A Population-Based Assessment of the Drug Interaction Between Levothyroxine and Warfarin
ABSTRACT Most drug interaction resources suggest that levothyroxine can dramatically potentiate the effect of warfarin. However, the mechanistic basis of the interaction is speculative, and little evidence supports a meaningful drug interaction. We conducted a population-based nested case-control study to examine the risk of hospitalization for hemorrhage following the initiation of levothyroxine in a cohort of 260,076 older patients receiving warfarin. In this group, we identified 10,532 case subjects hospitalized for hemorrhage and 40,595 controls. In the primary analysis, we found no association between hospitalization for hemorrhage during warfarin therapy and initiation of levothyroxine in the preceding 30 days (adjusted odds ratio 1.11, 95% confidence interval 0.67-1.86). Secondary analyses using more remote initiation of levothyroxine also found no association. These findings suggest that concerns about a clinically meaningful levothyroxine-warfarin drug interaction are not justified. Drug interaction resources that presently characterize this interaction as important should reevaluate this classification.Clinical Pharmacology & Therapeutics (2012); advance online publication 24 October 2012. doi:10.1038/clpt.2012.171.
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ABSTRACT: Objective: To review the literature regarding the interaction between amiodarone therapy, thyroid hormones and warfarin metabolism.Methods: A 73-year-old man with type 2 amiodarone induced thyrotoxicosis (AIT) who experienced a severe rise in the International Normalized Ratio (INR) values after starting warfarin therapy, owing to an unusual combination of an excess of thyroid hormones, amiodarone therapy and a genetic abnormality in warfarin metabolism.Results: The genetic analysis showed that the patient was CYP2C9*2 wild-type, CYP2C9*3/*3 homozygous mutant and VKORC1*3/*3 homozygous mutant. Review of the literature revealed that booth mutations can independently affect warfarin metabolism. In addition amiodarone therapy and the presence of thyrotoxicosis, per se, can affect warfarin metabolism and reduce the warfarin dose needed to maintain the INR in the therapeutic range. The association of the two genetic polymorphisms in a patient with AIT is extremely rare and strongly impairs warfarin metabolism, exposing the patient to a high risk of overtreatment.Conclusions: In patients with AIT, warfarin therapy should be gradually introduced, starting with a very low dose, because of the significant risk of a warfarin overtreatment. However, whether the genetic analysis of CYP2C9 and VKORC1 polymorphisms should be routinely performed in AIT patients remains conjectural.Endocrine Practice 06/2013; 19(6):1-27. DOI:10.4158/EP13093.RA · 2.59 Impact Factor
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ABSTRACT: Electronic prescribing is increasingly used, in part because of government incentives for its use. Many of its benefits come from clinical decision support (CDS), but often too many alerts are displayed, resulting in alert fatigue. To characterize the override rates for medication-related CDS alerts in the outpatient setting, the reasons cited for overrides at the time of prescribing, and the appropriateness of overrides. We measured CDS alert override rates and the coded reasons for overrides cited by providers at the time of prescribing. Our primary outcome was the rate of CDS alert overrides; our secondary outcomes were the rate of overrides by alert type, reasons cited for overrides at the time of prescribing, and override appropriateness for a subset of 600 alert overrides. Through detailed chart reviews of alert override cases, and selective literature review, we developed appropriateness criteria for each alert type, which were modified iteratively as necessary until consensus was reached on all criteria. We reviewed 157 483 CDS alerts (7.9% alert rate) on 2 004 069 medication orders during the study period. 82 889 (52.6%) of alerts were overridden. The most common alerts were duplicate drug (33.1%), patient allergy (16.8%), and drug-drug interactions (15.8%). The most likely alerts to be overridden were formulary substitutions (85.0%), age-based recommendations (79.0%), renal recommendations (78.0%), and patient allergies (77.4%). An average of 53% of overrides were classified as appropriate, and rates of appropriateness varied by alert type (p<0.0001) from 12% for renal recommendations to 92% for patient allergies. About half of CDS alerts were overridden by providers and about half of the overrides were classified as appropriate, but the likelihood of overriding an alert varied widely by alert type. Refinement of these alerts has the potential to improve the relevance of alerts and reduce alert fatigue.Journal of the American Medical Informatics Association 10/2013; 21(3). DOI:10.1136/amiajnl-2013-001813 · 3.93 Impact Factor
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ABSTRACT: Background: Drug interaction references report that initiation of levothyroxine potentiates the effects of warfarin, and recommend more frequent International Normalized Ratio (INR) monitoring, but the mechanism is not well understood. Objective: To assess the impact of levothyroxine initiation on INR response. Patients/Methods: A retrospective, self-controlled study was performed on patients aged >= 18 years receiving chronic warfarin therapy who were started on levothyroxine between 1 January 2006 and 30 June 2013, and who were followed for 90 days prior to and after levothyroxine initiation. The included patients had at least one elevated thyroid-stimulating hormone laboratory value in the pre-period, continuous warfarin therapy for 100 days prior to levothyroxine initiation, no purchases of medications known to interact with warfarin, no procedures requiring warfarin interruption, and no bleeding or thromboembolic event during the study period. The primary outcome was a comparison of the warfarin dose/INR ratio recorded before the initiation of levothyroxine with the ratio recorded during the post-period after two consecutive INRs with no warfarin dose change. Results: One hundred and two patients were included in the primary outcome. The mean warfarin dose/INR ratios in the pre-period and post-period were equivalent (P = 0.825). Although the mean warfarin dose was numerically lower in the post-period than in the pre-period, this difference did not reach statistical significance (P = 0.068). Conclusion: No difference in the mean warfarin dose/INR ratio before and after initiation of levothyroxine was detected. The results suggest that there is not a clinically significant interaction between warfarin and levothyroxine, and so additional monitoring may not be necessary.Journal of Thrombosis and Haemostasis 06/2014; 12(8). DOI:10.1111/jth.12626 · 5.55 Impact Factor