Relationship between site of initial symptoms and subsequent progression of disease in a prospective study of atherosclerosis progression in patients receiving long-term treatment for symptomatic peripheral arterial disease

Purpose: There have been few studies of the natural history of peripheral arterial disease (PAD), and none have used serial noninvasive laboratory examinations for the objective quantification of disease progression. The relationship between the site of initial symptoms of PAD (lower-extremity disease [LED] vs cerebrovascular disease [CVD]) and the site of subsequent symptomatic progression (LED vs CVD vs coronary heart disease [CHD]) has not been examined. Methods: This is a long-term, blinded prospective clinical research study of die relationship of PAD progression to multiple clinical, laboratory, and noninvasive vascular laboratory parameters. Patients with symptomatic LED, CVD, or both underwent comprehensive risk-factor assessment and were seen every 6 months for follow-up examinations. In addition to history and physical examination, all subjects underwent serial noninvasive lower-extremity and carotid artery testing. The relationship between the initial symptomatic site(s) and subsequent progression was examined by means of multivariate proportional hazards analysis, which was adjusted for age, diabetes mellitus, hypertension, smoking, cholesterol, homocysteine level, lowest initial ankle/brachial index (ABI), worst carotid stenosis, ABI progression, and carotid stenosis progression, because each of these factors was significantly associated with one or more aspects of progression. Results: There were 397 study subjects (mean age, 66 years; 38% women) with a mean follow-up period of 48.5 months. LED was initially present in 88% of subjects and CVD in 37% of subjects (both were present in 25% of subjects). There were 78 deaths, 47 (60%) of which were caused by cardiovascular disease (18% mortality rate after 5 years by means of life table). Progression of disease as documented by means of vascular laboratory findings occurred in 90% of subjects by means of life table after 5 years (ABI progression, 31%; carotid stenosis progression, 40%). Symptomatic clinical progression of disease occurred in 52% of subjects by means of life table after 5 years (LED progression, 22%; CVD progression, 23%; CHD progression, 31%). By means of multivariate analysis, no significant relationship was found between the site of initial symptoms of PAD and the site(s) of subsequent symptomatic clinical progression (LED vs CVD vs CHD; P = not significant for all hazard ratios). Conclusion: Patients with symptomatic PAD experience symptoms of ongoing LED, CVD, and CHD with a frequency that is not influenced by the site(s) of their original symptoms. The hypothesis that lesions and resulting symptoms of systemic atherosclerosis occur at various anatomic sites as a matter of random chance should be tested with other studies.