Fibrinolysis for Acute Intermediate-Risk Pulmonary Embolism

Published - Written by Gelareh Homayounfar

For anyone with an acute pulmonary embolism (PE), your prompt diagnosis and treatment can save a life. In patients with high-risk PE and signs of hemodynamic compromise, fibrinolysis is an established, clear choice that can reduce pulmonary artery resistance, prevent PE recurrence, and reduce mortality. Although fibrinolytic therapy is known to carry risks of major bleeding and stroke, the benefits of treatment outweigh these risks in high-risk PE. However, what is the role of fibrinolysis in normotensive patients with intermediate-risk PE? Does early reperfusion improve outcomes, as compared to standard anticoagulation with heparin? Trials seeking to answer these questions thus far have been inadequately sized, and controversy remains.

In this week’s NEJM, Meyer et al. report the findings of the largest multicenter randomized double-blinded trial of fibrinolysis for the treatment of intermediate-risk PE. Their findings help guide physicians in weighing the risks and benefits of fibrinolysis in this patient population.

In the Pulmonary Embolism Thrombolysis trial (PEITHO), 1006 patients with acute intermediate-risk PE were randomized to receive a single dose of the fibrinolytic tenecteplase plus heparin or to receive placebo plus heparin. Intermediate-risk PE was defined by the absence of hemodynamic instability and the presence of right ventricular dysfunction and myocardial injury at presentation. The primary outcome measure was a composite of death or hemodynamic decompensation within seven days of randomization. Secondary outcomes included death within seven and thirty days, as well as major extracranial bleeding and stroke within seven days.

Treatment with tenecteplase reduced the risk of death or hemodynamic decompensation (from 6% in the placebo group to 3% in the tenecteplase group, p=0.02). There was no statistically significant difference in mortality between the groups at seven or thirty days.

However, with the addition of tenecteplase, there was an increase in major bleeding (from 1% to 6%, p<0.001) and an increase in stroke (from 0.2% to 2%, p=0.003). The majority of the strokes in the tenecteplase group were hemorrhagic. Of those who suffered a hemorrhagic stroke, 40% died within a month of randomization, and the survivors were left with mild-to-moderate disability.

To further define who might benefit from fibrinolysis, the authors noted that patients 75 years of age or younger treated with tenecteplase have lower odds of death or hemodynamic decompensation and lower odds of major extracranial bleeding as compared to patients over 75. While it seems that younger patients benefit more and face fewer risks with tenecteplase than older patients, these differences in outcomes were not statistically significant.

Overall, the findings of the trial suggest that, in patients with acute intermediate-risk PE, fibrinolysis prevents hemodynamic decompensation while increasing the risk of major bleeding and stroke. Unfortunately, the trial was underpowered to detect a difference in mortality, which occurred relatively infrequently in both treatment and placebo groups. Further research and even larger study populations are needed. Nevertheless, this trial is larger than all others seeking to address the same question over the past 40 years combined, and these results can allow for more informed decisions about the treatment of intermediate-risk PE.

In the accompanying editorial, Dr. C. Gregory Elliott, Professor of Medicine at the University of Utah School of Medicine, writes, “What course should physicians chart when confronted with a normotensive patient with acute pulmonary embolism? PEITHO data provide valuable insight, but no definitive answer. PEITHO strengthens the case for risk stratification and for careful monitoring of patients with intermediate mortality risk. PEITHO also shows the relative safety of withholding fibrinolysis unless hemodynamic decompensation occurs. Therefore, it may be that overall risk can be minimized with a strategy of initial anticoagulation and rescue fibrinolysis for hemodynamic decompensation.”

For physicians and patients grappling with treatment decisions after a PE, weighing the benefits and risks of therapy is essential. As NEJM Deputy Editor Dr. John Jarcho notes, “In patients with PE, fibrinolysis is potentially beneficial but also potentially dangerous. The editors believe that clinicians will find it extremely useful to have the data from PEITHO to guide management decisions.”

Gelareh Homayounfar is a fifth-year student at Harvard Medical School who has recently completed a month-long elective at the NEJM editorial offices.