What is the range of increase in International Normalized Ratio (INR) due to argatroban and bivalirudin?

INR Increase Range with Argatroban and Bivalirudin

Argatroban significantly increases INR by 1.5 to 3 times baseline values, with maximum values often reaching 4-5 or higher (up to 16), while bivalirudin causes a more modest increase in INR that typically returns to baseline within 1 hour after discontinuation. 1, 2

Argatroban Effects on INR

Argatroban has a profound and predictable effect on INR measurements due to its direct thrombin inhibition mechanism:

• At therapeutic doses (1-2 mcg/kg/min), argatroban produces a linear increase in INR 2, 3
• During argatroban monotherapy, median INR values range from 1.7-7.0 (5th-95th percentile) 4
• During argatroban/warfarin co-therapy, INR values commonly increase to:
  • Median of 5.3 (range 2.4-16) at maximum 4
  • Median of 4.0 (range 2.2-11.6) immediately before argatroban cessation 4

Transitioning to Warfarin

When transitioning from argatroban to warfarin, the INR must be carefully monitored:

• Argatroban should only be discontinued when INR is at least 4 during co-therapy 1
• After argatroban cessation, INR typically drops to a median of 2.3 (range 1.3-7.3) within 10-12 hours 4
• The relationship between INR on co-therapy and warfarin alone depends on:
  • Argatroban dose
  • Thromboplastin reagent used (influenced by International Sensitivity Index) 3

Bivalirudin Effects on INR

Bivalirudin has a more moderate effect on INR compared to argatroban:

• Bivalirudin prolongs prothrombin time and increases INR 1, 5
• Due to its short half-life (approximately 25 minutes with normal renal function), coagulation times return to baseline approximately 1 hour following cessation 5
• Bivalirudin's effect on INR is significantly less than argatroban's at equivalent therapeutic doses 6

Comparative Effects

When comparing the direct thrombin inhibitors:

• Argatroban has the greatest effect on INR among direct thrombin inhibitors 2, 6
• In comparative studies, argatroban showed the most significant INR elevation, while lepirudin had the least effect, with bivalirudin falling in between 6
• The magnitude of INR increase depends on:
  • Drug concentration
  • Specific reagent used for testing
  • Patient-specific factors 6

Clinical Implications

Despite elevated INRs during argatroban therapy:

• Major bleeding is rare even with INRs >4 during argatroban/warfarin co-therapy 7, 4
• In a study of 111 patients with INRs >4 during argatroban/warfarin co-therapy, only 1 (0.9%) experienced major bleeding 7
• The risk of thrombosis (4.5%) actually exceeded the risk of bleeding (0.9%) in patients with elevated INRs >4 7

Monitoring Recommendations

For accurate monitoring during argatroban or bivalirudin therapy:

• Use activated partial thromboplastin time (aPTT) as first-line monitoring, with target 1.5-3 times baseline (not exceeding 100 seconds) 1
• More specific tests with linear dose-response include Ecarin clotting time (ECT) and diluted thrombin time (dTT) 1, 8
• When transitioning to warfarin, consider stopping argatroban for several hours to measure true warfarin effect 2

Remember that traditional paradigms concerning elevated INRs and bleeding risk may not apply to patients on direct thrombin inhibitors, as the thrombotic risk often exceeds bleeding risk despite elevated INR values.