What causes an elevated International Normalized Ratio (INR)?

Causes of Elevated International Normalized Ratio (INR)

An elevated INR can be caused by numerous factors including medications (especially antibiotics, NSAIDs, and acetaminophen), alcohol consumption, liver disease, vitamin K deficiency, and genetic variations in warfarin metabolism. Understanding these causes is crucial for proper management and prevention of bleeding complications.

Medication-Related Causes

Anticoagulants

• Warfarin (primary cause of elevated INR in clinical practice)
• Overdosage of prescribed warfarin 1
• Drug interactions affecting warfarin metabolism

Antibiotics and Antifungals

• Fluoroquinolones (ciprofloxacin) - inhibit CYP1A2 2
• Miconazole (even topical/vaginal formulations) 3
• Macrolides (erythromycin) 1

Anti-inflammatory Drugs

• NSAIDs - increase bleeding risk through pharmacokinetic and pharmacodynamic interactions 3
• Acetaminophen - dose-dependent effect, with 10-fold increased risk of INR >6 at doses >9.1g/week 3, 4

Other Medications

• Amiodarone
• Statins (particularly fluvastatin) 3
• Fibrates (gemfibrozil, fenofibrate) 3
• Cancer treatments (gemcitabine, paclitaxel) 3
• Fish oil supplements (1-2g/day) 3, 5

Dietary and Supplement Factors

Herbal Supplements

• St. John's Wort - decreases INR through CYP induction 3
• Cranberry - multiple case reports of warfarin potentiation 3
• Ginkgo biloba, garlic, ginseng - can increase warfarin effects 1

Dietary Factors

• Decreased vitamin K intake 4
• Decreased oral intake overall 4
• Excessive alcohol consumption (acute) 3

Disease States and Physiological Factors

Liver Disease

• Cirrhosis - reduced production of clotting factors 3
• Hepatitis 1

Gastrointestinal Issues

• Diarrheal illness - 3.5 times increased risk of INR >6 4
• Malabsorption syndromes

Other Medical Conditions

• Advanced malignancy - 16.4 times increased risk of INR >6 4
• Congestive heart failure 1
• Hyperthyroidism 1
• Fever and acute illness 3

Special Considerations

Critical Illness

• Critically ill patients may show unusual hypersensitivity to warfarin due to:
  • Decreased dietary intake
  • Reduced gut bacterial production of vitamin K
  • Impaired intestinal absorption
  • Hepatic dysfunction
  • Increased consumption of clotting factors 6

Monitoring Considerations

• Labile INRs (poor time in therapeutic range) 3
• Laboratory errors or inconsistent testing methods 3

High-Risk Combinations

Patients are at particularly high risk for elevated INR when multiple risk factors are present. For example:

• Elderly patients starting antibiotics while on warfarin
• Patients with acute illness who continue their regular warfarin dose
• Patients taking acetaminophen at doses >2g/day while on warfarin 3

Clinical Implications

The risk of bleeding increases significantly when INR exceeds 4.5 and rises exponentially above 6.0 3. In patients with INR >9:

• Outpatients on warfarin: 11% bleeding risk
• Inpatients on warfarin: 35% bleeding risk
• Patients with elevated INR not on warfarin (e.g., liver disease): 67% bleeding risk 7

Prevention Strategies

1. More frequent INR monitoring when:

   • Starting new medications, especially antibiotics
   • Changing dietary habits
   • During acute illness
   • After changes in alcohol consumption

2. Patient education about:

   • Consistent vitamin K intake in diet
   • Avoiding high-dose acetaminophen (>2g/day)
   • Reporting all supplements and over-the-counter medications

3. Healthcare provider vigilance:

   • Recognizing high-risk medication combinations
   • Considering warfarin dose adjustments when adding interacting medications

Understanding these various causes of elevated INR is essential for safe anticoagulation management and prevention of potentially serious bleeding complications.