, Parish RC. Effect of flurbiprofen andaspirin on platelet aggregation. Clin Pharmacol The 1991 ; 10 :935-8.

22 Brochier ML, for the Flurbiprofen French Trial. Evaluation offlurbiprofen for prevention of reinfarction and reocclusion aftersuccessful thrombolysis or angioplasty in acute myocardial inf-arction. Eur Heart J 1993 ; 14 : 951-7.

23 Montalescot G, Polle V, Collet JP, Leprince P, Bellanger A,Gandjbakhch I, et al. Low molecular weight heparin aftermechanical heart valve replacement. Circulation 2000 ; 14 :1083-6.

24 Arnaout MS, Kazma H, Khalil A, Shasha N, Nasrallah A,Karam K, et al. Is there a safe anticoagulation protocol forpregnant women with prosthetic valves? Clin Exp ObstetGynecol 1998 ; 25 : 101-4.

25 Harenberg J, Schwarz F, Dietz R, Leber G, Zimmermann R,Kubler W. Anticoagulation with low molecular-weight heparinin patients with prosthetic heart valve replacements. Z Kardiol1987 ; 76 : 284-8.

26 Ansell J, Hirsh J, Dalen JE, Bussey H, Anderson DR, Poller L,et al. Managing oral anticoagulant therapy. Sixth ACCP Con-sensus Conference on Antithrombotic Therapy. Chest 2001 ;119 (Suppl) : 22-38.

27 Samama M, Cohen AT, Darmon JY, Desjardins L, Eldor A,Janbon C, et al. A comparison of enoxaparin with placebo forthe prevention of venous thromboembolism in acutely ill medi-cal patients. N Engl J Med. 1999 ; 331 : 793-800.

Antiplatelets, anticoagulants and joint injections 11