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Multivitamin Supplements May Affect Warfarin Anticoagulation in Susceptible Patients

Fellow, Division of Clinical Pharmacology and Toxicology, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Aharon Lubetsky, MD

Clinical Specialist, Institute of Thrombosis and Hemostasis, Department of Hematology, Chaim Sheba Medical Center, and Sackler School of Medicine, Tel Aviv University

Ronen Loebstein, MD

Clinical Specialist, Division of Clinical Pharmacology and Toxicology, Chaim Sheba Medical Center, and Sackler School of Medicine, Tel Aviv University

Shlomo Almog, PhD

Laboratory Director, Division of Clinical Pharmacology and Toxicology, Chaim Sheba Medical Center, and Sackler School of Medicine, Tel Aviv University

Hillel Halkin, MD

Head, Institute of Clinical Pharmacology and Toxicology, Chaim Sheba Medical Center, and Sackler School of Medicine, Tel Aviv University

Reprints: Hillel Halkin MD, Division of Clinical Pharmacology and Toxicology, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel, FAX 972-3-535 1596, hhalkin{at}sheba.health.gov.il

OBJECTIVE: To report an interaction of a multivitamin preparation containing small amounts of vitamin K₁ (25 µg) with warfarin in a case series and to assess the prevalence of vitamin K₁ deficiency in ambulatory anticoagulated patients.

CASE SUMMARIES: We describe 3 patients whose anticoagulation was stabilized with warfarin in whom initiation or cessation of a self-prescribed multivitamin supplement delivering 25 µg of vitamin K₁ daily was associated with an otherwise unexplained significant fall or rise in international normalized ratio (INR), respectively, with major thrombosis or hemorrhage in 2. This interaction was rated probable on the Naranjo probability scale. Suspecting vitamin K₁ deficiency as an explanation for this oversensitivity, we assessed the prevalence of vitamin K₁ deficiency in our clinic by determining plasma vitamin K₁ levels in 179 stable consecutive patients, finding very low levels (<0.1 ng/mL) in 22 of 179 (12%).

DISCUSSION: Vitamin K₁ supplements of 25 µg daily are far below the dose thought to affect anticoagulant control. We hypothesize that, in our patients, unsuspected vitamin K₁ deficiency caused an oversensitivity to small vitamin K₁ supplements. In patients with low vitamin K₁ status, even such low doses represent a significant increment in daily intake, thus lowering the sensitivity to warfarin. Our analysis suggests that low vitamin K₁ status exists in a small, but important, minority of ambulatory patients undergoing anticoagulation.

CONCLUSIONS: Clinicians should instruct anticoagulated patients to report the use of multivitamin supplements and inquire about it in cases of unexplained INR changes.

Key Words: multivitamins, warfarin, antagonists and inhibitors

Published Online, September 10, 2003. www.theannals.com, DOI 10.1345/aph.1D102

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