Introduction: Peripheral artery disease (PAD) and diabetes mellitus (DM) are significant risk factors for atherothrombosis. Platelets mediate atherothrombosis and are therapeutic targets in PAD and DM. We investigated the relationships between PAD, DM, platelet activity, and cardiovascular risk. Methods: The Platelet Activity and Cardiovascular Events (PACE) study enrolled 289 PAD patients undergoing lower extremity revascularization (LER). Prior to LER, platelet activity was measured via light transmission aggregometry in response to submaximal ADP, collagen (coll), serotonin (ser), epinephrine (epi), and arachidonic acid (AA). Patients were followed for a median of 18 months for the composite of major adverse cardiac or limb events (MACLE; MI, stroke, death, major amputation, and limb revascularization). Results: There were 93 (32%) patients with insulin-dependent DM (IDDM), 60 (21%) with non-insulin dependent DM (NIDDM), and 136 (47%) without-DM. Patients with IDDM were more likely than those without DM to be female, non-white, and Hispanic, and to have history of coronary artery disease, heart failure, and critical limb ischemia (P<0.05 for all). Use of antiplatelet therapy was similar across groups. Maximum platelet aggregation was highest in the IDDM group in response to multiple agonists ( Figure) . MACLE occurred in 51%, 57%, and 69% of the without-DM, NIDDM, and IDDM groups, respectively (P=0.02). Compared to subjects without DM, only those with IDDM were at increased risk of MACLE after multivariable adjustment (aHR 1.6 [95% CI 1.02-2.4]; P=0.04) ( Figure ). After further adjustment for platelet aggregation, the association between IDDM and MACLE was no longer statistically significant (1.4 [0.9-2.3]; P=0.17); platelet aggregation mediated 24% of the excess MACLE risk in individuals with IDDM. Conclusions: In patients with PAD, IDDM is associated with increased platelet activity that mediates, in part, the risk for incident cardiac and limb events.
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