A Population-Based Assessment of the Drug Interaction Between Levothyroxine and Warfarin

Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 10/2012; 92(6). DOI: 10.1038/clpt.2012.171
Source: PubMed


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.

22 Reads
  • Source
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jun 2013 · Endocrine Practice
  • [Show abstract] [Hide abstract]
    ABSTRACT: Amiodarone is an effective medication for the treatment of cardiac arrhythmias. Originally developed for the treatment of angina, it is now the most frequently prescribed antiarrhythmia drug despite the fact that its use is limited because of potential serious side effects including adverse effects on the thyroid gland and thyroid hormones. Although the mechanisms of action of amiodarone on the thyroid gland and thyroid hormone metabolism are poorly understood, the structural similarity of amiodarone to thyroid hormones, including the presence of iodine moieties on the inner benzene ring, may play a role in causing thyroid dysfunction. Amiodarone-induced thyroid dysfunction includes amiodarone-induced thyrotoxicosis (AIT) and amiodarone-induced hypothyroidism (AIH). The AIT develops more commonly in iodine-deficient areas and AIH in iodine-sufficient areas. The AIT type 1 usually occurs in patients with known or previously undiagnosed thyroid dysfunction or goiter. The AIT type 2 usually occurs in normal thyroid glands and results in destruction of thyroid tissue caused by thyroiditis. This is the result of an intrinsic drug effect from the amiodarone itself. Mixed types are not uncommon. Patients with cardiac disease receiving amiodarone treatment should be monitored for signs of thyroid dysfunction, which often manifest as a reappearance of the underlying cardiac disease state. When monitoring patients, initial tests should include the full battery of thyroid function tests, thyroid-stimulating hormone, thyroxine, triiodothyronine, and antithyroid antibodies. Mixed types of AIT can be challenging both to diagnose and treat and therapy differs depending on the type of AIT. Treatment can include thionamides and/or glucocorticoids. The AIH responds favorably to thyroid hormone replacement therapy. Amiodarone is lipophilic and has a long half-life in the body. Therefore, stopping the amiodarone therapy usually has little short-term benefit.
    No preview · Article · Sep 2013 · Journal of Intensive Care Medicine
  • [Show abstract] [Hide abstract]
    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.
    No preview · Article · Oct 2013 · Journal of the American Medical Informatics Association
Show more