A Critical Unmet Need in Peripheral Artery Disease
Chronic limb-threatening ischemia (CLTI) represents the most severe manifestation of peripheral artery disease (PAD), affecting tens of thousands of Europeans each year. Characterized by rest pain, non-healing ulcers and gangrene in the lower extremities, CLTI carries exceptionally high rates of major adverse limb events (MALE) and major adverse cardiovascular events (MACE). Despite advances in revascularization techniques—ranging from minimally invasive angioplasty to open bypass surgery—post-procedural thrombosis continues to undermine patient outcomes. Until now, clinicians have extrapolated antithrombotic regimens from broader PAD guidelines, but the specific vulnerabilities of CLTI patients have remained unaddressed in a dedicated statement.
The New ESC Expert Consensus: Scope and Rationale
In June 2025, the European Society of Cardiology (ESC) Working Groups on Aorta and Peripheral Vascular Diseases and Cardiovascular Pharmacotherapy jointly published the first comprehensive guidance specifically tailored to antithrombotic management after lower limb revascularization (LLR) in CLTI patients. The accompanying systematic review, appearing in the European Heart Journal, synthesizes evidence from 34 studies—three randomized controlled trials (RCTs) in CLTI cohorts, eight RCTs in broader PAD populations, and 22 observational analyses—to craft practical recommendations for dual antiplatelet therapy (DAPT) and dual pathway inhibition (DPI).
Defining CLTI and Its High-Risk Profile
CLTI arises when arterial occlusive disease reduces blood flow to a degree that even rest is painful and tissue perfusion is inadequate for wound healing. Patients typically present with:
- Ischemic rest pain, often described as a burning or aching discomfort in the foot or calf when supine.
- Non-healing ulcers or gangrene, particularly on the toes or plantar surface.
- Signs of advanced microvascular dysfunction, such as cool skin, hair loss on the legs, and diminished ankle-brachial index readings.
This extreme ischemia predisposes to:
- MALE: Repeat revascularization, major (above-ankle) amputation, or limb-related mortality.
- MACE: Myocardial infarction, stroke or cardiovascular death—reflecting the systemic atherosclerotic burden.
Current Practice Gaps: One-Size-Fits-All Antithrombotic Approaches
Existing ESC and American Heart Association guidelines recommend antiplatelet therapy—typically aspirin monotherapy or DAPT for up to one month—after endovascular or surgical revascularization in PAD. However, these recommendations are based largely on studies that underinclude CLTI subgroups and rarely differentiate clinical outcomes by ischemia severity. CLTI patients face:
- Elevated thrombotic risk: Prolonged stasis and endothelial injury in reopened arteries.
- Heightened bleeding risk: Fragile collateral vessels, frequent comorbidities (e.g., renal impairment, diabetes), and older age.
Without evidence specifically addressing this group, clinicians often default to regimens proven in intermittent claudication populations, potentially under- or overtreating CLTI patients.
Systematic Review Highlights: Limited RCT Data, Promising Observational Signals
The ESC statement draws on:
Three CLTI-Specific RCTs
- None demonstrated a clear winner between traditional DAPT (aspirin plus clopidogrel) and monotherapy in reducing MALE or MACE.
- All were underpowered for limb-related endpoints and had short follow-up (3–6 months).
Eight PAD-Wide RCTs (Including Some CLTI Cases)
- Meta-analyses suggest a trend toward reduced repeat revascularization and above-ankle amputation with DAPT compared to aspirin alone.
- Bleeding rates increased modestly but rarely required intervention.
Twenty-Two Observational Studies
- Consistently associated DAPT with lower MALE rates (hazard ratios 0.7–0.85) and improved limb-salvage compared to single-agent therapy.
- Showed signal for improved overall survival, likely through both local and systemic antithrombotic effects.
Dual Pathway Inhibition: The Strongest Evidence to Date
A landmark RCT of DPI—combining low-dose rivaroxaban (2.5 mg twice daily) with aspirin—demonstrated:
- 25% relative risk reduction in MALE at one year (number needed to treat = 24).
- 18% relative risk reduction in MACE.
- No significant increase in fatal or intracranial bleeding versus aspirin alone.
This study, with robust methodology and over 3,000 enrolled PAD patients (including a significant CLTI subset), provides high-quality evidence that DPI can both protect the limb and the heart in this high-risk group.
Expert Recommendations: Tailoring Antithrombotic Regimens for CLTI
Immediate Post-Procedure Phase
- Endovascular Revascularization (Angioplasty ± Stent):
• DAPT (aspirin + clopidogrel) for 1 – 3 months in patients at low bleeding risk.
• DPI (aspirin + low-dose rivaroxaban) may be considered in those at high thrombotic but acceptable bleeding risk. - Surgical Bypass:
• DAPT for 3 – 6 months, particularly if prosthetic grafts are used.
• DPI for patients with prior cardiovascular events or extensive tissue loss.
Long-Term Maintenance (Beyond 6 Months)
- Monotherapy with low-dose rivaroxaban in combination with aspirin can be continued for ≥12 months in those with ongoing tissue loss or recurrent ischemic symptoms.
- For patients with major bleeding history, deescalate to single-agent aspirin or clopidogrel after the initial high-risk period.
Bleeding Risk Mitigation
- Regular assessment using validated tools (e.g., HAS-BLED score adapted for PAD).
- Proton-pump inhibitor co-therapy to reduce gastrointestinal bleeding.
- Patient education on recognizing bleeding signs and adhering strictly to dosing regimens.
Future Research Priorities: Bridging the Evidence Gaps
Professor Christian Heiss of the University of Surrey, co-author of the ESC statement, highlights the urgent need for:
- Large-scale, dedicated RCTs comparing DPI versus DAPT specifically in CLTI patients post-LLR.
- Stratified analyses by revascularization modality, lesion complexity and comorbid conditions.
- Biomarker-driven studies to identify patients most likely to benefit from intensified antithrombotic regimens.
Heiss comments, “Our review underscores the paucity of trials focused on the very patients at greatest risk. While DPI offers the most compelling data, we must refine our strategies through targeted research to optimize benefit-risk balances in CLTI.”
Implementing Guidance in Clinical Practice
Vascular surgeons, interventional cardiologists and multidisciplinary PAD teams are encouraged to:
- Integrate these ESC recommendations into institutional protocols and patient pathways.
- Educate patients on the rationale, benefits and potential risks of combined antithrombotic therapies.
- Monitor outcomes through registries and quality-metric programs, contributing real-world data to inform future updates.
Conclusion: Toward Personalized Antithrombotic Care in CLTI
Chronic limb-threatening ischemia patients face a dual jeopardy: limb loss and cardiovascular catastrophe. The new European guidance marks a pivotal step in recognizing their unique therapeutic needs. By endorsing evidence-based use of DAPT and, especially, DPI after lower limb revascularization, the ESC statement empowers clinicians to reduce both MALE and MACE. As research efforts intensify, the vision of personalized, risk-adapted antithrombotic regimens draws closer—offering hope for improved survival, limb preservation and quality of life for this vulnerable population.
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