What guides the decision to initiate warfarin (anticoagulant) in a patient with ischemic stroke?

Warfarin for Ischemic Stroke: Historical Context and Current Indications

Primary Indication: Cardioembolic Stroke with Atrial Fibrillation

Warfarin remains the anticoagulant of choice for ischemic stroke patients with valvular atrial fibrillation (moderate to severe mitral stenosis or mechanical heart valves), targeting an INR of 2.5 (range 2.0-3.0). 1

From 2000-2010, warfarin was the primary anticoagulant for secondary stroke prevention in patients with atrial fibrillation, as direct oral anticoagulants (DOACs) were not yet available or widely adopted. 1

Key Historical Recommendations (2000-2010 Era)

• For patients with ischemic stroke or TIA and persistent or paroxysmal AF, warfarin was recommended as Class I, Level A evidence with target INR 2.5 (range 2.0-3.0). 1

• Timing of initiation: Warfarin was typically started within 14 days of symptom onset in patients with minor strokes or TIAs, though delays were appropriate for large infarcts, hemorrhagic transformation, or uncontrolled hypertension. 1

• For patients unable to take warfarin, aspirin 325 mg daily was recommended as an alternative. 1

Specific Cardioembolic Indications

Mechanical Heart Valves

Warfarin is mandatory for mechanical prosthetic valves with target INR 3.0 (range 2.5-3.5), particularly for mitral position or older valve types. 1, 2

• For mechanical mitral valves with prior stroke, adding aspirin 75-100 mg daily to warfarin (INR target 3.0) is recommended. 1

• For bileaflet valves in aortic position, target INR 2.5 (range 2.0-3.0) is acceptable. 2

Acute Myocardial Infarction with LV Thrombus

For ischemic stroke caused by acute MI with documented LV thrombus, warfarin (INR 2.0-3.0) is reasonable for at least 3 months and up to 1 year. 1, 2

• Aspirin up to 162 mg daily should be used concurrently for coronary artery disease. 1

Rheumatic Mitral Valve Disease

For patients with rheumatic mitral valve disease (with or without AF), long-term warfarin with target INR 2.5 (range 2.0-3.0) is reasonable. 1

• Antiplatelet agents should not be routinely added to avoid additional bleeding risk. 1

Dosing and Monitoring Protocol

Initial Dosing

Start warfarin at 2-5 mg daily with lower doses (2 mg) for elderly, debilitated patients, or those with genetic variations in CYP2C9 and VKORC1. 2

• Large loading doses are not recommended as they increase hemorrhagic complications without faster protection. 2

Maintenance and Monitoring

Most patients are maintained on 2-10 mg daily with PT/INR checked daily until stable, then every 1-4 weeks. 2

• Target INR 2.5 (range 2.0-3.0) for most indications; INR >4.0 provides no additional benefit and increases bleeding risk. 2

• Time in therapeutic range should exceed 65% for optimal stroke prevention. 3

Bridging from Heparin

Overlap warfarin with full-dose heparin for 4-5 days until therapeutic INR is achieved before discontinuing heparin. 2

Critical Safety Considerations

INR and Stroke Risk

Subtherapeutic INR (<2.0) dramatically increases ischemic stroke risk in patients on warfarin presenting with acute neurological symptoms. 4

• In one study, mean INR was 1.7 in patients with ischemia versus 2.8 in stroke mimics (p<0.001). 4

• No patient with INR ≥3.6 experienced ischemia; INR ≥2.0 had 79% predictive value for non-ischemic etiology. 4

Hemorrhagic Complications

Risk of intracranial hemorrhage increases dramatically at INR >3.5, particularly in elderly patients and those with lobar hemorrhage patterns. 3, 1

• For warfarin-associated ICH, immediate reversal with vitamin K, prothrombin complex concentrate, or fresh frozen plasma is recommended. 1

• After ICH, resumption of warfarin should be delayed at least 4-10 weeks, with consideration of never restarting in lobar ICH due to amyloid angiopathy risk. 1

Underutilization Patterns (2000-2010)

Despite strong evidence, warfarin was significantly underused during this period, with only 54% of eligible patients receiving therapy. 5

• Advanced age was the strongest predictor of non-use: 75% of patients <75 years were anticoagulated versus only 33% of those >85 years. 5

• Women and elderly patients were consistently less likely to receive warfarin even without documented contraindications. 6, 7

• Patients with history-only AF (not ECG-documented) received warfarin only 49.4% of the time versus 78.8% with ECG documentation. 7

Comparison with Aspirin

The WARSS trial (2001) found no significant difference between warfarin (INR 1.4-2.8) and aspirin 325 mg for non-cardioembolic stroke, with primary endpoint rates of 17.8% versus 16.0% respectively (p=0.25). 8

• This established that for non-cardioembolic stroke, aspirin and warfarin are reasonable alternatives. 8

• However, for cardioembolic stroke with AF, warfarin remained superior to aspirin throughout the 2000-2010 period. 1

Common Pitfalls

• Failing to achieve therapeutic INR: Subtherapeutic anticoagulation provides minimal stroke protection while maintaining bleeding risk. 4

• Age-based discrimination: Elderly patients were systematically undertreated despite potentially greater absolute benefit. 5, 6

• Premature discontinuation after ICH: While caution is warranted, high-risk patients (mechanical valves, recent stroke) face significant thrombotic risk off anticoagulation. 1

• Inadequate monitoring frequency: INR should be checked at least monthly once stable, with additional checks when medications change. 2