When should warfarin (Coumadin) or acitrom (ximelagatran) be used in patients with a history of thromboembolic events or at high risk of thrombosis?

When to Use Warfarin or Acitrom

Warfarin should be used for venous thromboembolism, atrial fibrillation with stroke risk factors, mechanical heart valves, and post-myocardial infarction in high-risk patients, while acitrom (ximelagatran) should not be used at all as it was withdrawn from development due to hepatotoxicity. 1, 2

Critical Clarification About Acitrom/Ximelagatran

• Ximelagatran was an investigational oral direct thrombin inhibitor that showed promise in clinical trials but was never approved and was withdrawn from development due to liver toxicity concerns 1, 2
• The drug caused transient increases in liver enzymes (S-alanine aminotransferase) in approximately 4.3% of patients, with some developing jaundice within the first 6 months of therapy 1, 3
• Ximelagatran is not available for clinical use and should not be prescribed 1

Primary Indications for Warfarin

Venous Thromboembolism

• Prophylaxis and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) with target INR 2.0-3.0 4, 5
• Treatment duration: minimum 3 months for proximal DVT, 6 months for PE, and 6-12 months for idiopathic thrombosis 4, 5
• For patients with documented thrombophilia (Factor V Leiden, prothrombin 20210 mutation, antithrombin deficiency), 6-12 months treatment is recommended, with indefinite therapy suggested for idiopathic cases 5

Atrial Fibrillation

• Nonvalvular atrial fibrillation with high stroke risk (prior stroke/TIA, age >75 years, heart failure, hypertension, or diabetes) requires warfarin with target INR 2.0-3.0 4, 5
• Patients age 65-75 years with intermediate risk can receive either warfarin or aspirin 325 mg daily 5
• Atrial fibrillation with mitral stenosis requires anticoagulation regardless of rhythm 4, 5

Mechanical Heart Valves

• All mechanical prosthetic valves require warfarin - this is an absolute indication 5
• St. Jude Medical bileaflet valve in aortic position: target INR 2.5 (range 2.0-3.0) 5
• Tilting disk valves and bileaflet valves in mitral position: target INR 3.0 (range 2.5-3.5) 5
• Caged ball or caged disk valves: target INR 3.0 (range 2.5-3.5) plus aspirin 75-100 mg daily 5
• Bioprosthetic valves: warfarin with target INR 2.5 (range 2.0-3.0) for first 3 months only 4, 5

Post-Myocardial Infarction

• High-risk patients (large anterior MI, significant heart failure, intracardiac thrombus, or history of thromboembolism) should receive moderate-intensity warfarin (INR 2.0-3.0) plus low-dose aspirin ≤100 mg daily for 3 months 5
• In settings with meticulous INR monitoring, either high-intensity warfarin (INR 3.0-4.0) alone or moderate-intensity warfarin (INR 2.0-3.0) with aspirin can be continued up to 4 years 5

Congenital Heart Disease

• Adults with congenital heart disease and atrial fibrillation/flutter require warfarin with target INR 2.0-3.0 4, 6
• Patients with Fontan circulation (especially with atrial communication), systemic atrial enlargement, or systemic ventricular dysfunction should receive warfarin 4
• Those with prior thromboembolic events are at highest risk and warrant aggressive anticoagulation 4

Dosing Strategy for Warfarin

Initiation

• Start with 2-5 mg daily - loading doses are not recommended and increase bleeding risk 5, 7
• Lower initiation doses (2 mg) should be used for elderly/debilitated patients and those with CYP2C9 or VKORC1 genetic variations 4, 5
• When initiating for venous thromboembolism, give warfarin on day 1 with concurrent heparin or fondaparinux 8
• Continue heparin/fondaparinux for at least 5 days AND until INR ≥2.0 for two consecutive days 8

Maintenance

• Most patients require 2-10 mg daily to maintain therapeutic INR 5
• Adjust dose based on INR results, not arbitrary schedules 4, 7
• For subtherapeutic INR, adjust dose and recheck within 1 week 6

Managing Elevated INR

INR 3.0-5.0 Without Bleeding

• Omit one dose or reduce weekly dose by 10-15% 4, 9
• No vitamin K needed at this level 4, 9
• Identify and address cause (medication changes, dietary changes, illness) 4, 9

Emergency Reversal for Severe Bleeding

• Prothrombin complex concentrate (PCC) 50 IU/kg is first-line 4
• Add intravenous vitamin K 10 mg, but this may preclude re-warfarinization for several days 4
• Fresh frozen plasma is alternative only if PCC unavailable 4

Peri-Procedural Management

Risk Stratification

• Low thrombotic risk: No venous thromboembolism for >3 months, atrial fibrillation without prior stroke, bileaflet aortic valve 4
• High thrombotic risk: Recent thromboembolism (<3 months), mechanical mitral valve, older model cardiac valves 4

Management Protocol

• Low-risk patients: Stop warfarin 4 days before procedure, allow INR to normalize, resume postoperatively 4
• High-risk patients: Stop warfarin 4 days before procedure, start therapeutic-dose heparin or LMWH when INR falls below therapeutic range, stop heparin 5 hours (or LMWH 12-24 hours) before procedure, resume both postoperatively 4
• Bridging with LMWH is NOT routinely recommended for atrial fibrillation patients 4

Restarting After Gastrointestinal Bleeding

• Restart warfarin 7 days after lower GI bleeding in patients with low thrombotic risk 4
• Starting before 7 days results in twofold increase in rebleeding 4
• For high thrombotic risk patients (mechanical mitral valve, <3 months post-VTE), consider LMWH at 48 hours after hemostasis 4
• There is mortality benefit from restarting warfarin once bleeding has stopped 4

Special Considerations in Kawasaki Disease

• Giant coronary aneurysms (≥8 mm or Z-score ≥10) require warfarin (INR 2.0-3.0) plus low-dose aspirin 4
• Patients with recent coronary thrombosis may need "triple therapy" (aspirin + clopidogrel + warfarin/LMWH) temporarily, though bleeding risk is substantial 4
• LMWH may be preferred over warfarin in infants and when INR control is difficult 4

Common Pitfalls to Avoid

• Never use loading doses - they increase bleeding without faster therapeutic effect 5, 7
• Do not give vitamin K for INR 3.0-5.0 without bleeding - causes warfarin resistance 4, 9
• Avoid excessive dose reductions (>20%) in stroke patients - increases recurrent stroke risk 9
• Do not use warfarin with INR target >3.0-4.5 for arterial stroke prevention - dangerous bleeding rates 4
• Never combine NSAIDs with warfarin in elderly patients - markedly increases major bleeding risk 4
• Do not routinely bridge atrial fibrillation patients - increases bleeding without reducing thrombosis 4