GÖTTINGEN, GERMANY—Fear of elevating the bleeding risk has kept many physicians from prescribing thrombolytics for hemodynamically stable patients with pulmonary embolism (PE). A randomized controlled study now demonstrates that adding alteplase to heparin treatment is safe for patients with acute submassive PE and no contraindications to thrombolysis. Furthermore, the combination of alteplase and heparin can prevent clinical deterioration, cutting risk for treatment escalation or in-hospital death by almost two thirds.[1]

In a study supported by Boehringer Ingelheim Pharma, Stavros V. Konstantinides, MD, and colleagues compared outcomes with heparin plus placebo or alteplase in 256 patients with submassive PE. “We found that administration of the thrombolytic—that is, alteplase—together with heparin, resulted in an improved in-hospital outcome,” said Dr. Konstantinides, Associate Professor of Medicine at Georg August University in Göttingen. “There was less clinical deterioration prompting emergency measures in these patients.”

Uncontrolled data from registries previously indicated an increased risk for cerebral or fatal bleeding with alteplase, but the new findings contrast with this conclusion. “Under these controlled conditions, … thrombolytic therapy was not only effective … but it was also safe: We had no fatal bleeding and no cerebral bleeding in the group that received alteplase,” Dr. Konstantinides emphasized. Thus, said Samuel Z. Goldhaber, MD, who wrote an accompanying editorial,[2] “we should seriously consider thrombolytic therapy in patients with PE who have no contraindications, and who have moderate or severe right ventricular dysfunction based on echocardiogram.”

Dr. Konstantinides and colleagues enrolled acute PE patients who had pulmonary hypertension or right ventricular dysfunction within 96 hours of symptom onset in the prospective double-blind trial. Patients were excluded from the trial if they:
• Were older than 80.
• Were pregnant or lactating.
• Were receiving an oral anticoagulant.
• Had arterial hypotension, shock, diabetic retinopathy, or uncontrolled hypertension.
• Had received thrombolytic therapy, or had undergone major surgery or biopsy, within seven days.
• Had experienced major trauma within the previous 10 days; gastrointestinal bleeding within the previous three months; or stroke, transient ischemia, cerebral trauma, or neurological surgery within the previous six months.

FEWER EMERGENCY MEASURES NEEDED

The researchers randomly assigned 118 qualifying patients to receive heparin plus 100 mg of alteplase for a two-hour period; a control group of 138 patients received heparin plus placebo. Alteplase treatment significantly lowered the incidence of treatment escalation (emergency embolectomy, intubation, cardiopulmonary resuscitation, catecholamine infusion, or secondary thrombolysis) from 24.6% to 10.2%. Specifically, secondary thrombolysis was performed approximately one third as often in alteplase recipients. However, mortality was similarly low among those receiving alteplase (3.4%) and placebo (2.2%).

According to Dr. Goldhaber, Associate Professor of Medicine at Harvard Medical School in Boston, intracerebral bleeding events “occur anywhere from 1% to 3% of the time in most studies of thrombolysis for PE.” But, he said, “in this particular study, there were absolutely none: zero intracranial hemorrhages.” Contraindications for thrombolytic therapy might be overlooked more frequently in registry studies than in a controlled trial, possibly explaining why “in registries, the bleeding rates—the complications of this treatment—are always higher,” Dr. Konstantinides suggested. “Everyday practice is not always the gold standard,” he remarked.

RESULTS EXPAND CRITERIA, HASTEN USE

Demonstrating safety broadens the indications for thrombolytic therapy, which had been universally recommended only for patients already showing signs of shock. “Previously, the only criterion was blood pressure—if it was unstable, and the patient was in shock, you did give thrombolysis,” said Dr. Konstantinides. Instead, he argued, “right ventricular dysfunction, which one can [detect] very easily with an echocardiogram, should be used as a criterion to select the patients for thrombolysis.” Said Dr. Konstantinides, “Even in these patients, thrombolysis seems beneficial.”

If caregivers wait for a drop in blood pressure, Dr. Goldhaber pointed out, “it’s often too late, because by then, the patient’s already going into cardiogenic shock—at that point, no ‘heroic’ therapy works as well as [it would] before a patient goes into shock.” Therefore, he stressed, “it’s better to act early and aggressively, rather than holding off until the last possible moment.”

Despite the reduced need for intensive care with alteplase, mortality did not decrease. But, noted Dr. Goldhaber, “to do a mortality trial on PE might take 10,000 to 20,000 patients. This was a trial of only 250 patients—it was never designed to be a mortality trial.” He added, “this trial … is an important first step in contemporary investigation of thrombolytic therapy for PE, but it is not the last word. My hope is that pulmonary physicians and others interested in this illness will get together to do future investigations.”

—Mimi Zucker, PhD

References
1. Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347:1143-1150.
2. Goldhaber SZ. Thrombolysis for pulmonary embolism. N Engl J Med. 2002;347:1131-1132.

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