Potentiation of Vitamin K
Pulse high-dose intravenous methylprednisolone Antagonists by High-Dose
is widely used for the treatment of flares in Intravenous Methylprednisolone
inflammatory and autoimmune diseases (1). Most of these diseases carry a risk for venous and arterial occlusion (2–4). In addition, patients may have in- dividual indications for oral anticoagulation that are independent of inflammatory disease, such as atrial fibrillation and mechanical prosthetic heart valves.
Bertrand Diquet, MD; Annick Ankri, MD; and Therefore, oral anticoagulants and methylprednis- olone are often administered concomitantly in clin- Background: Oral anticoagulants and pulse high-dose
In early studies, oral anticoagulants had both en- intravenous methylprednisolone are often administeredconcomitantly, but no data on potential interactions are hanced (5) and diminished effects (6, 7) when given concurrently with oral corticosteroids. Corticosteroids are not thought to potentiate oral anticoagulants (8).
Objective: To assess possible potentiation of oral anti-
In a patient receiving oral anticoagulation, we coagulation by high-dose intravenous methylpred-nisolone.
observed a sharp increase in the international nor- malized ratio (INR) after concomitant administra- Design: Prospective cohort study.
tion of methylprednisolone. This observation, and Setting: University hospital in Paris, France.
the lack of relevant published data, prompted us to Patients: 10 consecutive patients concomitantly receiv-
conduct a prospective study of the potential inter- ing methylprednisolone and oral anticoagulants (fluindi- action of methylprednisolone with oral anticoagulants.
one and acenocoumarol) and 5 consecutive controls re-ceiving methylprednisolone alone.
tional normalized ratio (INR) and clotting factors duringadministration of pulse methylprednisolone. The total Patients
plasma fluindione concentration was determined in 3 pa- We studied 10 consecutive patients who were referred to the internal medicine department of Results: The mean INR was 2.75 (range, 2.02 to 3.81) at
Pitie´-Salpeˆtrie`re Hospital in Paris, France. The 4 baseline and increased to 8.04 (range, 5.32 to 20.0) after women and 6 men (mean age, 51 years [range, 20 to methylprednisolone administration. Plasma fluindione 79 years]) were taking oral anticoagulants and re- concentrations and the INR increased after methylpred- ceived methylprednisolone for giant-cell arteritis nisolone administration. Methylprednisolone alone did (n ϭ 2), autoimmune thrombocytopenic purpura (n ϭ 2), vasculitis (n ϭ 3), multiple myeloma (n ϭ Conclusions: The action of oral anticoagulants is poten-
1), lupus flare (n ϭ 1), or mediastinal fibrosis (n ϭ tiated by intravenous high-dose methylprednisolone. The 1). Methylprednisolone was given in the form of 1 g INR should be monitored daily during concomitant admin- or 500 mg of hemisuccinate methylprednisolone (Solu-Medrol, Pharmacia & Upjohn, Saint-Quentin en Yvelines, France) reconstituted in 5% dextrose in water (total volume, 250 mL) and was infused intravenously over 1 hour. All 10 patients were tak- ing vitamin K antagonists (fluindione [n ϭ 8] and acenocoumarol [n ϭ 2]) for atrial fibrillation (n ϭ 3), the antiphospholipid syndrome (n ϭ 3), thromboem- bolic events (n ϭ 2), distal limb ischemia (n ϭ 1), or the superior vena cava syndrome (n ϭ 1). Daily Ann Intern Med. 2000;132:631-635.
doses were 4 mg of acenocoumarol (n ϭ 2) and 5 For author affiliations, current addresses, and contributions, see mg (n ϭ 1), 10 mg (n ϭ 2), 20 mg (n ϭ 3), 25 mg (n ϭ 1), or 40 mg (n ϭ 1) of fluindione; these doses 18 April 2000 • Annals of Internal Medicine • Volume 132 • Number 8 had not been increased in the 10 days before ad- 20.0) after methylprednisolone administration (Fig-
ministration of the first methylprednisolone pulse.
ure 1). The maximum increase in the INR occurred
Except for the first patient, informed consent was after a mean of 92.7 hours (range, 29 to 156 hours).
obtained in each case before study enrollment.
