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Clinical Pharmacist, Physicians Inc.. 750 W High Street, Suite 250, Lima, Ohio 45801-3959, fax 419/225-9610, t-hoffmann{at}onu.edu
Director of Clinical Pharmacy, Assistant Professor of Clinical Pharmacy, Physicians Inc., Ohio Northern University
Internist, Physicians Inc.
Internist, Physicians Inc.
Published Online, May 2, 2006. www.theannals.com, DOI 10.1345/aph.1G474
The first patient, an 84-year-old woman on warfarin therapy (goal INR 2-3) for atrial fibrillation, was on a consistent maintenance dose of warfarin for approximately one year. The patient was then started on pioglitazone 15 mg daily. An effect on the INR was not seen immediately, but by week 12, the patient's INR was 1.2. At this point, she was given a one-time larger dose of warfarin and was asked to continue her current maintenance dose. INR was 1.2 when rechecked, and a therapeutic INR of 2.3 was reached only after the patient's weekly maintenance dose had increased from 8.5 mg/wk to 16 mg/wk, an 88% increase in the weekly warfarin requirement. Over the next 18 months, her INR has ranged from 1.9 to 3.2 on a similar maintenance dose, and the patient continues pioglitazone therapy (Figure 1).
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Our second patient was a 76-year-old man on warfarin therapy (goal INR 1.5-2) for atrial fibrillation. He was on a consistent maintenance dose of warfarin for approximately 18 months. The patient was started on rosiglitazone 4 mg daily. The INR had decreased to 1.1 by week 4 of rosiglitazone therapy, at which time the patient received a one-time larger dose of warfarin, and the weekly maintenance dose was increased by 13%. A therapeutic INR of 1.9 was reached only after warfarin was increased from 24 mg/wk to 42 mg/wk, a 75% increase in the weekly warfarin requirement. His INR has been maintained, for one year, at 1.7-2.6 on a similar maintenance dose, and the patient continues rosiglitazone therapy (Figure 1).
In both cases, the patients denied any other medication changes, including over-the-counter products and herbal supplements, and denied any change to diet, specifically foods containing vitamin K. One patient did claim 1 or 2 missed doses, but even if more doses were missed, the INR would not have remained depressed for such a prolonged period. Use of the Naranjo probability scale1 indicated a probable relationship between thiazolidinedione therapy and suppression of the INR in both cases.
Interestingly, there have been case reports of troglitazone increasing the INR in patients on concurrent warfarin therapy, exactly the opposite of what we have observed. This interaction was theorized to be due to displacement of warfarin from plasma proteins or inhibition of the CYP 450 system by troglitazone.2 Both pioglitazone and rosiglitazone are known to be metabolized by CYP 450 2C8 and to a lesser extent by 2C9. Additionally, pioglitazone is a weak inducer of 3A4, which could explain the interaction. We advise practitioners to monitor INR closely during the first few months of concomitant thiazolidinedione therapy. The interaction appears to manifest within 1-3 months of initiation, and adjustment of the warfarin dose may be necessary.
References
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