Peripheral arterial disease: improvement of perioperative care

Abstract

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis and is characterized by impaired arterial blood flow to the lower extremities. This can result in intermittent claudication or chronic limb-threatening ischemia. Despite advances in preventive and therapeutic strategies, patients with PAD remain at substantially increased risk of atherothrombotic complications, including major adverse cardiovascular events (MACE) and major adverse limb events (MALE). These complications contribute to reduced quality of life, increased morbidity, and higher mortality. However, optimal perioperative care for patients with PAD remains insufficiently defined due to limited high-quality evidence. This thesis aims to identify opportunities to improve perioperative care in PAD across three key domains: patient engagement, postoperative care, and vascular treatment. Patient engagement is addressed in Chapter Two, which focuses on medication adherence to antithrombotic therapy. Antithrombotic treatment is a cornerstone of PAD management, yet its effectiveness depends on adequate adherence. A systematic review conducted according to PRISMA guidelines demonstrated that approximately one-third of patients with PAD show poor adherence to antithrombotic therapy, with adherence declining over time. These findings highlight the need for strategies to improve long-term patient engagement and adherence. Chapters Three through Seven focus on postoperative care, particularly antiplatelet therapy (APT) following endovascular revascularisation (EVR), since the current evidence is limited and outdated. Chapter Three presents a retrospective multicenter analysis showing no significant differences in efficacy or safety between three months of dual antiplatelet therapy (DAPT) and single antiplatelet therapy (SAPT) after (infra)popliteal EVR. These findings provided the rationale for the CLEAR-PATH trial, described in Chapter Four. CLEAR-PATH is a multicenter, double-blind, placebo-controlled randomized trial comparing SAPT with DAPT in patients with symptomatic PAD undergoing EVR. The trial evaluates both efficacy and safety outcomes over one year, with a composite primary endpoint including mortality, cardiovascular events, limb ischemia, reinterventions, and major amputation. To support future implementation of CLEAR-PATH results, Chapter Five presents an early health economic evaluation. Using a microsimulation model, DAPT was shown to be potentially cost-effective compared with SAPT if it achieves even a modest reduction in MACE and MALE. Cost-effectiveness was primarily driven by reductions in reinterventions and major amputations. Chapter Six evaluates the safety of APT after EVR using early data from the CLEAR-PATH cohort. Bleeding rates were low overall and varied depending on the classification system used, with most bleeding events occurring within the first 30 days and largely related to vascular procedures. Chapter Seven explores the distribution of CYP2C19 polymorphisms in the CLEAR-PATH population. Approximately one-quarter of patients carried a loss-of-function allele, potentially reducing clopidogrel effectiveness, underscoring the relevance of personalized antiplatelet therapy. The third pillar, vascular treatment, is addressed in Chapter Eight, which investigates the role of intravascular ultrasound (IVUS) after below-the-knee EVR. IVUS demonstrated good sensitivity for detecting post-procedural lesions associated with MALE, supporting further research into IVUS-guided interventions. Finally, Chapter Nine examines barriers to investigator-initiated research in the Netherlands, identifying structural inefficiencies in trial initiation. The chapter concludes with recommendations for national policy-level reforms to improve the research climate and facilitate high-quality clinical research.