Effectiveness and Safety of Bolus Administration of Alteplase in Massive Pulmonary Embolism Jean-Luc Diehl, MD, Guy Meyer, MD, Janine Igual, MD, Marie Anne Collignon, MD, Mathilde Giselbrecht, MD, Philippe Even, MD, LSc, and Herv6 Sors, MD, MSc
Animal studies have demonstrated that thrombolysir with recombinant tissue-type plasminogen activator (rt-PA) is accelerated and that bleeding is reduced when rt-PA is infused over a short period. Prevtous clinkal studies in patients wtth venous thromboembolism have shown that &PA is an effective thrombolytic agent when administered by continuous infuston over 2 to 24 hours. Clinical experience of bohrs r&PA administratkm in patients with masstve acute pulmonary embolism (PE) is, however, limited. A prospective open study was conducted in whkh 94 patients with massive PE (Miller index 120 of 34) received a lo-minute btfusion of rt-PA at a dose of 1 mg/kg. Perfuston lung scanning was used to assess the change in pulmonary perfusion after drug administration. At 49 hours and 10 days, the mean absolute improvements in the perfusion defect were 11 and 31% respectively. In addition, a signtftcant clinical improvement occurred within 2 hours in 11 of the 15 shocked patients. Pave patients died (9%) as a result of per&tent shock (3 patients), neurologk damage (1 patient) or intracranial bleeding (1 patient). Major bleeding occurred in 8 patients (15%). Long-term follow-up information was avallable for 44 of the 49 discharged patten& 2 had died and 12 (27%) complained of perdstent exertional dyspnea, 7 of whom had an associated heart or lung disease or chronic thromboembolism at admission. These results suggest that a bohts regimen of r&PA could provide a convenient approach to thrombotytic therapy in patients with massive PE. However, further trials are necessary to assess the efficacy and safety of this reghnen against currently recommended dosages. (Am J Cardid 1992;70:1477-1490)
R
ecombinant tissue-type plasminogen activator @t-PA) has been shownto be a potent thromboytic agent in patients with acute pulmonary embolism (PE). When administered at a dose of 100 mg over 2 hours, single-chain r&PA (alteplase) induces faster angiographic reperfusion and hemodynamic improvement than the 12- or 24-hour urokinase regimens.lv2However, the bleeding rate in previous studies using this Food and Drug Administration (FDA)-approved rt-PA regimen remained important. Studies in experimental venous thromboembolism indicate that a rapid intravenous administration of a low dose of alteplase has a high thrombolytic efficacy’ and may be associatedwith a low bleeding rate.4 Recent clinical studies in patients with acute myocardial infarctioG’ and PE7 also suggest that bolus administration of &PA could be a safe and convenient thrombolytic regimen. This prospectiveopen study evaluates the efficacy and safety of a 1 mg/kg alteplaseinfusion administeredover 10 minutes in patients with massivePE.
METHODS Patknt m All patients referred to our institution with symptomssuggestiveof massivePE were considered for the study. A 6-view perfusion lung scan was routinely performed before pulmonary angiography. Patients underwent catheterization usually with brachial venous access.Mean pulmonary artery pressure was measured and selective bilateral pulmonary angiography was performed using standard, largeformat cutfilms. The severity of embolism was assessedby the method of Miller et al.* Patients with a Miller angio graphic score of at least 20 of 34, as judged by the physician in charge, were consideredfor entry into the study. The exclusion criteria were: major surgery in the past 10 days, intracerebral or intraspinal surgery in the past 3 months, head trauma or cerebrovascularaccident in the past 6 months, history of cerebral hemorrhage at any time, puncture of a noncompressiblevessel,or organ biopsy in the past 10 days, pregnancy,bleeding disorder or platelet count 180 mm Hg or diastolic blood pressure>l 10 mm Hg, or both, dissecting or other aneurysm, pericarditis or endocarditis. Treament regimen: All patients received alteplase (ActilyseQ’,Boehringer Ingelheim) as a bolus dose of 1 From the Service de Pneumologieet REanimation and the Service de mg/kg administered over 10 minutes (mean dose 67 M&k&e NucKaire, H8pital J.&mec, Paris, France. Manuscript re mg) through a peripheral vein. No patient received lOO mg regardlessof the weight below 50 or acceptedMay 26. beyond 100 kg. At the end of the alteplasetherapy, hep Addressfor reprints: He& Sors,MD, MSc, Sexvicede Pneumob gie et Rkmimation, H8pital Iaennec, 42 rue de Sties, 75007 Paris, arin was given as a continuous infusion of 400 IU/kg/ day. Heparin dosagewas subsequentlyadjusted so as to France. THROMBOLYSIS IN PULMONARY EMBOLISM
1477
TABLE I Patient Baseline Characteristics Characteristics No. of patients Men/women Age (years) No. of patients who had Surgery in past month Right heart failure Shock Cardiac arrest Heart rate (beats/min) Respiratory rate (rpm) PA pressure (mm Hg) (mean) Miller index PVOS (%I
Group A
Group B
40 19/21 702 11
14 717 71 t 11
10 17 11 3 100 f 24 f 29 2 25 + 73 2
2 6 4 0 20 5 7 2 9
992 27 -t 392 26 2 75 k
12 6 15 3 8
Total
54 26128 702 11 12 23 15 3 100 f 25 2 31+ 25 2 74 2
18 6 11 2 9
PA = pulmonary artery: PVOs = percentageof vascular obstruction by perfusion SCa”“l”g.
