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Lead aVR ST-segment deviation has been associated with increased mortality in ST-elevation myocardial infarction patients treated with fibrinolysis. However, its prognostic value in a contemporaneous population undergoing primary percutaneous coronary intervention is unknown.A core laboratory examined the 12-lead baseline electrocardiogram in 5,683 patients presenting within 6 hours of symptom onset in the APEX-AMI trial, and readers were blinded to study treatment and clinical outcomes. aVR ST-deviation was significantly associated with 90-day death when compared with patients with no aVR ST-deviation (aVR ST-depression [ST-D] 5%, aVR ST-elevation [ST-E] 10.2%, no ST-deviation [N] aVR 3.8%, P < .001). After multivariable adjustment, aVR ST-E was strongly associated with 90-day death in inferior myocardial infarction (MI) (adjusted hazard ratio [HR] 5.87, 95% CI 2.09-16.5), whereas aVR ST-D was associated with excess mortality in noninferior MI (1.53, 1.06-2.22; P [interaction] < .001). aVR ST-E was also significantly associated with the presence of left main coronary (N aVR 1.8%, aVR ST-E 7.7%, P ≤ .001) and multivessel coronary disease (N aVR 41.3%, aVR ST-E 53.3%, P ≤ .001).Lead aVR ST-deviation is common, occurring in one-third of all ST-elevation myocardial infarction patients and independently associated with increased 90-day death. Myocardial infarction location modulates the prognostic significance of aVR ST-deviation such that lead aVR ST-E in inferior MI and ST-D in noninferior MI represent 2 high-risk groups. There was also more frequent advanced coronary disease in patients with aVR ST-E.