March 27, 2012

March 27, 2012 (Chicago, Illinois) — A small pilot study of a lower, "safe" dose of thrombolytic--around half the standard dose of tPA conventionally used--has shown promise as an acute treatment for moderate pulmonary embolism (PE).

This dose of tPA effectively dissolved the blood clot and led to earlier hospital discharge and less pulmonary hypertension and recurrent PE, without causing bleeding or other major side effects, said Dr Mohsen Sharifi (Arizona Cardiovascular Consultants, Mesa), who presented the findings of the Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial during the late breakers at theAmerican College of Cardiology (ACC) 2012 Scientific Sessions today. Sharifi says he is offering this treatment option to patients presenting to the emergency room with a moderate PE in his institution, but others said the work would require verification in much larger randomized trials before physicians could even consider adopting this approach.

Dr Mohsen Sharifi

Panel chair Dr Michael Crawford (UCSF) said: "The guidelines state that you use thrombolytics only in hemodynamically unstable PE, the most severe patients. I don't think at this point, based on this pilot study, you are going to get a huge acceptance of moving back to cases that are hemodynamically stable but symptomatic." Hematologist Dr Charles S Abrams (University of Pennsylvania, Philadelphia) agrees: "There's nothing that I see here that would give me the impetus to start changing my practice," he told heartwire .

There's nothing that I see here that would give me the impetus to start changing my practice.

"The idea of giving these clot busters to people with PE is not a new idea; it's been kicking around for 50 years or so, and there have been lots of studies on it, and I think it's fair to say that there is no really good study that suggests this is a wise thing to do, unless the patient has such an overwhelming PE," Abrams adds. "The reason for this is that the benefit hasn't been shown to be there, and there is definitely a risk to doing it."

He is also particularly perplexed by the high incidence of pulmonary hypertension--which was the primary study outcome--reported in MOPETT. So were others. In the panel discussion following Sharifi's presentation, Dr Frans J Van der Werf (University of Leuven, Belgium) said: "I didn't realize pulmonary hypertension was this common in those with moderate PE." And Crawford said he was "a little surprised" by the fact that over half this moderate-PE population had pulmonary hypertension. "I don't understand this at all--in previous studies on the incidence of pulmonary hypertension in people who have [moderate] PE the numbers are 1% to 4%, at most. Something is odd here or the study is just so small that some fluke occurred; it's curious," said Abrams.

A Safe Way to Use Thrombolysis in Moderate-PE Patients Coming to the ER?

Sharifi pointed out that PE is a lethal disease: "It's the third leading cause of cardiovascular morbidity and the most common preventable cause of death. Every day in the US approximately 300 people die from it, and the majority of these mortalities can be prevented." He agreed that use of thrombolysis was "nothing new" in PE but has been reserved for patients who are very sick, "who present to the ER with cardiogenic shock, which constitutes approximately 5% of all comers."

There is reluctance among practitioners to use thrombolysis in those who have fairly large PEs but are stable, and this is understandable "due to the dreaded complications associated with administration of full-dose tPA: intracranial hemorrhage affecting 2% to 6% of patients and major bleeding affecting between 6% and 20%," he noted.

We believe that there is a safer way in the application of tPA in patients who have PE and are not severely unstable.

"We believe that there is a safer way in the application of tPA in patients who have PE and are not severely unstable: they have symptoms, their BP is okay, but they have fairly large PE on CT angiogram. These are the ones who in the long run have problems such as chronic pulmonary hypertension, right heart failure, and its associated sequelae," he observed. "From our experience, it constitutes approximately 70% of patients who come into the emergency room with PE. We are not talking about patients who are in the hospital for other reasons who develop PE with comorbid conditions."

Pulmonary Hypertension, Duration of Hospitalization, Reduced

In the study, Sharifi and colleagues randomized 121 patients presenting with moderate PE and gave 61 of them a "safe" dose of tPA, which was approximately half the standard thrombolytic dose (for those >50 kg, 10 mg in one minute followed by 40 mg in two hours; for those <50 kg, 0.5 mg/kg total dose: 10 mg in one minute followed by the remainder in two hours). They also received concomitant anticoagulation with around a 20% to 30% reduced dose of enoxaparin or heparin. The control group of 60 patients did not receive tPA; they received the standard regimen of anticoagulants alone.

"The rationale behind our approach was that we know from our work with deep vein thrombosis that lungs are exquisitely sensitive to thrombolysis, because they are the organs that receive the entire cardiac output; it's the point of convergence of all of the venous circulation," Sharifi noted.

The primary end point of the study was pulmonary hypertension, and there was also a composite primary end point of recurrent PE plus pulmonary hypertension. Pulmonary hypertension was defined as a pulmonary arterial systolic pressure (PASH) of >40 mm Hg, and the primary end point was the difference in PASH between the first and second echocardiograms performed, he said.

Pulmonary hypertension at 28 months was 16% in the thrombolysis group vs 57% in the control group (p<0.001). For the composite end point, the figures were 16% vs 63% (p<0.001). There were no recurrent PEs in the tPA group, compared with three in the control group (p=0.77)

For both groups, the pulmonary pressure was reduced, but the extent of the reduction was far greater in those who got the tPA than in those who did not.

"For both groups, the pulmonary pressure was reduced, but the extent of the reduction was far greater in those who got the tPA than in those who did not," Sharifi observed.

Secondary end points were in-hospital bleeding and duration of hospitalization. There was no bleeding in either group. Hospital stay was reduced in those in the tPA group--a mean of 2.2 days compared with 4.9 days in the control group (p<0.001).

"The duration of hospitalization could be reduced dramatically, and that may have significant health impacts in the future," said Sharifi. "The clinical implications are that the majority of patients with PE who are symptomatic can be safely treated, provided the practitioners use a modified dose of tPA and a lower dose of concomitant anticoagulation. It leads to early hospital discharge and a reduction in pulmonary hypertension in the long run."

Following Sharifi's presentation, van der Werf noted that an ongoing large trial of another thrombolytic, tenecteplase, in PE, called PEITHO, is expected to report findings at the AHA meeting later this year.

Sharifi reports being a consultant for Covidien.


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