Is Sulodexide (a glycosaminoglycan) effective in treating Peripheral Arterial Occlusive Disease (PAOD)?

Sulodexide Efficacy in Peripheral Arterial Occlusive Disease (PAOD)

Sulodexide is effective in improving pain-free walking distance in patients with peripheral arterial occlusive disease, but it is not included in current major clinical guidelines as a recommended therapy for PAOD. 1

Current Guideline Recommendations for PAOD Management

First-Line Therapies (Class I Recommendations)

• Supervised exercise training is recommended as the initial treatment for patients with intermittent claudication, performed for 30-45 minutes at least 3 times weekly for a minimum of 12 weeks 2, 3
• Cilostazol (100 mg orally twice daily) is indicated as first-line pharmacotherapy to improve symptoms and increase walking distance in patients with PAOD and intermittent claudication, showing 40-60% improvement in maximal walking distance after 12-24 weeks (contraindicated in heart failure) 2, 3
• Antiplatelet therapy with either aspirin (75-325 mg daily) or clopidogrel (75 mg daily) is recommended to reduce cardiovascular events in symptomatic PAOD patients 2, 3

Second-Line Therapies (Class IIb Recommendations)

• Pentoxifylline (400 mg three times daily) may be considered as a second-line alternative to cilostazol, though its clinical effectiveness is marginal and not well established 2
• Other therapies with limited evidence (Class IIb) include L-arginine, propionyl-L-carnitine, and ginkgo biloba 2

Not Recommended Therapies (Class III)

• Oral vasodilator prostaglandins (beraprost, iloprost) 2
• Vitamin E supplementation 2
• Chelation therapy 2

Evidence for Sulodexide in PAOD

Despite not being included in major guidelines, recent research shows promising results for sulodexide:

• A 2020 systematic review and meta-analysis demonstrated that sulodexide significantly improved initial claudication distance by +68.9 meters (95% CI ±11.9 m) compared to placebo (p<0.001) 1
• A randomized, double-blind, multicentre study with 286 PAOD patients showed:
  • 23.8% of sulodexide-treated patients achieved doubling of pain-free walking distance versus 9.1% in the placebo group (p=0.001) 4
  • Pain-free walking distance increased by 83.2±8.6 m (+64.7% from baseline) with sulodexide versus 36.7±6.2 m (+29.9%) with placebo (p=0.001) 4
  • Maximum walking distance increased by 142.3±15.8 m (+76.0%) with sulodexide versus 54.5±8.4 m (+27.9%) with placebo (p<0.001) 4

Mechanism of Action and Additional Benefits

• Sulodexide is a glycosaminoglycan containing heparan sulfate and dermatan sulfate with antithrombotic properties 5
• Beyond improving walking distance, sulodexide:
  • Reduces plasma fibrinogen levels (overall -13%, p<0.0001) 6
  • Decreases triglycerides (overall -28%, p=0.0015) and increases HDL cholesterol (24.4%, p=0.0007) 6
  • Reduces plasma and blood viscosity 5
  • Shows efficacy in both diabetic and non-diabetic PAOD patients 4, 6

Clinical Application and Considerations

When considering sulodexide for PAOD:

• Sulodexide appears to be well-tolerated with minimal side effects, primarily transient gastrointestinal intolerance (nausea, dyspepsia) 5
• It may be particularly suitable for elderly patients due to good tolerability and ease of management 5
• The treatment has a favorable cost-benefit ratio considering the high costs associated with PAOD care 6

Treatment Algorithm for PAOD

1. First-line approach:

   • Supervised exercise program (30-45 minutes, 3+ times weekly for 12+ weeks) 2, 3
   • Cilostazol 100 mg twice daily (if no heart failure) 2
   • Antiplatelet therapy (aspirin 75-325 mg daily or clopidogrel 75 mg daily) 2

2. If inadequate response to first-line therapy:

   • Consider pentoxifylline 400 mg three times daily as second-line pharmacotherapy 2
   • Consider sulodexide based on recent evidence showing significant improvement in walking distance 1, 4
   • Evaluate for endovascular or surgical revascularization if medical therapy fails 2

3. For patients with specific contraindications:

   • If cilostazol is contraindicated (e.g., heart failure), sulodexide may be a reasonable alternative based on efficacy data 4, 6
   • For patients with dyslipidemia and PAOD, sulodexide offers additional benefits through improvement in lipid profile 6, 5

Conclusion

While sulodexide shows promising efficacy in improving walking distance and quality of life in PAOD patients, it has not yet been incorporated into major clinical guidelines. Current guidelines still recommend supervised exercise, cilostazol, and antiplatelet therapy as first-line treatments. However, the positive results from recent studies suggest sulodexide could be considered as an alternative therapy, particularly in patients who cannot tolerate or have contraindications to standard treatments.