COMMENTARY

Administering Thrombolytics: Which PE Patients? When?

Andrew F. Shorr, MD, MPH

Disclosures

August 08, 2014

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This is Andy Shorr from Washington, DC, with a pulmonary and critical care literature update. I want to highlight an article by Chatterjee and colleagues [and a related editorial][1,2] in the June 18 issue of JAMA. These authors looked at the role of thrombolytics in patients with pulmonary embolism (PE).

PE remains a substantial challenge for those of us in pulmonary and critical care medicine. The question often arises: For whom should we consider thrombolytics? Certainly for patients who are already in shock, a thrombolytic is something we consider reaching for if we have not already reached for it. We never consider it for patients who are hemodynamically stable. But what do we do with the intermediate-risk group of patients who, for some reason, progress? We have always been led by the theory that progression can be predicted based on evidence of right ventricular (RV) dysfunction, which is a harbinger of eventual shock in this disease state.

These authors tried to bracket the uncertainty about the risk-benefit equation related to the use of thrombolytics in these intermediate-risk patients. For this meta-analysis, they reviewed a number of trials and eventually identified 16 that looked at this intermediate-risk group of patients and reported mortality issues as well as the risk for bleeding. Specifically, they defined intermediate-risk patients as patients who had evidence of RV dysfunction as part of the entry criteria for the trial.

The 16 studies went back as far as 1970 and included about 2000 patients overall -- about 1000 randomly assigned to thrombolytics and 1000 randomly assigned to placebo. The largest individual trial was the PEITHO trial,[3] which was published in 2014 in the New England Journal of Medicine and accounted for half of the patients overall in the meta-analysis.

The authors' observations were rather striking. First, in a pooled analysis across the 16 trials, the use of thrombolytics in this intermediate-risk group of patients was substantial. The mortality risk reduction associated with thrombolytics was about 50%. Overall, the number needed to treat to save 1 life was 59, a very useful number.

Similarly, when they looked at intracerebral hemorrhage, the number needed to harm -- that is, the number of patients who received thrombolytics and developed an intracerebral hemorrhage -- was 78. Thus, this brackets very nicely the order of magnitude of the trade-off between bleeding and death when using thrombolytics for these patients with PE. It clearly shows that thrombolytics are not benign.

The Subgroup Analyses

An important subgroup analysis looked at patients who were over age 65 as a surrogate marker of high risk for bleeding. They saw substantial bleeding in that population that was very different compared with the risk for bleeding in patients under 65 years. The benefit in terms of mortality did not vary much based on age above or below 65 years.

Similarly, they performed a subgroup analysis of the trials that included more consistent and objective assessments of RV dysfunction, such as cardiac biomarkers, echocardiography, or CT scanning to assess the size of the right ventricle. In that subpopulation of 8 randomized controlled trials, the treatment effect was fairly consistent. Overall, these more recent studies, which used more modern assessments of RV dysfunction, provided a clearer signal regarding the benefit of thrombolytics on mortality. Even in that subpopulation, however, the signal of harm and the risk for intracerebral hemorrhage was also clear. Whether we look at the entire population of studies or at the more narrow population of more recent, better defined studies, we cannot ignore the trade-off.

This meta-analysis is important because it summarizes the literature very clearly and puts into perspective the trade-offs that we in pulmonary and critical care have to weigh when we think about patients. It does not tell us who is clearly a good candidate and who is clearly not a good candidate. It certainly suggests that we should search for RV dysfunction when we meet the patient with PE who is not responding to their therapy. But when deciding whether to use thrombolytics, we have to weigh the mortality benefit against the risk for bleeding. For anyone who has any increased risk for bleeding because of age, recent surgery, or any other concerns, I will be very cautious. I certainly will have a conversation with the patient or the patient's family or surrogate decision-makers about the trade-offs with the use of thrombolytics.

Again, in the June 18 issue of JAMA, take a look at this very important meta-analysis about thrombolytics and PE by Chatterjee and colleagues. Thank you very much.

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