Smokeless Tobacco Linked to Subtherapeutic INR in Warfarin-Treated Patient

Failure to achieve a therapeutic international normalized ratio (INR) with warfarin was associated with chronic exposure to vitamin K-rich smokeless chewing tobacco in a recent case report published in the Journal of Thrombosis and Haemostasis. These findings suggest that tobacco cessation is an important additional treatment target to consider when prescribing the anticoagulant.

“To our knowledge… this is the second case report of warfarin failure during exposure to smokeless tobacco,” Diala Nicolas, PharmD, of St. Elizabeth’s Medical Center in Brighton, Massachusetts, and colleagues, wrote. Warfarin dosing can be challenging and subtherapeutic INR can be caused by a variety of factors, so “multiple causes need to be considered and ruled out before attributing warfarin resistance to chronic accumulation of vitamin K resulting from smokeless tobacco.”

In their report, the investigators described the patient as a 33-year-old man who had a history of intravenous (IV) drug use. The patient also had a history of infective endocarditis, which had required placement of a mechanical mitral valve – one of the few remaining indications for which warfarin is the firstline therapy (there are fewer data for novel anticoagulants).

Warfarin treatment was prescribed with an INR goal between 2.5 and 3.5. While the patient did not smoke cigarettes, he admitted to using chewing tobacco daily for the past 16 years. On admission to the hospital for detox after a 4-week, warfarin-free period of heavy drinking, the patient’s INR was 0.9. Clinicians subsequently started an IV heparin drip to bridge the patient to warfarin therapy.

The clinicians were unable to determine whether INR had been therapeutic, as the patient had an inconsistent follow-up history with his warfarin clinic. Treatment of warfarin doses of up to 30 mg per day were unable to achieve therapeutic INR during his hospitalization. Warfarin nonadherence, diet, genetic factors, and drug interactions were considered causes of subtherapeutic INR, but were later considered unlikely for this patient’s case.

Excessive alcohol consumption also was considered as a risk factor for this patient’s reduced INR levels. However, heavy alcohol intake was felt to be a less likely cause of increased requirements for warfarin after his liver function tests were only mildly elevated, with a normal bilirubin, and warfarin resistance remained despite reduction of alcohol consumption.

The team then performed a literature review to identify potential causes of the patient’s subtherapeutic INR. Findings from this review determined that the patient’s resistance to warfarin therapy may have been a result of exposure to high levels of vitamin K derived from exposure to smokeless tobacco both before and during hospitalization.

The patient finally achieved an increase in INR, to 2.4, following 3 doses of warfarin 30 mg. Heparin was discontinued, and the clinicians started subcutaneous enoxaparin 1 mg/kg every 12 hours. Treatment prescribed at discharge consisted of enoxaparin and warfarin 20 mg daily.

At discharge, the patient was made aware of the concerns of smokeless tobacco, including its interaction with warfarin, but he refused to stop using chewing tobacco.

“[Tobacco cessation may] leave the anticoagulant effects of warfarin unopposed … [which] can potentially lead to life-threatening hemorrhage.”

—Diala Nicolas, PharmD

Given that warfarin is the best-established treatment option for this patient, the medical team decided to continue increasing the warfarin dose to maintain a target INR. Clinicians also asked the patient to let them know if he stopped or reduced chewing tobacco so they could monitor the INR and adjust the warfarin based on any changes. According to Dr. Nicolas and colleagues, tobacco cessation may “leave the anticoagulant effects of warfarin unopposed, and at such high doses, this can potentially lead to life-threatening hemorrhage.”

The authors also recommended that clinicians document smokeless tobacco use in the medical record of warfarin-treated patients with known smokeless tobacco exposure. “Careful INR monitoring and warfarin dose adjustment should be undertaken in the event that tobacco use is stopped or reduced to prevent potentially fatal bleeding from leaving the effects of warfarin unopposed,” they wrote.

Limitations of this report included the lack of information on the patient’s pre-admission warfarin doses and INR values.

The authors report no relevant conflicts of interest.


Nicolas D, Elmouhayyar C, Nicolas S, et al. Subtherapeutic INR due to warfarin interaction with smokeless tobacco. J Thromb Haemost. 2020 August 13. [Epub ahead of print]