Because the INR reached life-threatening levels in The control group consisted of five consecutive five patients (patients 1, 2, 4, 6, and 8), we admin- patients (mean age, 50 years [range, 21 to 80 years]) istered vitamin K, which decreased the INR in 4 to who were receiving methylprednisolone for giant- 12 hours (Figure 1). In four other patients (patients
cell arteritis (n ϭ 2), lupus flare (n ϭ 1), idiopathic 3, 5, 7, and 9), oral anticoagulation was discontin- retroperitoneal fibrosis (n ϭ 1), or Crohn disease ued and the INR returned to baseline in 36 to 48 (n ϭ 1). Controls did not receive oral anticoagulants hours (Figure 1).
before or during methylprednisolone administration.
Levels of protein C; free protein S; and vitamin All of the cases were reported to the Paris-Pitie´- K–dependent factors II, VII, IX, and X decreased Salpeˆtrie`re regional pharmacovigilance center.
as the INR increased. However, levels of factor V remained normal in every case (data not shown).
Concomitant Medications
Concomitant medications were screened for International Normalized Ratio after
drugs known to potentiate oral anticoagulants (8, 9).
Methylprednisolone Alone
Two patients were receiving concomitant amioda- To determine whether INR elevation was caused rone therapy, but the doses had not been modified by the action of methylprednisolone on clotting fac- during the 6 months before the study began and tors, we assessed the prothrombin time in five con- were not modified during the study. Three patients secutive controls who received methylprednisolone were receiving acetaminophen, but the weekly dose (1 g/d for 3 days) without concomitant oral antico- was less than 4550 mg (the minimum dose that has agulation. The prothrombin time was checked every been found to increase the INR) during the week day and remained stable for 7 days after the first dose of methylprednisolone was administered (Fig-
Elevation of the International Normalized Ratio
Clotting Tests
after Concomitant Administration of
The prothrombin time, interpreted as the INR, Methylprednisolone and Oral Anticoagulation
was measured by using the Simplastin Excel S re- agent with an international sensitivity index of 1.31 To rule out in vitro interference between methyl- (Organon Teknika Corp., Durham, North Carolina).
prednisolone and INR reagents, we collected Factors II, VII, IX, and X were routinely measured plasma from nine patients who were being treated by using an STA IX analyzer (Diagnostica Stago, with fluindione and added methylprednisolone at Asnie`res-sur-Seine, France), as described elsewhere concentrations of 0 mg/L, 5 mg/L, and 20 mg/L (11). Levels of protein C and free protein S were (based on the peak concentration of methylpred- assayed by using an amidolytic method (Berichrom nisolone in vivo in patients treated with methylpred- Protein C, Dade Behring, Liederbach, Germany) nisolone [13]). The resulting INRs were not influ- and a procoagulant method (Protein S Reagent, enced by the baseline INR or by the dose of Dade Behring), respectively, on a Behring Coagula- methylprednisolone added (data not shown).
tion Timer (Dade Behring). Total (free and protein- Total plasma fluindione concentrations were se- bound) fluindione levels were assayed by using high- rially assayed in three patients (patients 6, 8, and performance liquid chromatography, as described 10). Fluindione concentrations and the INR always increased after methylprednisolone administration (Figure 1).
To determine whether methylprednisolone po- International Normalized Ratio after
tentiated oral anticoagulation, we studied variations Administration of High-Dose Intravenous
of the INR in 10 consecutive patients who were Methylprednisolone
taking oral anticoagulants and received methylpred- For all patients, the target INR was 2.0 to 4.0.
nisolone concomitantly. The INR increased sharply, The INR was checked during the 12 hours before exceeding 6.0 in almost all patients. In contrast, methylprednisolone infusion. At baseline, the mean methylprednisolone alone did not interfere with INR was 2.75 (range, 2.02 to 3.81). In all patients, clotting factors (prothrombin time). These results the INR increased to a mean of 8.04 (range, 5.32 to suggest that INR elevation was due to potentiation 18 April 2000 • Annals of Internal Medicine • Volume 132 • Number 8 Figure 1.
