Published Online, 11 October 2005, www.theannals.com, DOI 10.1345/aph.1G020b.
The Annals of Pharmacotherapy: Vol. 39, No. 11, pp. 1956-1957. DOI 10.1345/aph.1G020b
© 2005 Harvey Whitney Books Company.
David W Kubiak, PharmD
Senior Clinical Pharmacist Department of Pharmacy—Tower L2
Brigham and Women's Hospital 75 Francis Street Boston, Massachusetts
02115-6110 fax 617/566-2396
dwkubiak{at}partners.org
Paul M Szumita, PharmD BCPS
Clinical Pharmacy Practice Manager Brigham and Women's
Hospital
John R Fanikos, BSPharm MBA
Assistant Director of Pharmacy Services Brigham and Women's
Hospital
Published Online, October 11, 2005. www.theannals.com, DOI 10.1345/aph.1G020b
AUTHORS' REPLY: We appreciate Drs. Spinler and Dager's insightful
considerations concerning our patient with confirmed symptomatic
upper-extremity DVT requiring
treatment.1
In retrospect, it may have been prudent to wait until all coagulation
parameters had returned to within normal limits prior to administration of an
alternative anticoagulant. There was concern with avoiding surgical or
thrombolytic procedures and also preserving venous access for continued
chemotherapy cycles. This sense of urgency prompted us to choose an aggressive
strategy, thereby initiating therapy with fondaparinux as a bridge to
warfarin. Our patient received only one dose of fondaparinux, administered
17.5 hours after stopping the argatroban infusion and 27.5 hours after his
last warfarin dose. Laboratory tests performed 3 hours prior to fondaparinux
administration were significant for INR 10.9 and aPTT 66.0 seconds. Based on
argatroban's elimination half-life of 30-51
minutes,2 we
felt an adequate period had elapsed prior to fondaparinux administration. We
recognize that the effects of FFP and rVIIa are short-lived, but contend that
they were used to treat an active hemorrhage and not to manage the prolonged
aPTT and INR.
Studies suggesting a linear correlation between argatroban dose and INR
were performed in young healthy
volunteers.3-5
Our patient's course was complicated by liver and lung metastases, age >65
years, malnourishment, and a recently completed chemotherapy cycle. All of
these comorbidities are known to alter warfarin dosing and impact the
INR.6
Warfarin when given concomitantly with heparin can contribute to a prolonged
aPTT. This effect has been studied only in a small cohort of patients, in
which there was considerable
variation.7
Prolonged aPTT in patients receiving argatroban and warfarin has not been
evaluated conclusively. A recent study suggests that ecarin clotting time may
be a more effective predictor of anticoagulation when bridging from argatroban
to warfarin, but this assay has been used only in clinical research and is not
widely
available.8
To our knowledge, as of September 29, 2005, there are no data evaluating the
impact of metastatic liver cancer on coagulation. Research needs to be
performed to examine the pharmacodynamics of intravenous and oral
anticoagulants in these patients.
The current Chest guidelines provide recommendations for
thromboprophylaxis and long-term management, but not initial treatment, of
anticoagulation therapy in cancer
patients,9
making it challenging to appropriately dose anticoagulants in this population.
In addition, we agree that our patient's initial renal dysfunction was most
likely attributable to dehydration, as stated in the Discussion section, and
that this condition improved with fluid replacement. In the absence of
previous anticoagulation therapy, we attributed his initial elevated baseline
INR to dehydration, a recent antibiotic course, and decreased albumin (2.2
mg/dL). We did not feel a baseline coagulopathy workup would yield any value.
In hindsight, since his INR was still elevated 5 days after stopping warfarin,
we agree that a full investigation into possible coagulopathy would have been
warranted.
References
- Kubiak DW, Szumita PM, Fanikos JR. Extensive prolongation of aPTT
with argatroban in an elderly patient with improving renal function, normal
hepatic enzymes, and metastatic lung cancer. Ann Pharmacother 2005;39: 1119-23.
Epub 10 May 2005. DOI 10.1345/aph.1G020[Abstract/Free Full Text]
- Product information. Argatroban. Research Triangle
Park, NC: GlaxoSmithKline Beecham, February 2002.
- Gosselin RC, Dager WE, King JH, Janatpour K, Mahackian K, Larkin
EC, et al. Effect of direct thrombin inhibitors, bivalirudin, lepirudin, and
argatroban on prothrombin time and INR values. Am J Clin Pathol 2004;121:593-9.[CrossRef][Medline]
- Sheth SB, Dicicco RA, Hursting MJ, Montaguet T, Jorkasky DK.
Interpreting the international normalized ratio (INR) in individuals receiving
argatroban and warfarin. Thromb Haemost 2001;85:435-40.[Medline]
- Hursting MJ, Zehnder JL, Joffrion JL, Becker JC, Knappenberger GD,
Schwarz RP. The international normalized ratio during concurrent warfarin and
argatroban anticoagulation: differential contributions of each agent and
effects of the choice of thromboplastin used. Clin Chem 1999;45:409-12.[Free Full Text]
- Product information. Coumadin (warfarin).
Wilmington, DE: Du Pont Pharmaceuticals, revised 11/99, reviewed
7/2000.
- Kearon C, Johnston M, Moffat K, McGinnis J, Ginsberg JS. Effect of
warfarin on activated partial thromboplastin time in patients receiving
heparin. Arch Intern Med 1998;158:1140-3.[Abstract/Free Full Text]
- Harder S, Graff J, Klinkhardt U, von Hentig N, Walenga JM, Watanabe
H, et al. Transition from argatroban to oral anticoagulation with
phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial
thromboplastin time, and ecarin clotting time. Thromb Haemost 2004;91:1137-45.[Medline]
- Schünemann HJ, Munger H, Brower S, O'Donnell M, Crowther M,
Cook D, et al. Methodology for guideline development for the Seventh American
College of Chest Physicians Conference on Antithrombotic and Thrombolytic
Therapy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic
Therapy. Chest 2004;126(3
suppl): 174S-8S.[Abstract/Free Full Text]
