Why do International Normalized Ratio (INR) levels fluctuate?

Why INR Levels Fluctuate

INR levels fluctuate due to multiple interacting factors including dietary vitamin K intake changes, intercurrent illness, medication interactions, gastrointestinal disturbances, and physiologic stressors—even when patients believe they are maintaining consistent habits. 1, 2

Primary Causes of INR Fluctuation

Dietary Factors (Most Common)

• Inconsistent vitamin K intake is the leading cause of INR fluctuations, even when patients report dietary compliance 2, 3
• Subtle changes in vegetable preparation dramatically alter vitamin K content: cooked frozen spinach contains 1027.3 μg vitamin K per cup versus only 144.9 μg in raw spinach 2, 3
• Hidden vitamin K sources frequently go unrecognized: canola oil contains 141 μg/100g while corn oil has only 2.91 μg/100g; soybean oil in processed foods can contain up to 193 μg/100g 2
• Olestra-containing snack foods have extremely high vitamin K content at 347 μg/100g 2
• Decreased oral intake during illness reduces vitamin K consumption, leading to elevated INR even without increased warfarin absorption 4, 5

Illness and Physiologic Factors

• Intercurrent illness significantly destabilizes INR and requires more frequent monitoring during any period of sickness 1, 2, 6
• Fever enhances warfarin's anticoagulant effect, causing INR elevation 1, 2
• Diarrhea causes INR elevation through two mechanisms: malabsorption of vitamin K and decreased dietary intake during the illness 5
• Vomiting paradoxically can increase INR by eliminating dietary vitamin K intake while warfarin continues to be absorbed rapidly (within 90 minutes) on an empty stomach 4
• Hepatic dysfunction alters warfarin metabolism unpredictably 1, 2, 6
• Congestive heart failure influences warfarin metabolism and response 1, 2
• Thyroid disorders (both hyperthyroidism and hypothyroidism) significantly affect warfarin sensitivity and metabolism 1, 2, 6

Medication and Supplement Interactions

• Unreported over-the-counter medications or herbal supplements significantly affect warfarin metabolism even when patients deny taking new medications 1, 2, 6
• Antibiotics can dramatically alter INR, even if taken intermittently rather than newly prescribed 1, 2
• The FDA label lists extensive drug interactions through multiple mechanisms: enzyme induction, enzyme inhibition, reduced plasma protein binding, synergism, and competitive antagonism 6

Lifestyle and Behavioral Factors

• Physical or psychological stress can elevate INR through unknown mechanisms, possibly related to decreased warfarin metabolism during stress 7
• Weight loss increases risk of overanticoagulation 8
• Below-average physical activity is positively associated with overanticoagulation 8
• Recent decrease in alcohol intake (not habitual consumption level) increases risk of INR ≥6.0 8
• Vacation represents a risk factor for overanticoagulation, likely due to dietary and routine changes 8
• Poor medication compliance causes unpredictable fluctuations 1

Age-Related Factors

• Elderly patients experience more frequent INR fluctuations and require more intensive monitoring 1, 2
• Infants under 1 year are most susceptible to INR fluctuations due to low vitamin K in breast milk versus high concentrations in formula 1
• Older adults have increased pharmacodynamic response to warfarin, requiring lower maintenance doses (typically <5 mg daily) 1

Biological Variation in Stable Patients

• Even in steady-state patients on constant warfarin doses, biological variation exists with a coefficient of variation of 14.5% for warfarin, though this varies by drug type 1
• Short-acting acenocoumarol shows higher biological variation than long-acting phenprocoumon 1
• The type of thromboplastin reagent used for INR measurement affects observed biological variation 1

Critical Clinical Pitfalls

Common Errors in Assessment

• Failing to recognize subtle dietary changes that affect vitamin K intake, particularly changes in cooking oils or processed food consumption 2
• Overlooking intercurrent illness as a cause of INR instability, even minor illnesses without obvious symptoms 1, 2
• Inadequate monitoring frequency during periods of illness or medication changes contributes to dangerous INR instability 1, 2
• Not questioning patients about over-the-counter medications and supplements leads to missed drug interactions 1, 2, 6

High-Risk Situations Requiring Increased Monitoring

• Any intercurrent illness, regardless of severity 1, 2
• Gastrointestinal disturbances including diarrhea or vomiting lasting more than 1-2 days 4, 5
• Recent changes in physical activity level or stress 7, 8
• Weight changes or dietary modifications 8
• Initiation, discontinuation, or irregular use of any medication including antibiotics 1, 2, 6

Monitoring Strategy Based on Stability

Initial Phase

• Check INR daily until therapeutic range reached and sustained for 2 consecutive days 1
• Then check 2-3 times weekly for 1-2 weeks 1, 2
• Then weekly for 1 month 1, 2

Maintenance Phase

• For stable patients, INR testing can occur as infrequently as every 4 weeks 1
• Some guidelines support testing intervals up to 12 weeks in highly stable patients with consistent diet 2
• Resume frequent monitoring whenever dose adjustments are required or risk factors emerge 1

Special Populations

• Elderly patients require more frequent monitoring due to increased fluctuation risk 1, 2
• Patients with multiple comorbidities are at higher risk for unstable anticoagulation 1, 2
• Infants under 1 year require close monitoring due to dramatic variations in vitamin K intake with developmental stage 1

Management of Unexplained Fluctuations

When INR fluctuates without obvious cause, systematically evaluate:

• Unrecognized dietary changes: cooking oil switches, processed food consumption, restaurant meals, vitamin K-containing supplements 2, 3
• Occult illness: fever, subclinical infections, thyroid dysfunction, hepatic changes 1, 2, 6
• Medication adherence: missed doses, timing changes, pill splitting errors 1
• Recent stressors: physical or psychological stress, sleep deprivation, travel 7, 8
• Gastrointestinal changes: even brief episodes of diarrhea or decreased appetite 5
• Alcohol intake changes: recent increases or decreases rather than absolute consumption level 8