What can increase International Normalized Ratio (INR)?

Factors That Can Increase INR

Multiple medications, dietary factors, and clinical conditions can significantly increase International Normalized Ratio (INR), potentially leading to dangerous bleeding complications. 1, 2

Medications That Increase INR

NSAIDs and Antiplatelet Agents

• NSAIDs (including aspirin) potentiate warfarin's effect by:
  • Displacing warfarin from plasma proteins
  • Adding direct antiplatelet effects
  • Creating a 3-6 fold increased risk of GI bleeding when combined with warfarin 1
  • Higher risk with meloxicam specifically 3

Antibiotics

• Fluoroquinolones (ciprofloxacin)
• Macrolides (azithromycin, clarithromycin)
• Metronidazole
• Trimethoprim-sulfamethoxazole 2, 4

Other Common Medications

• Acetaminophen (dose-dependent effect):
  • Doses ≥9100 mg/week increase odds of INR >6.0 by 10-fold 5
  • Even at doses >2g/day can increase INR by an average of 0.7 by day 3 1
• Amiodarone (potent inhibitor of warfarin metabolism) 4
• Omeprazole and other proton pump inhibitors 1
• Statins 2

Clinical Conditions That Increase INR

Gastrointestinal Issues

• Diarrheal illness (increases risk of INR >6.0 by 3.5 times) 5
• Decreased oral intake (increases risk by 3.6 times) 5
• Malabsorption 4

Other Medical Conditions

• Advanced malignancy (increases risk of INR >6.0 by 16.4 times) 5
• Liver disease (impairs clotting factor synthesis) 2
• Hyperthyroidism 2
• Congestive heart failure 2
• Febrile illness/elevated temperature 2
• Active bleeding itself can paradoxically increase INR 6

Dietary and Lifestyle Factors

Vitamin K Intake

• Low vitamin K intake can lead to INR instability 1
• Fluctuations in vitamin K consumption (rather than consistent high intake) 1

Alcohol

• Acute alcohol ingestion inhibits hepatic enzymes and impairs warfarin clearance 1
• Interestingly, habitual moderate alcohol consumption (1 drink every other day to 2 drinks/day) may decrease risk of excessive anticoagulation 5

Other Factors

• Taking more warfarin than prescribed (increases risk by 8.1 times) 5
• Smoking (both cigarettes and shisha) 4

Herbal Supplements That Increase INR

• St. John's Wort (well-documented to enhance warfarin clearance) 1
• Hawthorn (associated with elevated INR >8 and serious bleeding events) 4
• Ginseng 4
• Garlic, ginkgo biloba (antiplatelet and fibrinolytic properties) 2
• Dong quai, danshen, and other botanicals containing natural coumarins 2

Risk Factors for Dangerous INR Elevation

Patients most vulnerable to dangerous INR increases include:

• Those on high maintenance doses of warfarin (>40 mg/week) 3
• Patients taking multiple medications that interact with warfarin 3
• Elderly patients (≥65 years) 2
• Patients with renal insufficiency 2, 7
• Patients with alcohol use disorder 7

Clinical Implications

When INR rises above 4.0, bleeding risk increases significantly. For INR values >9.0:

• Outpatients on warfarin: 11% experience bleeding
• Hospitalized patients on warfarin: 35% experience bleeding with 17% mortality
• Patients not on anticoagulants with INR >9: 67% experience bleeding with 74% mortality 7

Monitoring Recommendations

• More frequent INR monitoring when starting or stopping medications that interact with warfarin 2
• Close monitoring when acetaminophen is initiated, especially at doses >2g/day 1
• Maintain stable vitamin K intake rather than avoiding vitamin K-rich foods 1
• Monitor INR more frequently during acute illness, particularly with fever or diarrhea 2, 5

Understanding these factors can help prevent dangerous INR elevations and reduce the risk of serious bleeding complications in patients on warfarin therapy.