A Population-Based Assessment of the Drug Interaction Between Levothyroxine and Warfarin
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Cites
Oral Anticoagulants: Mechanism of Action, Clinical Effectiveness, and Optimal Therapeutic Range
Hirsh, J., Dalen, J. E., Anderson, D. R., Poller, L., Bussey, H. I., Ansell, J., & Deykin, D. (2001) · CHEST Journal · doi:10.1378/chest.119.1_suppl.8s · Cited by 1,813 · see citing works
Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study
Juurlink, D. N., Mamdani, M. M., Lee, D. S., Kopp, A., Austin, P. C., Laupacis, A., & Redelmeier, D. A. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040135 · Cited by 1,761 · see citing works
Self-citationEstimation of the Warfarin Dose with Clinical and Pharmacogenetic Data
The International Warfarin Pharmacogenetics Consortium (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0809329 · Cited by 1,573 · see citing works
Systematic overview of warfarin and its drug and food interactions
Holbrook, A. M. (2005) · Archives of Internal Medicine · doi:10.1001/archinte.165.10.1095 · Cited by 1,160 · see citing works
Polymorphism of human cytochrome P450 enzymes and its clinical impact
Zhou, S., Liu, J., & Chowbay, B. (2009) · Drug Metabolism Reviews · doi:10.1080/03602530902843483 · Cited by 832 · see citing works
A population-based study of the drug interaction between proton pump inhibitors and clopidogrel
Juurlink, D. N., Gomes, T., Ko, D. T., Szmitko, P. E., Austin, P. C., Tu, J. V., Henry, D. A., Kopp, A., & Mamdani, M. (2009) · Canadian Medical Association Journal · doi:10.1503/cmaj.082001 · Cited by 764 · see citing works
Self-citationDrug-Drug Interactions Among Elderly Patients Hospitalized for Drug Toxicity
Juurlink, D. N., Mamdani, M., Kopp, A., Laupacis, A., & Redelmeier, D. A. (2003) · JAMA · doi:10.1001/jama.289.13.1652 · Cited by 759 · see citing works
Self-citationHemorrhagic Complications of Anticoagulant and Thrombolytic Treatment
Schulman, S., Beyth, R. J., Kearon, C., & Levine, M. N. (2008) · CHEST Journal · doi:10.1378/chest.08-0674 · Cited by 737 · see citing works
Bleeding Complications With Warfarin Use
Wysowski, D. K., Nourjah, P. A., & Swartz, L. (2007) · Archives of Internal Medicine · doi:10.1001/archinte.167.13.1414 · Cited by 547 · see citing works
Outpatient gatifloxacin therapy and dysglycemia in older adults.
Park-Wyllie, L. Y., Juurlink, D. N., Kopp, A., Shah, B. R., Stukel, T. A., Stumpo, C., Dresser, L., Low, D. E., & Mamdani, M. M. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa055191 · Cited by 367 · see citing works
Self-citationImproved Comorbidity Adjustment for Predicting Mortality in Medicare Populations
Schneeweiß, S., Wang, P. S., Avorn, J., & Glynn, R. J. (2003) · Health Services Research · doi:10.1111/1475-6773.00165 · Cited by 330 · see citing works
Influence of CYP2C9 genotype on warfarin dose requirements—a systematic review and meta-analysis
Lindh, J. D., Holm, L., Andersson, M. L., & Rane, A. (2008) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-008-0584-5 · Cited by 216 · see citing works
Interaction of Warfarin With Drugs, Natural Substances, and Foods
Greenblatt, D. J., & Moltke, L. L. (2005) · The Journal of Clinical Pharmacology · doi:10.1177/0091270004271404 · Cited by 199 · see citing works
Accuracy of coding for possible warfarin complications in hospital discharge abstracts
Arnason, T., Wells, P. S., van Walraven, C., & Forster, A. J. (2005) · Thrombosis Research · doi:10.1016/j.thromres.2005.06.015 · Cited by 192 · see citing works
Drug Interactions with Coumarin Anticoagulants