Potentiation of vitamin K antagonists by intravenous high-dose methylprednisolone in patients 1 through 10. Arrows indicate
administration of pulse intravenous high-dose methylprednisolone; bars indicate total fluindione concentration; solid lines indicate the international normalizedratio (INR).
of oral anticoagulation by methylprednisolone. Al- Although our study included a small number of though no bleeding complications occurred in this patients, it is unlikely that the INR increased be- small series, the INR elevation was severe enough cause of spontaneous fluctuations in each patient’s to warrant vitamin K supplementation or withdrawal response to oral anticoagulants. The INR reached 6 of the vitamin K antagonist, and we were therefore in almost all of our consecutive patients; however, unable to observe the maximum potential increase in a recent study of 29 000 INRs observed during a 6-month period (15), only 85 exceeded 6.0. Further- Our data are in keeping with those of Kaufman more, our patients did not have any of the condi- (14), who described two patients with multiple scle- tions reported to increase the INR, such as alcohol- rosis who were receiving warfarin: one for a pros- ism, liver disease, frequent modification of oral thetic valve and one for pulmonary embolism. In anticoagulant dose, and recent withdrawal or initia- these patients, the INR reached 10.0 and 12.0, re- tion of medications known to interact with oral spectively, after methylprednisolone administration.
anticoagulants. In a study of 55 625 INRs in which Of note, two patients in our study received aceno- 131 patients had INRs that exceeded 8.0, one of two coumarol, a coumarin congener that chemically dif- hemorrhage-related deaths involved a patient taking fers from warfarin only by its nitro group at the warfarin who was receiving high-dose steroids for 18 April 2000 • Annals of Internal Medicine • Volume 132 • Number 8 Figure 2.
Lack of effect of intravenous high-dose methylprednisolone alone on prothrombin time in five controls. Arrows indicate adminis-
tration of pulse intravenous high-dose methylprednisolone.
Although the precise mechanism of the interac- possible that high-dose methylprednisolone potenti- tion between methylprednisolone and oral antico- ates vitamin K antagonists by inhibiting their cyto- agulants is unclear, several lines of evidence strongly suggest that it is due to inhibition of oral anticoag- Our series and the two cases reported by Kauf- ulant catabolism by high-dose methylprednisolone.
man (14) reflect the diverse conditions that can lead First, the increase in the INR observed after methyl- to concomitant administration of oral anticoagulants prednisolone administration occurred through a vi- and methylprednisolone in clinical practice. Some tamin K–dependent pathway. The INR increased examples are cancer, transplantation, multiple scle- regardless of the anticoagulant used (acenocoumarol, rosis, and various rheumatic diseases. Physicians warfarin, or fluindione, a noncoumarin indanedione must be aware that intravenous high-dose methyl- anticoagulant that is common in Europe). In addi- prednisolone can cause life-threatening potentiation tion, this increase was rapidly reversed by adminis- of oral anticoagulation and that the INR must be tration of vitamin K (14). Second, because oral an- ticoagulants are almost completely absorbed from monitored daily during combined administration.
the gastrointestinal tract (9), it is unlikely that ele- The risk may be severe enough to warrant reducing vated fluindione concentrations were due to in- the oral anticoagulant dose before administering creased absorption. Third, because we measured total fluindione, it is unlikely that the elevated con- centrations resulted from a change in the ratio be- From Groupe Hospitalier Universitaire Pitie´-Salpeˆtrie`re, Paris, tween free and protein-bound fluindione. Fourth, methylprednisolone inhibits the cytochrome P450 Requests for Single Reprints: Zahir Amoura, Service de Me´decine enzyme system (17), which is involved in the me- Interne, Hoˆpital Pitie´-Salpeˆtrie`re, 47-83 boulevard de l’Hoˆpital, tabolism of oral anticoagulants (18). It is therefore 75013 Paris, France; e-mail, [email protected].
18 April 2000 • Annals of Internal Medicine • Volume 132 • Number 8 Requests To Purchase Bulk Reprints (minimum, 100 copies): Bar- 3. Goodman BW. Temporal arteritis. Am J Med. 1979;67:839-52.
bara Hudson, Reprints Coordinator; phone, 215-351-2657; e-mail, 4. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR.
