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The Safety of Levofloxacin in Patients on Warfarin
The American Journal of Medicine (2007) 120, e13
LETTER The Safety of Levofloxacin in Patients on Warfarin To the Editor: We would like to commend Stroud and colleagues for their excellent work regarding the safety of levofloxacin use in elderly patients on warfarin.1 Their large populationbased study attempts to rectify the conflicting evidence regarding the warfarin-levofloxacin interaction. They correctly note that prior case reports and case series appear to contradict data from more controlled trials. They also note a paucity of studies evaluating this interaction in acutely ill individuals, their so-called “real-world practice.” We have recently published data on the impact of the addition of antibiotics to warfarin in a real-world setting by studying acutely ill patients who were on stable warfarin doses and had stable international normalized ratios (INRs).2 In our retrospective cohort study, the incidence of supratherapeutic INR was 33% in those who were given levofloxacin (n ⫽ 27) with a mean increase in INR of .85. Nineteen percent and 11% of patients had an elevation of their INR to ⬎ 4.0 and ⬎ 5.0, respectively. Consequently, our study and that of others clearly suggest that there is an interaction in terms of elevation of INRs. There are several limitations to Stroud et al’s study that may have contributed to their negative findings. First, their study design does not allow for knowledge of laboratory monitoring either before or after commencement of the antibiotic and as such the stability of the patients’ anticoagulation. Second, they were unable to document potential anticipatory dosing changes (ie, lowering of warfarin doses) or more frequent monitoring after adding an antibiotic. It is possible that the reason patients did not bleed was not because of a lack of interaction but rather because of increased monitoring and dose adjustments. Third, significant elevations of the INR may have occurred, which may not have led to hospitalization for bleeding, but still put the
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved.
patient at higher risk for a hemorrhagic complication. Fourth, the study database did not evaluate emergency department or clinic visits, so it is possible that some less severe hemorrhages were missed. Finally, it is also possible that co-existing medication changes around the time of illness could have reduced the hypoprothrombinemic effects of warfarin, thus offsetting the potentiating effects of levofloxacin. Even though our data, like Stroud and colleagues’, did not demonstrate an increase in hemorrhagic events, this likely relates to the small sample size (warfarin and levofloxacin users) in both studies. Still, we did show a very significant increase in INR, which is a strong risk factor for warfarin-related bleeding, and we believe that the remaining body of literature still strongly supports the interaction between warfarin and levofloxacin in acutely ill patients. Thus, the results of this research should not alter the clinical dictum that close monitoring of INR levels after the addition of any medication, including quinolone antibiotics, is mandatory. Jeffrey J. Glasheen, MD Division of General Internal Medicine Department of Medicine University of Colorado at Denver Health Sciences Center
Allan V. Prochazka, MD, MSc Division of General Internal Medicine Department of Medicine Denver VA Medical Center University of Colorado at Denver Health Sciences Center
doi:10.1016/j.amjmed.2006.02.034
References 1. Stroud LF, Mamdami MM, Kopp A, Bell CM. The safety of levofloxacin in elderly patients on warfarin. Am J Med. 2005;118:1417.e71417.e12. 2. Glasheen JJ, Fugit RV, Prochazka AV. The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med. 2005;20:653-656.
LETTER The Safety of Levofloxacin in Patients on Warfarin To the Editor: We would like to commend Stroud and colleagues for their excellent work regarding the safety of levofloxacin use in elderly patients on warfarin.1 Their large populationbased study attempts to rectify the conflicting evidence regarding the warfarin-levofloxacin interaction. They correctly note that prior case reports and case series appear to contradict data from more controlled trials. They also note a paucity of studies evaluating this interaction in acutely ill individuals, their so-called “real-world practice.” We have recently published data on the impact of the addition of antibiotics to warfarin in a real-world setting by studying acutely ill patients who were on stable warfarin doses and had stable international normalized ratios (INRs).2 In our retrospective cohort study, the incidence of supratherapeutic INR was 33% in those who were given levofloxacin (n ⫽ 27) with a mean increase in INR of .85. Nineteen percent and 11% of patients had an elevation of their INR to ⬎ 4.0 and ⬎ 5.0, respectively. Consequently, our study and that of others clearly suggest that there is an interaction in terms of elevation of INRs. There are several limitations to Stroud et al’s study that may have contributed to their negative findings. First, their study design does not allow for knowledge of laboratory monitoring either before or after commencement of the antibiotic and as such the stability of the patients’ anticoagulation. Second, they were unable to document potential anticipatory dosing changes (ie, lowering of warfarin doses) or more frequent monitoring after adding an antibiotic. It is possible that the reason patients did not bleed was not because of a lack of interaction but rather because of increased monitoring and dose adjustments. Third, significant elevations of the INR may have occurred, which may not have led to hospitalization for bleeding, but still put the
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved.
patient at higher risk for a hemorrhagic complication. Fourth, the study database did not evaluate emergency department or clinic visits, so it is possible that some less severe hemorrhages were missed. Finally, it is also possible that co-existing medication changes around the time of illness could have reduced the hypoprothrombinemic effects of warfarin, thus offsetting the potentiating effects of levofloxacin. Even though our data, like Stroud and colleagues’, did not demonstrate an increase in hemorrhagic events, this likely relates to the small sample size (warfarin and levofloxacin users) in both studies. Still, we did show a very significant increase in INR, which is a strong risk factor for warfarin-related bleeding, and we believe that the remaining body of literature still strongly supports the interaction between warfarin and levofloxacin in acutely ill patients. Thus, the results of this research should not alter the clinical dictum that close monitoring of INR levels after the addition of any medication, including quinolone antibiotics, is mandatory. Jeffrey J. Glasheen, MD Division of General Internal Medicine Department of Medicine University of Colorado at Denver Health Sciences Center
Allan V. Prochazka, MD, MSc Division of General Internal Medicine Department of Medicine Denver VA Medical Center University of Colorado at Denver Health Sciences Center
doi:10.1016/j.amjmed.2006.02.034
References 1. Stroud LF, Mamdami MM, Kopp A, Bell CM. The safety of levofloxacin in elderly patients on warfarin. Am J Med. 2005;118:1417.e71417.e12. 2. Glasheen JJ, Fugit RV, Prochazka AV. The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med. 2005;20:653-656.