Prospective Investigation of Pulmonary Embolism Diagnosis Study - PIOPED


Alteplase for angiographic outcomes in pulmonary embolism.


(1) rt-PA in combination with heparin has potential for the treatment of acute pulmonary embolism. (2, 3) Because a normal V/Q lung scan excludes the diagnosis of clinically significant acute pulmonary embolism, optimized V/Q lung scans are useful for accurate diagnosis when interpreted as representing a very low, low, intermediate or high probability of acute pulmonary embolism with a concordant clinical likelihood of acute pulmonary embolism.

Study Design

Study Design:

Patients Screened: (1) 13; (2, 3) 3,016
Patients Enrolled: (1) 13; (2, 3) 1,493
NYHA Class: not given
Mean Follow Up: (1) 24 hours; (2, 3) 1 year
Mean Patient Age: (1) 58.5 years; (2, 3) 56.1 years
Female: (1) 31%; (2, 3) 55%
Mean Ejection Fraction: not given

Patient Populations:

(1) occlusion of a lobar artery or at least two segmental arteries evident at angiography
(2, 3) risk factors, signs, symptoms or laboratory findings which were unexplained and suggestive of acute pulmonary embolism


Shock (systolic blood pressure <80 mmHg despite vasopressor treatment)
Major disability from pulmonary embolism
Pregnancy at any age and the first ten days postpartum
Uncontrolled hypertension (diastolic blood pressure >110 mmHg by several measurements or hypertensive retinopathy with hemorrhages or exudates
Present bleeding disorder
History of gastrointestinal (GI) bleeding within six months or symptoms of active GI diseases which have a propensity to bleed
Renal insufficiency (creatinine >3.0 mg/dL)
Severe hepatic insufficiency
Evidence of a lesion known to be associated with intracranial hemorrhage (including cerebral malignancy, aneurysm, abscess or head trauma)
History of cerebrovascular disease
Neurosurgery within six months
Uncontrolled hypocoagulable state (including coagulation factor deficiencies, platelet abnormalities or other spontaneous hemorrhagic or purpuric phenomena; oral anticoagulation with warfarin; therapy with thrombolytic agent within the past three days [therapy with aspirin on the same day was a relative contraindication])
Severe trauma within two months
Any surgical or invasive procedure (including biopsies, deep tissue aspirations, depot injections, unsuccessful attempts at central line placement or removal of successfully placed central lines [e.g., subclavian or internal jugular] within ten days of study entry; previous arterial punctures of femoral or brachial are relative contraindications)
Placement of central venous line within 48 hours
Ophthalmologic surgery within six weeks
Cardiopulmonary resuscitation (one minute or more of external cardiac massage) within two weeks of study entry
Previous participation in the PIOPED rt-PA randomized trial
Psychological or physical inability to participate

(2, 3)
Scan requests cancelled
Scans requested for research purposes
Diagnosis other than acute pulmonary embolism
Contraindications to angiography
Creatinine level >260 æmol/L
Hypersensitivity to contrast material
Signed informed consent (once approached for the study, patients with recurrences of acute pulmonary embolism were not approached for recruitment a second time.)

Primary Endpoints:

Fragment-D dimers (in vivo clot lysis indicator), total pulmonary resistance.
Death, suspicion of recurrent pulmonary embolism, complications of angiography or therapy.

Secondary Endpoints:

Occlusion grade (1-3), size grade (0.1, 0.3, 1 to 3, 6)
Consensus in the assessment of the probability of pulmonary embolism; assessment of the probability of pulmonary embolism (high-, intermediate-, low-, very low-, and normal-probability) after one year of follow-up

Drug/Procedures Used:

rt-PA, in the study group 80mg IV at a rate of approximately 1 mg/minute for first 3 patients then 64mg for fourth patient (hemorrhage interrupted intended 80mg dose) and finally dose reduced to 40mg for the remaining 5 patients in study group to redu

Concomitant Medications:

76% sodium and meglumine diatrizoates, 40 to 50 ml injected either in the left or right pulmonary artery; technetium 99m (99mTc) macroaggregated albumin, 4 mCi (millicuries)
xenon 133 (133Xe), 15 to 30 mCi (millicuries); technetium 99m (99mTc) macroaggregated albumin, 4 mCi

Principal Findings:

PIOPED rt-PA randomized trial:
A lytic effect was observed 1.5 and three hours after the onset of therapy with rt-PA based upon elevated levels of fragment-D dimers.
Among the patients who received rt-PA, there was a modest improvement of the total pulmonary resistance 1.5 hours after the start of therapy, but the angiograms showed no significant changes in two hours.
After 24 hours, the lung scans showed a trend toward greater improvement with rt-PA, but the rate of improvement in comparison to control subjects was not statistically significant.
Massive bleeding occurred in one patient.

PIOPED ventilation/perfusion (V/Q) scan trial:
A normal V/Q lung scan excludes the diagnosis of clinically significant pulmonary embolism (PE). The usefulness of the V/Q lung scan was optimized when interpreted as representing a very low, low or high probability of PE with a concordant clinical likelihood of PE.
Patients with a V/Q lung scan interpreted as representing an intermediate probability of PE or patients with discordant clinical likelihood of PE and lung scan interpretation will often require further investigations to diagnose or exclude acute venous thromboembolism.


PIOPED rt-PA randomized trial:
The observations in this study suggest that rt-PA has little effect in two hours on angiographic clot burden, but may produce some improvement in hemodynamics. The treatment, however, is not without risk.

PIOPED ventilation/perfusion (V/Q) scan trial:
The results of the PIOPED study support the use of V/Q lung scanning in the diagnostic evaluation of patients with suspected PE.


1. Chest 1990;97:528-33. rt-PA randomized trial
2. JAMA 1990;263:2753-9. Ventilation/Perfusion (V/Q) Scan Study
3. J Nucl Med 1995;36:2380-7. Review

Clinical Topics: Anticoagulation Management, Dyslipidemia, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Lipid Metabolism

Keywords: Pulmonary Embolism, Heparin, Venous Thromboembolism, Risk Factors, Tissue Plasminogen Activator, Hemodynamics

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