Koch‐Weser, J., & Sellers, E. M. (1971) · New England Journal of Medicine · doi:10.1056/nejm197109022851005 · Cited by 181 · see citing works
Blood Coagulation in Thyroid Dysfunction
Simone, J. V., Abildgaard, C. F., & Sghulman, I. (1965) · New England Journal of Medicine · doi:10.1056/nejm196511112732001 · Cited by 126 · see citing works
Warfarin Pharmacology, Clinical Management, and Evaluation of Hemorrhagic Risk for the Elderly
Jacobs, L. G. (2008) · Cardiology Clinics · doi:10.1016/j.ccl.2007.12.010 · Cited by 123 · see citing works
Polymorphisms of human cytochrome P450 2C9 and the functional relevance
Zhou, S.-F., Zhou, Z.-W., & Huang, M. (2009) · Toxicology · doi:10.1016/j.tox.2009.08.013 · Cited by 119 · see citing works
Yang, L., Ge, W., Yu, F., & Zhu, H. (2009) · Thrombosis Research · doi:10.1016/j.thromres.2009.10.017 · Cited by 111 · see citing works
Kamali, F., & Wynne, H. (2009) · Annual Review of Medicine · doi:10.1146/annurev.med.070808.170037 · Cited by 109 · see citing works
Drug interactions with warfarin: what clinicians need to know
Juurlink, D. N. (2007) · Canadian Medical Association Journal · doi:10.1503/cmaj.070946 · Cited by 107 · see citing works
Self-citationComplex Drug-Drug-Disease Interactions Between Amiodarone, Warfarin, and the Thyroid Gland
Kurnik, D., Loebstein, R., Farfel, Z., Ezra, ., Halkin, H., & Olchovsky, D. (2004) · Medicine · doi:10.1097/01.md.0000123095.65294.34 · Cited by 83 · see citing works
Wright, A. J., Gomes, T., Mamdani, M., Horn, J. R., & Juurlink, D. N. (2011) · Canadian Medical Association Journal · doi:10.1503/cmaj.100702 · Cited by 79 · see citing works
Self-citationII. The effect of D‐thyroxine, clofibrate, and norethandrolone
Schrogie, J. J., & Solomon, H. M. (1967) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt196781part170 · Cited by 76 · see citing works
Problems of Anticoagulation with Warfarin in Hyperthyroidism
Kellett, H. A., Sawers, J. S. A., Boulton, F. E., Cholerton, S., Park, B. K., & Toft, A. D. (1986) · QJM · doi:10.1093/oxfordjournals.qjmed.a067939 · Cited by 63 · see citing works
Effect of Sodium Dextrothyroxine in Patients Receiving Anticoagulants
Owens, J. C., Neely, W. B., & Owen, W. R. (1962) · New England Journal of Medicine · doi:10.1056/nejm196201112660205 · Cited by 60 · see citing works
Warfarin Pharmacology, Clinical Management, and Evaluation of Hemorrhagic Risk for the Elderly
Jacobs, L. G. (2006) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2005.09.001 · Cited by 39 · see citing works
Solomon, H. M., & Schrogie, J. J. (1967) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt196786797 · Cited by 31 · see citing works
The relationship between thyroid function and anticoagulant therapy
Walters, M. B. (1963) · The American Journal of Cardiology · doi:10.1016/0002-9149(63)90043-2 · Cited by 24 · see citing works
Warfarin-induced hypoprothrombinemia. Potentiation by hyperthyroidism
Self, T. H. (1975) · JAMA · doi:10.1001/jama.231.11.1165 · Cited by 24 · see citing works
The effect of thyroid function on the prothrombin time response to warfarin in rats
Lowenthal, J., & Fisher, L. M. (1957) · Cellular and Molecular Life Sciences · doi:10.1007/bf02157446 · Cited by 22 · see citing works
Potentiation of Oral Anticoagulant Effect by L-thyroxine
COSTIGAN, D. C., Freedman, M. H., & Ehrlich, R. M. (1984) · Clinical Pediatrics · doi:10.1177/000992288402300308 · Cited by 19 · see citing works
Oral Anticoagulants and Drugs Which Alter Thyroid Function
Hansten, P. D. (1980) · Annals of Pharmacotherapy · doi:10.1177/106002808001400502 · Cited by 18 · see citing works
Enhancement of warfarin-induced hypoprothrombinemia by thyrotoxicosis.
