What is International Normalized Ratio (INR)?

What is INR (International Normalized Ratio)?

The INR is a standardized mathematical conversion of the prothrombin time (PT) test, specifically designed and validated exclusively for monitoring vitamin K antagonist (warfarin) therapy—it was never intended as a general predictor of bleeding risk or coagulopathy in other clinical contexts. 1, 2

Definition and Calculation

The INR standardizes PT results across different laboratories and thromboplastin reagents using the following formula 1:

INR = (patient PT/mean normal PT)^ISI

Where:

• Patient PT = the prothrombin time measured in the patient's plasma 1
• Mean normal PT = geometric mean from 20 healthy individuals (not interchangeable with laboratory control PT) 1
• ISI = International Sensitivity Index, reflecting the thromboplastin reagent's responsiveness to vitamin K-dependent clotting factor reduction 1

The more responsive the thromboplastin reagent, the lower the ISI value (modern recombinant preparations have ISI values of 0.9-1.0) 1

Historical Context and Purpose

The INR system was introduced by the World Health Organization in 1983 to address dangerous variability in PT reporting that led to excessive and erratic anticoagulation in North America 1, 3. Before INR standardization, thromboplastin responsiveness varied dramatically (ISI values ranged from 1.4 to 2.8 in 1992), causing clinically important differences in warfarin dosing between countries and laboratories 1. The INR calibration model was derived exclusively from plasma samples of patients on stable warfarin therapy for at least 6 weeks, specifically excluding patients with bleeding tendencies, acute illness, liver disease, or other anticoagulants 1. Implementation increased from 21% to 97% of U.S. laboratories between 1991 and 1997 1

Critical Limitations and Common Pitfalls

The INR is less reliable early in warfarin therapy (before 6 weeks of stable dosing), though it remains more reliable than unconverted PT ratios even in this context 1. The American Heart Association and American College of Cardiology emphasize that despite its success in warfarin monitoring, the INR is now widely misapplied in routine clinical practice where it was never validated 1, 2.

Specific Clinical Contexts Where INR Should NOT Be Used:

• Bleeding risk assessment in non-warfarin patients: A systematic review found weak or no association between pre-procedural INR and bleeding in 78 of 79 studies, with sensitivity under 50% 2
• Liver disease coagulopathy: The INR is a poor predictor of bleeding risk despite its use in MELD scoring 2
• General coagulopathy screening: The test was never designed or validated for this purpose 1, 2
• Guiding plasma transfusion for mildly elevated INR (<2.0): Randomized trials show no reduction in bleeding when prophylactic plasma corrects INR values, and this practice lacks biological plausibility 2

Therapeutic Ranges for Warfarin Monitoring

When used appropriately for warfarin therapy, specific INR targets apply 3:

• Atrial fibrillation, venous thromboembolism, bioprosthetic valves: INR 2.0-3.0 (target 2.5) 3
• Mechanical heart valves (tilting disk, bileaflet in mitral position): INR 2.5-3.5 (target 3.0) 3
• St. Jude bileaflet valve in aortic position: INR 2.0-3.0 (target 2.5) 3
• INR >4.0 provides no additional benefit and increases bleeding risk 3

Monitoring Recommendations

For patients on warfarin, the FDA label specifies 3:

• Check PT/INR daily after initial dose until results stabilize in therapeutic range 3
• Once stable: Check every 1-4 weeks based on patient reliability and response 3
• Additional testing required when switching warfarin products or when other medications are initiated, discontinued, or taken irregularly 3
• Quality improvement: Anticoagulation clinics, self-testing, and computer-assisted management achieve 56-93% time in therapeutic range versus 33-64% in usual care 3

Technical Factors Affecting Accuracy

Several variables can compromise INR reliability 1:

• Citrate concentration: Higher concentrations (3.8%) yield higher INR values; underfilled tubes spuriously prolong PT 1
• Automated clot detectors: Can influence accuracy since INR is based on manual clot detection methods 1
• Lupus anticoagulants: Usually cause only slight PT prolongation, making INR monitoring uncertain in these patients 1
• ISI calibration errors: Manufacturer-provided ISI values are not invariably correct and local calibration may be needed 1