We thank Dr Kline and colleagues for their letter and the chance to respond to their comments. Regarding increased mortality associated with thrombolytic treatment in normotensive patients with acute symptomatic pulmonary embolism (PE), we suggest several possible explanations. Importantly, our study supported the concept that patients who receive thrombolytics have an increased risk of bleeding-related mortality . The normotensive subgroup matched analysis showed a trend toward increased 90-day bleeding-related mortality in patients who received versus those who did not receive thrombolytics (four of 217 patients, 1.48% [95% CI, 0.04–2.91] vs. one of 217 patients, 0.37% [95% CI, 0–1.09]; P = 0.37). Alternatively, though less likely, treatment with thrombolytics may have increased the risk of adverse outcomes by some other physiological or biological pathway. In addition, based on the study design, unmeasured differences in baseline co-morbidities between those treated and those not treated with thrombolytics may have led to the differences in mortality. Though the study adjusted for known important confounders, we did lack information on certain important risk factors such as size of PE or size of concomitant deep vein thrombosis (DVT) if present. For example, a previous study suggested that concomitant DVT increases the risk of death in patients with acute symptomatic PE . Moreover, we agree with Dr Kline and colleagues that in the absence of an inferior vein cava filter, fibrinolysis may increase the probability of detachment and embolization of residual and mobile DVT .
Notably, normotensive patients who received thrombolytics had a higher frequency of residual DVT in comparison to those who did not receive thrombolytics (80 of 121 patients, 66% [95% CI, 58–75] vs. 59 of 114 patients, 52% [95% CI; 43–61]; P = 0.03). The normotensive subgroup matched analysis showed a significantly increased 90-day PE-related mortality in patients who received thrombolytics in comparison to those who did not receive lytics (12 of 217 patients, 5.53% [95% CI, 2.49–8.57] vs. 0 of 217 patients, 0%). Of note, eight of the 12 patients who received thrombolytics and died had concomitant DVT at the time of PE diagnosis. After adjusting for residual DVT at the time of acute PE diagnosis, thrombolytic therapy did not show a statistically significant adverse effect on survival in the normotensive subgroup of patients, though it did show a concerning trend (odds ratio [OR] 1.9; 95% CI, 0.7–5.1; P = 0.2). Most likely, a combination of these potential explanations led to the increased mortality risk observed in patients receiving treatment with thrombolytics.
Two trials will provide further guidance regarding the use of thrombolytic therapy in normotensive patients with acute PE:  an ongoing large, multinational, randomized trial that aims to determine the efficacy and safety of early thrombolytic treatment in normotensive patients with right ventricular dysfunction, as detected on an echocardiogram or CT scan, and evidence of myocardial injury, as indicated by a positive troponin test (NCT00639743); and  a Randomized Trial of Tenecteplase to Treat Severe Submassive Pulmonary Embolism that will assess the efficacy and safety of tenecteplase in patients with severe submassive PE (NCT00680628). However, the results of our study do not support the use of thrombolytic agents in most normotensive patients with acute symptomatic PE.