Major Adverse Cardiovascular Events and Mortality in Peripheral Artery Disease

Abstract

Peripheral artery disease (PAD) is the third most prevalent atherosclerotic disorder after coronary artery and cerebrovascular disease. Irrespective of how it manifests clinically, PAD is consistently linked with excessive rates of major adverse cardiovascular events (MACE) and mortality. This thesis examines many contributing factors and provides new insights into the management of patients with this condition. The introductory chapter considers the evidence for treating individual risk factors and the prescription of guideline-recommended medications in PAD. Many prior observational studies have found an under-prescription of therapies and suboptimal risk factor control in PAD, compared with coronary artery disease-only. It is known from diabetes studies that control of multiple risk factors can have a complex interaction, whereby the sum of the parts does not equal the whole. Multiple risk factor control is recommended universally, although little is known regarding the effect on PAD. Chapter 2 is a post hoc analysis of the ACCELERATE trial that included 12,092 patients with atherosclerotic cardiovascular disease. The rates of MACE are compared between PAD and coronary artery disease-only patients in the setting of individual and combined risk factor control. It is believed that PAD patients have high-risk coronary artery plaque that is more critical, diffuse and prone to thrombotic occlusion, but this has not been proven. Chapter 3 pools data from three clinical trials of lipid-lowering therapy, whereby, coronary artery disease was monitored using serial intravascular ultrasound imaging. Plaque burden and disease progression are compared between PAD and non-PAD patients, according to risk factor control. Individual PAD studies indicate that there are gender discrepancies in symptoms, functional status, and treatment utilisation. It remains uncertain whether this translates to different long-term outcomes. Chapter 4 is a systematic review and meta-analysis to assess gender differences in MACE and mortality. Chapter 5 evaluates the gender differences in outcomes for the PAD patients from ACCELERATE. Lower extremity revascularisation, either through endovascular or surgical means, can be complicated by major adverse limb events and mortality. Persisting debate exists as to which approach has greater long-term durability and outcomes. Chapter 6 compares the long-term outcomes of endovascular and surgical revascularisation in unmatched and propensity-score matched groups. Dysfunctional high-density lipoprotein cholesterol (HDL-C) is an emerging cardiovascular risk factor that could be a therapeutic target. Previously, qualitative abnormalities of HDL-C were observed in Indigenous Australians, when they were compared to non-Indigenous Australians. Chapter 7 tests for an association between dysfunctional HDL and early PAD in Indigenous Australians. Significant health disparities are affecting young Indigenous Australians. The estimation of cardiovascular risk is especially problematic in this population. Chapter 8 reviews a young Indigenous group that was screened for PAD. Their risk of cardiovascular disease is estimated using traditional Framingham-based algorithms. Questions remain whether all patients with PAD should be treated with the most intensive therapies, or if there is a role for a risk-stratified approach akin to atrial fibrillation management. Chapter 9 evaluates several CHADS2-based scores for predicting MACE in PAD following hospital presentations, compared with clinical manifestations of other vascular territories.