What are the guidelines for anticoagulation therapy in patients with a cryptogenic (of unknown origin) stroke?

Anticoagulation Guidelines for Cryptogenic Stroke

For patients with cryptogenic stroke, anticoagulation therapy is recommended over antiplatelet therapy when PFO closure is not performed, as it may decrease ischemic stroke recurrence by approximately 7.1% over five years compared to antiplatelet therapy alone. 1

Understanding Cryptogenic Stroke and Treatment Options

Cryptogenic stroke refers to ischemic stroke of unknown origin despite thorough diagnostic evaluation. When evaluating treatment options for these patients, three main strategies exist:

1. PFO closure plus antiplatelet therapy
2. Anticoagulation therapy
3. Antiplatelet therapy alone

Patient Evaluation

Before determining the optimal anticoagulation strategy:

• Confirm diagnosis of non-lacunar embolic ischemic stroke by imaging
• Rule out alternative causes through:
  • Prolonged rhythm monitoring to exclude atrial fibrillation
  • Transoesophageal echocardiography to rule out aortic atherothrombosis or left atrial clot
  • Carotid ultrasonography, CT, or MRI to rule out cerebrovascular disease

Treatment Algorithm for Cryptogenic Stroke

First-Line Approach: PFO Closure Assessment

1. For patients ≤60 years with confirmed PFO:

   • PFO closure plus long-term antiplatelet therapy is strongly recommended if:
     • Stroke is confirmed as non-lacunar embolic ischemic stroke
     • PFO is determined to be the most likely cause after thorough evaluation
     • Patient has high-risk PFO features 2
   • PFO closure reduces absolute risk of stroke by 8.7% at five years compared to antiplatelet therapy alone 1

2. When PFO closure is not possible or contraindicated:

   • Proceed to anticoagulation vs. antiplatelet decision

Second-Line Approach: Anticoagulation vs. Antiplatelet Therapy

When PFO closure is not performed, the choice between anticoagulation and antiplatelet therapy must be made:

Anticoagulation Therapy

• Recommended when:

  • Patient has a high RoPE score (>8) with clinical risk factors 2
  • Evidence of hypercoagulable state or venous thrombosis exists 2
  • Patient has had recurrent cerebral ischemic events despite antiplatelet therapy 2

• Benefits:

  • May decrease ischemic stroke recurrence by 7.1% absolute risk reduction over 5 years compared to antiplatelet therapy (low quality evidence) 1
  • Oral anticoagulants are associated with a 39% relative risk reduction in recurrent ischemic stroke compared to antiplatelet therapy 3

• Risks:

  • Probably increases major bleeding by 1.2% absolute risk increase over 5 years (moderate quality evidence) 1
  • Non-significant increased risk of major bleeding (RR 1.61,95% CI 0.76 to 3.40) 3

Antiplatelet Therapy

• Recommended when:
  • Patient is >60 years (PFO likely incidental rather than causal) 2
  • Patient has low RoPE score (suggesting PFO may be incidental) 2
  • Patient has contraindications to anticoagulation
  • Patient strongly prefers to avoid bleeding risks associated with anticoagulation

Specific Anticoagulation Recommendations

Warfarin Dosing

• Target INR of 2.0-3.0 is recommended 4
• Initial dosing should be 2-5 mg daily with adjustments based on INR response 4
• Lower initial doses should be considered for elderly, debilitated patients, or those with genetic variations in CYP2C9 and VKORC1 enzymes 4

Duration of Therapy

• For patients with cryptogenic stroke of unknown etiology, a moderate dose regimen (INR 2.0-3.0) is recommended 4
• Duration should be individualized based on risk factors and recurrence
• An INR >4.0 provides no additional therapeutic benefit and increases bleeding risk 4

Common Pitfalls and Considerations

1. Overtreatment in older patients:

   • Recommending PFO closure in patients >60 years despite lack of proven benefit 2
   • In older patients, PFO is more likely incidental rather than causal for stroke events

2. Neglecting other stroke etiologies:

   • Failure to perform comprehensive evaluation for other causes of stroke 2
   • Not considering hypercoagulable states that would benefit from anticoagulation

3. Monitoring challenges:

   • Warfarin requires regular INR monitoring and dose adjustments
   • DOACs may be preferred in patients with difficulty maintaining stable INRs, but have less evidence in cryptogenic stroke

4. Bleeding risk assessment:

   • Major bleeding risk is approximately 1.16 per 100 patient-years with anticoagulation vs. 0.68 with antiplatelet therapy 5
   • Individual bleeding risk should be assessed before initiating anticoagulation

Evidence Quality and Limitations

The recommendation for anticoagulation over antiplatelet therapy is based on moderate to low quality evidence. The BMJ guideline notes that anticoagulation may decrease ischemic stroke but probably increases major bleeding 1. More recent meta-analyses suggest that oral anticoagulants are associated with a significant reduction in recurrent stroke risk compared to antiplatelet therapy 3.

For patients with high RoPE scores (suggesting PFO is likely causative), anticoagulation may be particularly beneficial, with one study showing a significant reduction in recurrent stroke (OR = 0.22,95% CI 0.06-0.8) 6.