SAN FRANCISCO, California — The addition of the thrombolytic agent tenecteplase to standard treatment with heparin in patients with intermediate-risk pulmonary embolism (PE) significantly reduced the primary end point of death or hemodynamic collapse within seven days of randomization in the PE Thrombolysis Study (PEITHO), reported today in a late-breaking clinical-trial session at the American College of Cardiology 2013 Scientific Sessions.

However, the benefits of thrombolysis came at the cost of a significantly increased risk of major hemorrhage, said Dr Stavros Konstantinides (Center for Thrombosis and Hemostasis, University of Mainz, Germany), who presented the findings and is the study's co–principal investigator.

"There is a price to pay, and we would not say that everybody in this group should receive thrombolysis," he noted. An analysis by age was performed by the group and suggests that this may be an important factor, he noted.

Dr Stavros Konstantinides

"Overall, the study strongly supports the concept that risk stratification of patients makes sense and that these patients need something to prevent deterioration. Patients who were less than 75 years old had most of the benefit and a tendency toward fewer hemorrhagic strokes," Konstantinides said. "The dose of the drug that we used could be lowered in older patients, and alternative methods of delivering thrombolytics could be explored," he suggested.

But Dr Sanjay Kaul (University of California, Los Angeles), who discussed the trial results in a press conference after the late-breaking trial session, said: "I would like to have seen some more data about treatment by age, with regard to safety and efficacy. Based on evidence external to this trial, it's been well described that patients over the age of 75 are at increased risk of hemorrhagic complications, so you wouldn't be unreasonable to limit this therapy [to those under 75] in patients with submassive [intermediate] PE who have an acceptable risk of bleeding."

PEITHO by Far Largest Trial Ever of Thrombolysis for Intermediate-Risk PE

There is a price to pay and we would not say that everybody in this group should receive thrombolysis.

Konstantinides said acute PE is the third most frequent acute cardiovascular syndrome after stroke and ACS, with a prevalence of 80 to 100 cases per 1000 population, and "it is estimated that in the US there at least 100 000 deaths annually from this disease."

PE has a very wide spectrum of severity and is not fatal for everyone; "there are some who have an excellent prognosis but some who have circulatory collapse at the beginning," he noted. There is also a 'gray area' in the middle--patients who come in with normal BP and appear quite stable but who have evidence on echo or CT scan that their right heart chamber is not okay," he explained.

These intermediate, or submassive, patients are at risk of imminent collapse and represent about 15% to 20% of patients with PE, he added. Until now, this patient population has been treated with heparin, and this was considered sufficient, "but it has been hypothesized that they might need something more urgent, such as clot-busting drugs, to prevent them from going into shock."

The data on this have been sparse; hence the decision to conduct PEITHO, which Konstantinides noted "is the name of the Greek goddess of persuasion."

The PEITHO trial is "by far the largest ever" in this indication, he explained, and was conducted from 2007 to mid-2012 in 1006 patients (mean age 70 years) in 13 countries in Europe and Israel, who were randomized to heparin plus placebo or heparin plus a weight-adapted bolus of tenecteplase. The combined primary end point was death from any cause or circulatory system (hemodynamic) collapse after seven days.

"It's a Wash": Benefits of Tenecteplase Equal Risks From Bleeding

The primary end point was reduced by 56% in patients treated with tenecteplase and heparin, compared with the heparin-only group (2.6% in the tenecteplase group vs 5.6% in the placebo group, p=0.015).

But major bleeding was significantly increased with tenecteplase: 6.3% vs 1.5% in the placebo group (p<0.001). There were 10 hemorrhagic strokes in the tenecteplase group and one in the placebo group.

"With regard to safety, the study confirmed what we know from previous thrombolysis studies; these are very active drugs that may cause bleeding, and this was confirmed by this large trial," said Konstantinides.

But despite these bleeding complications, he noted that the number of deaths tended to be lower in the thrombolytic vs placebo group--six vs nine--although the difference was not significant, "as the study was not designed to test mortality as an end point; this would have required huge numbers of patients and would not have been feasible."

Dr Sanjay Kaul

Nevertheless, "thrombolysis appeared to prevent death or hemodynamic collapse in these patients and many of the hemodynamic complications that might have resulted in death if not treated promptly," he stressed.

Kaul pointed out that the reduction in the primary end point was "mainly driven by the less robust component of the composite, hemodynamic collapse, at a cost of increased bleeding complications. If you balance the clinically relevant benefit with the clinically relevant harm, it appears to be a wash," he noted.

Kaul also pointed out also that tenecteplase is not US FDA approved for acute PE, but other thrombolytic agents, including streptokinase, alteplase, and urokinase, are.

Further Work Needed, Including Score for Bleeding Risk in PE

In the subgroup analysis by age, Konstantinides and colleagues found that in the younger patients (<75 years) there was a large reduction, by 67%, of the primary end point and a 1.1% risk of stroke. In the older population, the reduction in the primary end point was 37% and the risk of stroke almost 2%.

However, he agreed that further work was needed. "Our future priorities are now to refine our risk-stratification concept even further, to better identify those patients who will benefit most with less risk of bleeding."

He noted that unlike atrial-fibrillation patients, "there is no accepted score for bleeding risks in PE, so we have a deficit as a PE community."

Asked whether they had any data on right ventricular function in the trial, Konstantinides said they did not collect this information at 30 days. "But we are conducting a two-year follow-up, which will be ready in about a year. Patients will come back for clinical follow-up and echo."

The study was sponsored by Assistance Publique-Hôpitaux de Paris and funded by the French Ministry of Health, the German Ministry of Education and Research, and by a grant by Boehringer Ingelheim to the sponsor; the company also provided the study drug. Konstantinides indicated no conflicts of interest.


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