DENVER – Adding thrombolytic therapy to standard anticoagulation with heparin did not significantly improve overall survival at 3 months in patients with acute symptomatic pulmonary embolism – and reduced survival rates for some normotensive patients, according to a large international retrospective cohort study.
Thrombolytic therapy as initial treatment did produce a nonsignificant trend toward survival among patients who presented with systolic hypotension, according to a subanalysis of the study data, while significantly worsening survival among normotensive patients.
Dr. David Jimenez
However, thrombolysis had no significant impact on survival among normotensive patients when researchers accounted for differences in troponin and the presence of right ventricular dysfunction.
"Based on these findings, we cannot recommend thrombolysis in normotensive patients without more data from randomized controlled trials. We need to better determine how to risk stratify these patients," said Dr. David Jimenez of the Ramon y Cajal Hospital and Alcala de Henares University, Madrid.
Current guidelines from the American College of Chest Physicians recommend thrombolytic therapy in addition to anticoagulation for patients with evidence of hemodynamic compromise (grade 1B evidence) and for "selected high-risk patients without hypotension who are judged to have a low risk of bleeding (grade 2B)." The guidelines advise physicians to base that decision on the severity of the pulmonary embolism (PE), the patient’s prognosis, and risk of bleeding (Chest 2008;133:454S-545S).
The current study was done to fill in the evidence gap for those recommendations, explained Dr. Jimenez, who presented the study results at an international meeting of the American Thoracic Society. He and his colleagues from Spain and the United States analyzed data from 15,944 patients with acute pulmonary embolism enrolled in the Spanish registry Registro Informatizado de la Enfermedad Tromboembólica. Thrombolytic therapy had been used in 2.7% (430) of the patients.
In general, those patients were younger, had fewer comorbid conditions, and more signs of clinical severity. In order to overcome that bias, a propensity analysis was conducted in order to match patients for those differences.
Patients were also grouped into those with systolic blood pressure less 100 mm Hg (hypotensive) and those with 100 mm Hg and higher (normotensive).
Comparing 94 propensity score–matched patients with systolic hypotension who received thrombolysis with 94 patients who did not, there was a nonsignificant trend in reduction in all-cause mortality with thrombolytic therapy, with an odds ratio of 0.72.
For two groups of 217 normotensive patients each who received or did not receive thrombolysis, there was a statistically significant increased risk of death for those receiving thrombolysis, with an odds ratio of 2.32. However, when missing troponin and echocardiogram data were added to the analysis, the effect of thrombolysis was no longer significant, with an odds ratio 1.67.
The reasons for the increased risks from thrombolysis for normotensive patients with PE aren’t entirely clear, the investigators said.
However, because the risk of dying from pulmonary embolism is low among normotensive, hemodynamically stable PE patients, those patients’ risk of dying from thrombolysis is therefore elevated by comparison and approaches that of hypotensive patients, Dr. Jimenez speculated. Only half of all patients with pulmonary embolism actually die of the embolism, he noted, while the rest die of other causes such as infections, cancer, and bleeding.
Indeed, there has only been one previous randomized clinical trial showing benefit from thrombolysis in patients with PE, Dr. Jimenez said, and that was in 10 patients with life-threatening PE (J. Thromb. Thrombolysis 1995;2:227-9).
"Thrombolysis is only useful for those who are at high risk for dying from PE," Dr. Jimenez said. "I think we have to test in a randomized, controlled trial whether thrombolysis is helpful in a subgroup of normotensive patients who have high risk due to right ventricular dysfunction and elevated troponin," Dr. Jimenez said.
Such a trial is now underway. The prospective, double-blind, placebo-controlled Pulmonary Embolism Thrombolysis Study (PEITHO) will examine the particular subgroup of normotensive patients with acute PE who have echocardiographic and laboratory evidence of right ventricular dysfunction.
The study investigators want to enroll 1,000 patients at 12 European centers, and they hope to have data by the end of 2012, said Dr. Jimenez, whose hospital is one of the study centers.
Dr. Jimenez stated that he has no financial disclosures.