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Introduction: When the diagnosis of stroke is not completely certain, the benefits of rapid treatment with tPA are widely thought to outweigh the minimal risk of complication associated with thrombolysis of stroke mimics (SM). However, acceptable rates of hospital-level SM treatment have not been well established.Hypothesis: A cost-reimbursement (CR) analysis will identify a threshold of SM treatment with tPA above which the CR ratio is unacceptably high.Methods: We used stochastic modeling with probability distributions to mathematically examine various tPA treatment scenarios. The main hospital-level variables used were: (1) case-mix or rate of SM and (2) percent of all eligible cases treated with tPA. For each case, a hospital cost was assigned based on whether or not tPA was given, onset to treatment time (OTT), length of stay based on severity distribution and expected clinical outcome, and whether the case was a true stroke or SM. The costs associated with index hospitalization, treatment complications, and non-treatment of true stroke patients were estimated from published rates and data. Reimbursement for stroke with and without thrombolysis as well as treated SM were estimated from Medicare rates. We calculated a CR ratio and identified thresholds of hospital SM treatment rates above which CR ratios are >1.0 and >1.5.Results: Assuming that 75% of true eligible stroke patients are treated with tPA with median OTT of 120 minutes, we found an increase in CR ratio from 0.97 (0% SM rate) to 1.61 (100% SM rate). The SM rate of <10% was associated with CR of <1; the SM rate of >10% was associated with CR ratio >1.0 while SM rate >80% was required for a CR ratio >1.5. For each OTT interval (0-90 minutes, 90-180 minutes, 180-270 minutes), the CR ratio was on average 0.1 lower for a hospital with a 5% SM rate compared to a hospital with a 20% SM rate.Conclusions: In a simulation study, we found the CR ratio increased with increasing OTT and hospital SM treatment rate. As other researchers have suggested, hospitals may need to carefully monitor rates of SM patients treated with tPA and establish performance metrics to lower costs and reduce patient harm.