Preemptive warfarin dose reduction after initiation of sulfamethoxazole-trimethoprim or metronidazole

Abstract

To evaluate the utility of a preemptive warfarin dose reduction at the time of initiation of either sulfamethoxazole-trimethoprim or metronidazole, a retrospective chart review of patients who received an outpatient prescription for warfarin and either sulfamethoxazole-trimethoprim and/or metronidazole from July 1, 2011 to July 1, 2015 was conducted. Clinical outcomes compared Veterans who had a warfarin dose reduction and those who did not within 120 h (5 days) of antibiotic initiation. The primary outcome compared the pre-and post-antibiotic International Normalized Ratio (INR) of patients in the intervention group (warfarin dose reduction) with those in the control group (no intervention). Secondary outcomes assessed incidence of thromboembolic and major bleeding events within 30 days of antibiotic completion. Fifty patients were assessed. Forty-nine patients had at least one follow-up appointment; 126 follow-up visits were evaluated. There was a statistically significant difference for the change in therapeutic INR at the first follow-up appointment (p = 0.029) for those patients in the control group. On average, the patients in the intervention group required fewer follow-up visits (p = 0.019). There were no statistically significant differences for the overall rate of therapeutic INR values between groups, as well as no instances of a thromboembolic or major bleeding events during the follow-up period. Clinically significant differences were observed for patients who received a preemptive warfarin dose reduction upon initiation of sulfamethoxazole-trimethoprim or metronidazole. Patients in the intervention group required fewer follow-up appointments and were more likely maintain a therapeutic INR within the 30 days following the antibiotic course. Results of this study will be presented the at Pharmacy and Therapeutics committee in an effort to seek approval for policy development to initiate a local preemptive warfarin dose adjustment as a standard of practice.

Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach

“…37 It was therefore expected that the concomitant use of metronidazole and warfarin notably increased the INR levels in our study, although to a lesser extent than miconazole or amiodarone. Hence, concomitant therapy with metronidazole should be optimized through warfarin dose adjustment, as the results of a recent study suggest; Powers et al 38 found that a pre-emptive mean reduction of 25% in warfarin dose resulted in maintained therapeutic INR levels in the 30 days following metronidazole course and fewer follow-up visits, compared with the group of patients without this intervention.…”

Preemptive Dose Adjustment Effect on the Quality of Anticoagulation Management in Warfarin Patients With Drug Interactions: A Retrospective Cohort Study

“…These results were more pronounced in patients on metronidazole and sulfamethoxazole-trimethoprim than in patients on levofloxacin. 23–25 On the other hand, both RCTs on warfarin–prednisone and warfarin–doxycycline interactions, found more control patients with INR of more than 1 point over the goal upper limit compared to the intervention group but these results did not reach statistical significance. 26,27 There was also a statistical significance increase in the incidence of subtherapeutic INRs in the preemptive group.…”

“…Benefit of the use of preemptive warfarin dose adjustment has been studied by others, however, results were conflicting. [23][24][25][26][27] Three of these studies were retrospective observational studies that focused on preemptive dose reduction of warfarin in patients initiating metronidazole, 23,25 sulfamethoxazole-trimethoprim, 23,24 and levofloxacin. 24 While 2 other studies were randomized controlled trials (RCTs) by Dowd and colleagues and they compared preemptive warfarin dose reduction to reactive warfarin dose adjustment in patients receiving prednisone 26 and in patients receiving doxycycline.…”

Drug-drug interactions in an era of multiple anticoagulants: a focus on clinically relevant drug interactions

“…Given the reputation of these drugs for causing significant changes in the INR, some clinicians may advocate for empiric warfarin dose adjustments 24,32,[34][35][36] to avoid risk of supratherapeutic or subtherapeutic INR and potentially reduce the number of INR monitoring visits surrounding the drug interaction. Although these drug interactions are fairly common and this may be an effective strategy in some patients, not all patients will respond uniformly, and an empiric dose adjustment in a nonresponder could result in an out-of-range INR.…”