Purpose: The concomitant use of azathioprine (AZA) and warfarin (WAR) occurs commonly in solid organ transplant (SOT) recipients. Case reports in non-SOT patients have suggested that a drug interaction exists between these two agents, and is often under recognized. Despite these reports, little guidance is published to assist clinicians in the appropriate and safe use of the combination. To address this issue, we analyzed the effects of the use of AZA and WAR in SOT recipients.

Methods: A retrospective study was performed evaluating adult SOT recipients receiving concomitant AZA and WAR between 1/1/1999 and 10/1/2012. Weekly WAR dose resulting in a therapeutic INR when AZA and WAR were used concomitantly was compared to WAR alone. Secondary outcomes included: incidence and number of days of subtherapeutic INR in the first 30 days when AZA was added to WAR compared to WAR alone, incidence and number of days of supratherapeutic INR post-AZA withdraw from an AZA/ WAR combination, and the incidence of thromboembolic or bleeding events during periods of supra- or subtherapeutic INR.

Results: A total of 101 SOT recipients were included: 2 (2%) kidney-pancreas, 4 (4%) pancreas, 8 (7.9%) heart, 42 (41.6%) lung, and 45 (44.6%) kidney. The most common indications for WAR were treatment of DVT (55.4%) and atrial fibrillation (20.8%). Warfarin doses required to achieve a therapeutic INR were higher in patients receiving AZA/WAR combination compared to WAR alone (40.6 ± 20.7 mg/week vs. 25.5 ± 11.4 mg/week, p<0.001). 89.6% of patients had a subtherapeutic INR after AZA was added to patients on WAR vs. 10.4% prior to AZA initiation (p<0.001). There was also a significant increase in the number of days the patients had a subtherapeutic INR (16.8 ± 11.9 vs. 8 ± 11.9, p=0.005). When AZA was discontinued from patients on an AZA/ WAR combination, there was a significant increase in the incidence (63.2% vs. 25.6%, p=0.006) and number of days (9.7 ± 10.9 vs. 2.1 ± 5.5, p=0.008) of supratherapeutic INR. Two bleeding events, but no re-thrombosis occurred during AZA/ WAR combination therapy.

Conclusions: This is the first large case series to describe the significant drug interaction between AZA and WAR post-SOT. Our results demonstrate the need for a 60% increase in weekly WAR dose to maintain a therapeutic INR when patients are receiving concomitant AZA therapy and alert the clinician to the need for close monitoring to prevent supra- or subtherapeutic INR values.

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