Vagenakis, A. G., Cote, R., Miller, M. E., Braverman, L. E., & Stohlman, F. (1972) · PubMed · Cited by 15 · see citing works
Decreased sensitivity to warfarin in patients with myxedema
RICE, A. J., McINTOSH, T. J., Fouts, J. R., Brunk, S. F., & WILSON, W. R. (1971) · The American Journal of the Medical Sciences · doi:10.1097/00000441-197110000-00003 · Cited by 14 · see citing works
Potentiation of warfarin sodium by amiodarone-induced thyrotoxicosis.
Woeber, K. A., & Warner, I. (1999) · PubMed · Cited by 11 · see citing works
Effect of Hyperthyroidism on Hypoprothrombinemic Response to Warfarin
Self, T. H., Straughn, A. B., & Weisburst, M. R. (1976) · American Journal of Health-System Pharmacy · doi:10.1093/ajhp/33.4.387 · Cited by 11 · see citing works
Prothrombinopenic activity of the salicylates and pharmacologically related drugs.
Clark, B. B., & Spitalny, M. (1946) · PubMed · Cited by 4 · see citing works
Effect of sodium dextrothyroxine in patients receiving anticoagulants.
OWENS, J. C., Neely, W. B., & Owen, W. R. (1962) · PubMed · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Association Between Wait Time and 30-Day Mortality in Adults Undergoing Hip Fracture Surgery
Pincus, D., Ravi, B., Wasserstein, D. N., Huang, A., Paterson, J. M., Nathens, A. B., Kreder, H. J., Jenkinson, R., & Wodchis, W. P. (2017) · JAMA · doi:10.1001/jama.2017.17606 · Cited by 717 · see citing works
Self-citationOverrides of medication-related clinical decision support alerts in outpatients
Nanji, K. C., Slight, S. P., Seger, D. L., Cho, I., Fiskio, J. M., Redden, L. M., Volk, L. A., & Bates, D. W. (2014) · Journal of the American Medical Informatics Association · doi:10.1136/amiajnl-2013-001813 · Cited by 219 · see citing works
Rodrigues, M. C. S., & de Oliveira, C. M. (2016) · Revista Latino-Americana de Enfermagem · doi:10.1590/1518-8345.1316.2800 · Cited by 241 · see citing works
Drug–drug interactions with warfarin: A systematic review and meta‐analysis
Wang, M., Zeraatkar, D., Obeda, M., Lee, M., Garcia, M. C., Nguyen, L., Agarwal, A., Al‐Shalabi, F., Benipal, H., Ahmad, A., et al. (2021) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14833 · Cited by 116 · see citing works
Amiodarone-Induced Thyroid Dysfunction
Danzi, S. E., & Klein, I. L. (2013) · Journal of Intensive Care Medicine · doi:10.1177/0885066613503278 · Cited by 67 · see citing works
Trifirò, G., Parrino, F., Sultana, J., Giorgianni, F., Ferrajolo, C., Bianchini, E., Medea, G., Benvenga, S., Cricelli, I., Cricelli, C., et al. (2015) · Clinical Drug Investigation · doi:10.1007/s40261-015-0271-0 · Cited by 40 · see citing works
Reporting and evaluating wait times for urgent hip fracture surgery in Ontario, Canada
Pincus, D., Wasserstein, D. N., Ravi, B., Byrne, J. P., Huang, A., Paterson, J. M., Nathens, A. B., Kreder, H. J., Jenkinson, R., & Wodchis, W. P. (2018) · Canadian Medical Association Journal · doi:10.1503/cmaj.170830 · Cited by 31 · see citing works
Self-citationPopulation Impact of Drug Interactions with Warfarin: A Real-World Data Approach
Martín‐Pérez, M., Gaist, D., de Abajo, F. J., & Rodríguez, L. A. G. (2018) · Thrombosis and Haemostasis · doi:10.1055/s-0038-1627100 · Cited by 23 · see citing works
Tomisti, L., Re, M. D., Bartalena, L., Tanda, M. L., Pucci, A., Pambianco, F., Pambianco, A., Braverman, L. E., Martino, E., & Bogazzi, F. (2013) · Endocrine Practice · doi:10.4158/ep13093.ra · Cited by 21 · see citing works
