Defining QT/QTc Prolongation During ST-Elevation Myocardial Infarction and Reperfusion

Before novel drugs are approved, the US FDA mandates an adequate safety evaluation, including evaluation of measurable QT interval changes. Defining the safety profile of drugs for patients in disease states is a particular challenge, including patients suffering ST-elevation myocardial infarction (STEMI). Although STEMI therapies are effective in restoring perfusion at the epicardial level, ongoing cellular injury “downstream” can result in adverse arrhythmic events and remains an area of active research. To determine if therapies administered during STEMI create an increased safety risk, QT behavior from the disease itself needs to be quantified sufficiently to define boundary conditions evaluative of acute arrhythmic risk. We conducted a feasibility study to define the expected QT range during STEMI and reperfusion. Four cardiologists each measured QT and RR in a random sample of 44 subjects selected from a larger database of 24-hour, continuously recorded, 12lead electrocardiograms (ECG) previously analyzed for ST-segment deviation. Seven prespecified time points related to ST deviation were utilized. QTcF mean estimates were computed at each time point using repeated measures analysis, demonstrating the range, accuracy, and variation across different periods of ST deviation and the consistency across readers. More than 1,400 ECGs were measured with mean QTcF estimates by decreasing ST deviation from 416±5.2 to 431±5.2 msec, demonstrating a significant negative correlation between ST-segment deviation and QTcF (p=0.02). Intra-observer correlation among each pair of readers ranged from 0.87 to 0.94 and 0.90 to 0.99 for QT and RR, respectively. Study results could provide a global first-in-kind reference standard for patients in a disease state, complementing the existing standards utilized for thorough QT studies in normal volunteers. This STEMI ST-QT reference standard would further inform drug safety research and development paths in actual population of use STEMI studies. Boundaries around the mean QT for risk related to drugs given during STEMI would enable outliers to be characterized as safety concerns for proarrhythmic risk.