keep the activated partial thromboplastin time between 2 to 3 times the control value. Oral treatment with warfarin was started 5 to 10 days after admission and the dose was adjusted daily to maintain the international normalized ratio between 2.0 and 3.0. All the surviving patients were taking oral anticoagulants at the time of discharge. my: The effectiveness Amessmdofof the bolus alteplase therapy was assessedby comparing the baselinepercentageof scintigraphic vascular ob struction with that obtained at 42 to 54 hours and between 7 and 21 days after inclusion. Each perfusion lung scan was scoredby one of us, unaware of the angiographic severity at admissionand clinical outcome,according to a method previously described.9Since this scoring systemwas establishedand validated in patients free of previous cardiopulmonary disease,we differentiated, before perfusion lung scan assessment,patients free of significant cardiac, pulmonary and chronic thromboembolic disease(group A) from those presenting with such a condition (group B). Patients were considered as having chronic thromboembolism preceding the acute episodeif they met at least 1 of the following criteria: (1) symptoms suggestiveof PE >l month be fore inclusion, (2) mean pulmonary artery pressure>50 mm Hg at admission, and (3) angiographic features of chronic thromboembolism.1°Group allocation was decided by a consensusof 2 of us who were unaware of the scintigraphic and clinical outcomes. Adverse aventer Recurrent PE and other adverse events were noted throughout the hospital stay. The following bleeding complications were recorded:hemorrhagic stroke, hematomasof >5 cm in diameter, retro peritoneal, mediastinal, pleural and pericardial bleeding, hemoptysis,epistaxis, grosshematuria, blood transfusion and need for surgery or any other special measure to control bleeding. Major bleeding was pro spectively defined as bleeding that required blood transfusion, surgical control, or caused a decreasein herno globin level of 15 g/ 100 ml, and hemorrhagic stroke that had to be confiied by computed tomography or autopsy. Lmg-term fdlowq: A follow-up of dischargedpatients was performed through hospital outpatient visits, 1478
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
and’ interviews of the patient or of the patient’s physician. Statistical analysis: Results are expressedas mean f standard deviation. Quantitative comparisons were tested for statistical significance with unpaired 2-tailed Student’s t test. A p value
Animal studies have demonstrated that thrombolysir with recombinant tissue-type plasminogen activator (rt-PA) is accelerated and that bleeding is reduced when rt-PA is infused over a short period. Prevtous clinkal studies in patients wtth venous thromboembolism have shown that &PA is an effective thrombolytic agent when administered by continuous infuston over 2 to 24 hours. Clinical experience of bohrs r&PA administratkm in patients with masstve acute pulmonary embolism (PE) is, however, limited. A prospective open study was conducted in whkh 94 patients with massive PE (Miller index 120 of 34) received a lo-minute btfusion of rt-PA at a dose of 1 mg/kg. Perfuston lung scanning was used to assess the change in pulmonary perfusion after drug administration. At 49 hours and 10 days, the mean absolute improvements in the perfusion defect were 11 and 31% respectively. In addition, a signtftcant clinical improvement occurred within 2 hours in 11 of the 15 shocked patients. Pave patients died (9%) as a result of per&tent shock (3 patients), neurologk damage (1 patient) or intracranial bleeding (1 patient). Major bleeding occurred in 8 patients (15%). Long-term follow-up information was avallable for 44 of the 49 discharged patten& 2 had died and 12 (27%) complained of perdstent exertional dyspnea, 7 of whom had an associated heart or lung disease or chronic thromboembolism at admission. These results suggest that a bohts regimen of r&PA could provide a convenient approach to thrombotytic therapy in patients with massive PE. However, further trials are necessary to assess the efficacy and safety of this reghnen against currently recommended dosages. (Am J Cardid 1992;70:1477-1490)
R
ecombinant tissue-type plasminogen activator @t-PA) has been shownto be a potent thromboytic agent in patients with acute pulmonary embolism (PE). When administered at a dose of 100 mg over 2 hours, single-chain r&PA (alteplase) induces faster angiographic reperfusion and hemodynamic improvement than the 12- or 24-hour urokinase regimens.lv2However, the bleeding rate in previous studies using this Food and Drug Administration (FDA)-approved rt-PA regimen remained important. Studies in experimental venous thromboembolism indicate that a rapid intravenous administration of a low dose of alteplase has a high thrombolytic efficacy’ and may be associatedwith a low bleeding rate.4 Recent clinical studies in patients with acute myocardial infarctioG’ and PE7 also suggest that bolus administration of &PA could be a safe and convenient thrombolytic regimen. This prospectiveopen study evaluates the efficacy and safety of a 1 mg/kg alteplaseinfusion administeredover 10 minutes in patients with massivePE.