Guglielmi, V., Bellia, A., Bianchini, E., Medea, G., Cricelli, I., Sbraccia, P., Lauro, D., Cricelli, C. A., & Lapi, F. (2017) · Endocrine · doi:10.1007/s12020-017-1412-4 · Cited by 20 · see citing works
Rikala, M., Hauta‐aho, M., Helin‐Salmivaara, A., Lassila, R., Korhonen, M. J., & Huupponen, R. (2014) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.12373 · Cited by 15 · see citing works
on behalf of the Italian Group for Appropriate Drug prescription in the Elderly (I-GrADE), Comoretto, R. I., Rea, F., Lucenteforte, E., Mugelli, A., Trifirò, G., Cascini, S., Roberto, G., Chinellato, A., Filippelli, A., et al. (2018) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-018-2467-8 · Cited by 10 · see citing works
Jödicke, A. M., Curkovic, I., Zellweger, U., Tomka, I. T., Neuer, T., Kullak-Ublick, G. A., Roos, M., & Egbring, M. (2018) · Annals of Pharmacotherapy · doi:10.1177/1060028018775914 · Cited by 8 · see citing works
An evaluation of the potential drug interaction between warfarin and levothyroxine
Wood, M., Delate, T., Clark, M., Clark, N. P., Horn, J. R., & Witt, D. M. (2014) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12626 · Cited by 7 · see citing works
Comprehensive Exploration of Medications That Affect the Bleeding Risk of Oral Anticoagulant Users
Kawano, Y., Nagata, M., Nakamura, S., Akagi, Y., Suzuki, T., Tsukada, E., Hoshiko, M., Kujirai, A., Nakamatsu, S., Nishikawa, T., et al. (2021) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b20-00791 · Cited by 4 · see citing works
Thyroid Hormones, Iodine and Iodides and Antithyroid Drugs
Bilder, G. E. (2014) · Side effects of drugs annual · doi:10.1016/b978-0-444-63407-8.00041-1
Moustafa, F., Malhomme, R., Pereira, B., Barrès, A., Saint-Denis, J., Dutheil, F., Batisse‐Lignier, M., & Schmidt, J. (2017) · Clinical Drug Investigation · doi:10.1007/s40261-017-0545-9
Administration of Immune Checkpoint Inhibitors to Patients on Warfarin May Elevate PT-INR
Uenoyama, K., Onoue, M., Katayama, T., Makihara, K., Yamamoto, H., Takagi, M., Omoto, K., & Rikitake, Y. (2024) · YAKUGAKU ZASSHI · doi:10.1248/yakushi.24-00087
- Authors
- Pincus, D., Gomes, T., Hellings, C., Zheng, H., Paterson, J. M., Mamdani, M. M., & Juurlink, D. N.
- Affiliations
- University of Toronto (CA)
- Institute for Clinical Evaluative Sciences (CA)
- St. Michael's Hospital (CA)
- Corresponding author
- Juurlink, D N
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2012-10-24
- Volume
- 92
- Issue
- 6
- Pages
- 766-770
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- PMC
- PMC3711799
- OpenAlex
- W2086349371
- Cited by
- 18
- References
- 39
- Citations by year
- 2024: 1 · 2021: 2 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 1 · 2014: 3 · 2013: 3
- FWCI
- 1.44
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Institute for Clinical Evaluative Sciences
- Canadian Institutes of Health Research (92247_1)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- levothyroxine, warfarin, drug interactions, hemorrhage, anticoagulation, hospitalization, elderly patients, thyroid hormones, bleeding risk
- MeSH terms
- Aged, Aged, 80 and over, Anticoagulants, Drug Interactions, Female, Hemorrhage, Hospitalization, Humans, Male, Population, Thyroxine, Warfarin, Cohort Studies, Odds Ratio, Case-Control Studies, Treatment Outcome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
