What are the causes of a supratherapeutic International Normalized Ratio (INR) with warfarin (coumarin)?

From the Guidelines

Supratherapeutic International Normalized Ratio (INR) with warfarin is primarily caused by factors that enhance warfarin's anticoagulant effect, such as medication interactions, dietary changes, acute illness, liver dysfunction, and genetic variations, which can increase the risk of hemorrhage. When considering the management of excessive anticoagulation, it is crucial to weigh the risk of bleeding against the risk of thromboembolism, as noted in the 2008 guidelines for the management of patients with valvular heart disease 1. Some key factors that contribute to a supratherapeutic INR include:

• Medication interactions, such as those with antibiotics, antifungals, amiodarone, and NSAIDs, which can inhibit warfarin metabolism or displace it from protein binding sites
• Dietary changes with decreased vitamin K intake, which can enhance warfarin's effect
• Acute illness, especially with fever, diarrhea, or poor oral intake, which can affect warfarin metabolism and increase INR
• Liver dysfunction, which impairs clotting factor synthesis and warfarin metabolism
• Advanced age, which increases sensitivity to warfarin
• Genetic variations in CYP2C9 and VKORC1 enzymes, which can make some patients more sensitive to warfarin
• Dosing errors, including accidental double-dosing or pharmacy dispensing mistakes, which are preventable causes
• Alcohol consumption, particularly binge drinking, which can temporarily increase INR by affecting liver metabolism As highlighted in the guidelines, patients with risk factors such as atrial fibrillation, previous thromboembolism, LV dysfunction, hypercoagulable conditions, older-generation thrombogenic valves, mechanical tricuspid valves, or more than 1 mechanical valve are at increased risk of thromboembolism and require careful management of their anticoagulation therapy 1. Withholding warfarin and monitoring INR levels is often the recommended approach for managing excessive anticoagulation, with low-dose intravenous vitamin K (1 mg) appearing safe in this situation, as noted in the guidelines 1.

From the FDA Drug Label

Numerous factors, alone or in combination, including changes in diet, medications, botanicals and genetic variations in the CYP2C9 and VKORC1 enzymes may influence the response of the patient to warfarin The following factors, alone or in combination, may be responsible for INCREASED PT/INR response: ENDOGENOUS FACTORS: blood dyscrasias — diarrhea hyperthyroidism elevated temperature poor nutritional state cancer hepatic disorders steatorrhea collagen vascular disease infectious hepatitis vitamin K deficiency congestive heart failure jaundice EXOGENOUS FACTORS: Potential drug interactions with warfarin sodium tablets are listed below by drug class and by specific drugs.

The causes of a supratherapeutic International Normalized Ratio (INR) with warfarin (coumarin) include:

• Endogenous factors:
  • Blood dyscrasias
  • Diarrhea
  • Hyperthyroidism
  • Elevated temperature
  • Poor nutritional state
  • Cancer
  • Hepatic disorders
  • Steatorrhea
  • Collagen vascular disease
  • Infectious hepatitis
  • Vitamin K deficiency
  • Congestive heart failure
  • Jaundice
• Exogenous factors:
  • Potential drug interactions with warfarin sodium tablets, including:
    • Other medications affecting blood elements which may modify hemostasis
    • Dietary deficiencies
    • Prolonged hot weather
    • Unreliable PT/INR determinations
    • Specific drugs, such as fluoroquinolones, testosterone derivatives, and others listed in the drug label 2
    • Botanicals, such as garlic, Ginkgo biloba, and others listed in the drug label 2

From the Research

Causes of Supratherapeutic International Normalized Ratio (INR) with Warfarin

The causes of a supratherapeutic International Normalized Ratio (INR) with warfarin (coumarin) can be attributed to several factors, including:

• Patient-specific factors such as age, with elderly patients being at a higher risk of supratherapeutic INR 3
• Duration of warfarin therapy, with longer durations increasing the risk of supratherapeutic INR 3, 4
• Use of complementary and alternative medicine (CAM), such as cayenne, ginger, willow bark, St. John's wort, and coenzyme Q(10), which can interact with warfarin and increase the risk of bleeding 5
• Renal failure, cancer, anaemia, respiratory infections, and chronic obstructive pulmonary disease, which can increase the risk of over-anticoagulation 4
• Polypharmacy, with the use of 10 or more medications increasing the risk of supratherapeutic INR 4
• Low socio-economic status and residency in rural areas, which can also increase the risk of over-anticoagulation 4
• Low factor IX levels, which can underestimate the level of anticoagulation and increase the risk of bleeding even with a therapeutic INR 6

Risk Factors for Supratherapeutic INR

Several risk factors have been identified as predictors of supratherapeutic INR, including:

• Warfarin indication, such as valvular atrial fibrillation and valve replacement 4
• HAS-BLED scores, which can predict the risk of supratherapeutic INR 3
• High target INR, which can increase the risk of bleeding 5
• Diarrhea, acetaminophen use, increased alcohol consumption, and increased age, which can also increase the risk of bleeding 5