METHODS Patknt m All patients referred to our institution with symptomssuggestiveof massivePE were considered for the study. A 6-view perfusion lung scan was routinely performed before pulmonary angiography. Patients underwent catheterization usually with brachial venous access.Mean pulmonary artery pressure was measured and selective bilateral pulmonary angiography was performed using standard, largeformat cutfilms. The severity of embolism was assessedby the method of Miller et al.* Patients with a Miller angio graphic score of at least 20 of 34, as judged by the physician in charge, were consideredfor entry into the study. The exclusion criteria were: major surgery in the past 10 days, intracerebral or intraspinal surgery in the past 3 months, head trauma or cerebrovascularaccident in the past 6 months, history of cerebral hemorrhage at any time, puncture of a noncompressiblevessel,or organ biopsy in the past 10 days, pregnancy,bleeding disorder or platelet count 180 mm Hg or diastolic blood pressure>l 10 mm Hg, or both, dissecting or other aneurysm, pericarditis or endocarditis. Treament regimen: All patients received alteplase (ActilyseQ’,Boehringer Ingelheim) as a bolus dose of 1 From the Service de Pneumologieet REanimation and the Service de mg/kg administered over 10 minutes (mean dose 67 M&k&e NucKaire, H8pital J.&mec, Paris, France. Manuscript re mg) through a peripheral vein. No patient received lOO mg regardlessof the weight below 50 or acceptedMay 26. beyond 100 kg. At the end of the alteplasetherapy, hep Addressfor reprints: He& Sors,MD, MSc, Sexvicede Pneumob gie et Rkmimation, H8pital Iaennec, 42 rue de Sties, 75007 Paris, arin was given as a continuous infusion of 400 IU/kg/ day. Heparin dosagewas subsequentlyadjusted so as to France. THROMBOLYSIS IN PULMONARY EMBOLISM
1477
TABLE I Patient Baseline Characteristics Characteristics No. of patients Men/women Age (years) No. of patients who had Surgery in past month Right heart failure Shock Cardiac arrest Heart rate (beats/min) Respiratory rate (rpm) PA pressure (mm Hg) (mean) Miller index PVOS (%I
Group A
Group B
40 19/21 702 11
14 717 71 t 11
10 17 11 3 100 f 24 f 29 2 25 + 73 2
2 6 4 0 20 5 7 2 9
992 27 -t 392 26 2 75 k
12 6 15 3 8
Total
54 26128 702 11 12 23 15 3 100 f 25 2 31+ 25 2 74 2
18 6 11 2 9
PA = pulmonary artery: PVOs = percentageof vascular obstruction by perfusion SCa”“l”g.
keep the activated partial thromboplastin time between 2 to 3 times the control value. Oral treatment with warfarin was started 5 to 10 days after admission and the dose was adjusted daily to maintain the international normalized ratio between 2.0 and 3.0. All the surviving patients were taking oral anticoagulants at the time of discharge. my: The effectiveness Amessmdofof the bolus alteplase therapy was assessedby comparing the baselinepercentageof scintigraphic vascular ob struction with that obtained at 42 to 54 hours and between 7 and 21 days after inclusion. Each perfusion lung scan was scoredby one of us, unaware of the angiographic severity at admissionand clinical outcome,according to a method previously described.9Since this scoring systemwas establishedand validated in patients free of previous cardiopulmonary disease,we differentiated, before perfusion lung scan assessment,patients free of significant cardiac, pulmonary and chronic thromboembolic disease(group A) from those presenting with such a condition (group B). Patients were considered as having chronic thromboembolism preceding the acute episodeif they met at least 1 of the following criteria: (1) symptoms suggestiveof PE >l month be fore inclusion, (2) mean pulmonary artery pressure>50 mm Hg at admission, and (3) angiographic features of chronic thromboembolism.1°Group allocation was decided by a consensusof 2 of us who were unaware of the scintigraphic and clinical outcomes. Adverse aventer Recurrent PE and other adverse events were noted throughout the hospital stay. The following bleeding complications were recorded:hemorrhagic stroke, hematomasof >5 cm in diameter, retro peritoneal, mediastinal, pleural and pericardial bleeding, hemoptysis,epistaxis, grosshematuria, blood transfusion and need for surgery or any other special measure to control bleeding. Major bleeding was pro spectively defined as bleeding that required blood transfusion, surgical control, or caused a decreasein herno globin level of 15 g/ 100 ml, and hemorrhagic stroke that had to be confiied by computed tomography or autopsy. Lmg-term fdlowq: A follow-up of dischargedpatients was performed through hospital outpatient visits, 1478
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
and’ interviews of the patient or of the patient’s physician. Statistical analysis: Results are expressedas mean f standard deviation. Quantitative comparisons were tested for statistical significance with unpaired 2-tailed Student’s t test. A p value