The management of thrombosis in the antiphospholipid-antibody syndrome.
N Engl J Med. 1995;332:993-7.
5. Brozovic M, Gurd LJ. Prothrombin during warfarin treatment. Br J Haema-
Current Author Addresses: Drs. Costedoat-Chalumeau, Amoura, Wechsler, Cacoub, Huong Du, and Piette: Service de Me´decine 6. Cosgriff SW, Diefenbach AF, Vogt W Jr. Hypercoagulability of blood
Interne, Groupe Hospitalier Universitaire Pitie´-Salpeˆtrie`re, 47-83 associated with ACTH and cortisone therapy. Am J Med. 1950;9:752-6.
boulevard de l’Hoˆpital, 75013 Paris, France.
7. Chatterjea JB, Salomon L. Antagonistic effect of ACTH and cortisone on the
Drs. Aymard and Diquet: Service de Pharmacologie, Groupe anticoagulant activity of ethyl biscoumacetate. Br Med J. 1954;2:790-2.
Hospitalier Universitaire Pitie´-Salpeˆtrie`re, 47-83 boulevard de 8. Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral
anticoagulants: mechanism of action, clinical effectiveness, and optimal ther- apeutic range. Chest. 1998;114:445S-69S.
Drs. Sevin and Ankri: Laboratoire d’He´mostase, Groupe Hospi- 9. Physician’s Desk Reference. http://www.pdr.net. Accessed 1999.
talier Universitaire Pitie´-Salpeˆtrie`re, 47-83 boulevard de l’Hoˆpital, 10. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetamino-
phen and other risk factors for excessive warfarin anticoagulation. JAMA.
Author Contributions: Conception and design: N. Costedoat-Chal- 11. Mentre F, Pousset F, Comets E, Plaud B, Diquet B, Montalescot G, et
al. Population pharmacokinetic-pharmacodynamic analysis of fluindione in
umeau, Z. Amoura, G. Aymard, A. Ankri, J.C. Piette.
patients. Clin Pharmacol Ther. 1998;63:64-78.
Analysis and interpretation of the data: N. Costedoat-Chal- 12. Aymard G, Legrand M, Comets E, Mentre F, Diquet B. Rapid and simple
umeau, Z. Amoura, G. Aymard, J.C. Piette.
micromethod for the quantification of fluindione in human plasma using Drafting of the article: N. Costedoat-Chalumeau, Z. Amoura.
high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl.
Critical revision of the article for important intellectual con- 13. Patel PM, Selby PJ, Graham MA, Viner C, Newell DR, McElwain TJ.
Pharmacokinetics of high dose methylprednisolone and use in hematological Final approval of the article: Z. Amoura, J.C. Piette.
malignancies. Hematol Oncol. 1993;11:89-96.
Provision of study materials or patients: Z. Amoura, G. Ay- 14. Kaufman M. Treatment of multiple sclerosis with high-dose corticosteroids
mard, O. Sevin, B. Wechsler, P. Cacoub, L.T. Huong Du, B.
may prolong the prothrombin time to dangerous levels in patients taking Administrative, technical, or logistic support: Z. Amoura.
15. Brigden ML, Kay C, Le A, Graydon C, McLeod B. Audit of the frequency
Collection and assembly of data: Z. Amoura.
and clinical response to excessive oral anticoagulation in an out-patient pop-ulation. Am J Hematol. 1998;59:22-7.
16. Murphy PT, Casey MC, Abrams K. Audit of patients on oral anticoagulants
with International normalized ratios of eight or above. Clin Lab Haematol.
17. Pichard L, Fabre I, Fabre G, Domergue J, Saint Aubert B, Mourad G, et
al. Cyclosporin A drug interactions. Screening for inducers and inhibitors of
cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepa-
1. Roujeau JC. Pulse glucocorticoid therapy. The ’big shot’ revisited. Arch Der-
tocytes and in liver microsomes. Drug Metab Dispos. 1990;18:595-606.
18. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol
2. Wechsler B, Du LT, Piette JC. Behcet’s disease. Eur J Med. 1992;1:387-90.
18 April 2000 • Annals of Internal Medicine • Volume 132 • Number 8

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