Tissue Plasminogen Activator for the Treatment of Acute Pulmonary Embolism

20 Apr
2011

A lthough recombinant tissue plasminogen activator would seem to have great potential for the treat­ment of acute pulmonary embolism, experience with this agent is limited, and no comparisons to placebo have been published. The purpose of the present study, therefore, was preliminarily to evaluate the efficacy of rt-PA, especially in combination with hep­arin, compared to placebo plus heparin as treatment for patients with acute pulmonary embolism. The thrombolytic effects of rt-PA may be enhanced when administered in combination with heparin because the addition of new fibrin to the thrombus is prevented by heparin during lytic therapy.

Methods

Between Nov 30, 1986, and June 30, 1987 (seven months), 13 patients were studied; nine received rt-PA and four received heparin but no rt-PA. The protocol and consent forms were approved by institutional review boards at the six participating hospitals, the data and coordinating center and the National Heart, Lung and Blood Institute. Among those who received rt-PA, eight of nine received heparin simultaneously. All patients received either rt-PA or placebo in a randomized double-blind fashion; twice as many patients were randomly assigned to the treatment group as to the control group.

Patient Enrollment

All patients had the onset of symptoms of pulmonary embolism within seven days of the angiogram. For the patient to be eligible for the study, occlusion of a lobar artery or at least two segmental arteries had to be evident at angiography. Among the patients in this study, nine were men and four were women. The patients ranged in age from 20 to 78 years (Table 1). levitra professional

Table 1 —Age, Sex, and Heparin Administration

rt-PA Dose

Heparin

Age

Sex*

None

Yes

42

M

Yes

69

M

Yes

51

M

Yes

78

M

40 mg

No

48

F

Yes

69

M

Yes

59

F

Yes

51

M

Yes

67

M

64 mg

Yes

81

F

80 mg

Yes

68

M

Yes

20

F

Yes

57

M

Patients with shock or major disability due to pulmonary embo­lism were excluded because random assignment to a placebo group was considered unethical. A large number of other exclusions were made in order to enhance the safety of the study (Table 2). Even though there were approximately 5,500 hospital beds among the six clinical centers, the rate of patient accession was slow. Therefore, the independent Study Policy and Data Safety Monitoring Board recommended that the investigators discontinue recruitment, al­though the initial study design called for 50 patients.
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Dose and Route of rt-PA Administration

Patients received rt-PA produced by Genentech, Inc (rt-PA, Genentech G11014). The rt-PA was administered intravenously at a rate of approximately 1 mg/min. Initially, a dose of 80 mg was selected as a modest dose on the basis of experience with myocardial infarction. After one major hemorrhage, the investigators reduced the dose to 40 mg in the interest of further reducing the risk of rt-PA was administered over 40 minutes. The 80 mg dose was administered over 90 minutes.

During the infusion of rt-PA, heparin was administered to all but one patient in an open fashion; doses were determined by the attending physician. In one patient, heparin was discontinued during the double-blind administration of rt-PA.

Pulmonary Arteriography

Pulmonary arteriograms were obtained before the administration of rt-PA and 2 hours following the double-blind therapy. Pretreat- ment pulmonary arteriograms were bilateral in 12 of 13 patients. Posttreatment pulmonary arteriograms were obtained in 12 patients and were bilateral in eight. No posttreatment study was obtained in the one patient who hemorrhaged while receiving rt-PA.

Pulmonary arteriograms were obtained in the anterior-posterior projection using 14 inch by 14 inch cut film. Forty to 50 ml of 76 percent sodium and meglumine diatrizoates was injected at a rate of 20 to 25 ml/s either in the left or right pulmonary artery. Filming was carried out at a rate of three films per second for 3 seconds followed by one film per second for 4 to 6 seconds.

The radiologist who interpreted the pulmonary arteriograms was a consultant, and was not from a participating institution. He was unaware of the clinical data and mode of therapy. The pulmonary arteriograms were scored according to the size and number of pulmonary arterial branches that contained intraluminal filling defects. Each vessel, irrespective of its size, received a vessel occlusion score as follows:

Vessel Occlusion

Occlusion Grade

Mild (< 1/3 vessel diameter):

1

Moderate (1/3 to 2/3 vessel diameter):

2

Marked (> 2/3 vessel diameter):

3

For each vessel, the occlusion grade (shown above) was multiplied by a grade which was dependent upon the size of the vessel. These grades were as follows:

Vessel

Size Grade

Pulmonary trunk

6

Main pulmonary artery

3

Intermediate artery

2

Lobar artery

1

Segmental artery

0.3

Subsegmental artery

0.1

The size grades entered in each column were added and multiplied by the occlusion grade assigned to the vessel. The total clot size score was then obtained by adding the clot size scores for each vessel. If the entire pulmonary arterial tree were filled with clots, a total of 102 units would be obtained for clot size. The total clot size, therefore, approximated the percentage of obstructed vascular volume in the two lungs.

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