Reduced TPA Regimen Safely Treats Pulmonary Embolism

CHICAGO – A reduced-dose regimen of tissue plasminogen activator and parenteral anticoagulant safely led to improved outcomes in hemodynamically stable patients with a pulmonary embolism in a pilot study with a total of 121 patients treated at one U.S. center.

None of the 61 patients treated with the regimen, which halved the standard dosage of tissue plasminogen activator (TPA) and cut the dosage of enoxaparin or heparin by about 20%-30%, had an intracranial hemorrhage or a major bleeding event, compared with a historic 2%-6% incidence of intracranial hemorrhage and a 6%-20% incidence of major bleeds in hemodynamically unstable pulmonary embolism patients who receive the standard, full dose of both the thrombolytic and anticoagulant, Dr. Mohsen Sharifi said at the meeting.

Mitchel L. Zoler/IMNG Medical Media

While he acknowledged that the results need confirmation in a larger study, "in our experience treating deep vein thrombosis [with a similarly low dosage of TPA], we are comfortable that this amount of TPA can be given safely," said Dr. Sharifi, an interventional cardiologist who practices in Mesa, Ariz.

The findings also showed that applying this reduced-dose intervention to hemodynamically stable patients with a pulmonary embolism (PE), who are typically not treated, substantially improved their long-term prognosis by reducing their development of pulmonary hypertension. After an average of 28 months follow-up, 9 of the 58 patients (16%) followed long term and treated with the reduced-dose regimen had pulmonary hypertension, defined as a pulmonary artery systolic pressure greater than 40 mm Hg, compared with pulmonary hypertension in 32 of the 56 control patients (57%) managed by standard treatment with anticoagulation only.

Current guidelines from the American Heart Association call for fibrinolytic treatment only in patients with a massive, acute PE, or in patients with a submassive PE who are hemodynamically unstable or have other clinical evidence of an adverse prognosis (Circulation 2011;123:1788-830). According to Dr. Sharifi, about 5% of all PE patients fall into this category. He estimated that broadening thrombolytic treatment to hemodynamically stable patients who met his study’s inclusion criteria could broaden TPA treatment to an additional 70% of PE patients currently seen in emergency departments.

"I think that, based on the results of this pilot study, you won’t get broad acceptance of treating hemodynamically stable PE patients with thrombolysis," commented Dr. Michael Crawford, chief of general cardiology at the University of California, San Francisco. Two larger studies nearing completion are both examining the efficacy and safety of thrombolysis in patients with submassive PE.

Dr. Sharifi said that despite the small study size, he and his associates were convinced enough by their findings to use the reduced TPA dosage tested in this study on a routine basis when they see patients who meet their enrollment criteria.

The MOPETT (Moderate Pulmonary Embolism Treated with Thrombolysis) study enrolled patients with a PE affecting at least two lobar segments, pulmonary artery systolic pressure greater than 40 mm Hg; right ventricular hypokinesia and enlargement; and at least two symptoms, which could include chest pain, tachypnea greater than 22 respirations/min, tachycardia with a resting heart rate of more than 90 beats/min, dyspnea, cough, oxygen desaturation, and jugular venous pressure more than 12 mm H₂O. The average age of the patients was about 59 years, and slightly more than half were women. Their average pulmonary artery systolic pressure at entry was about 50 mm Hg.

Dr. Sharifi and his associates randomized half the patients to receive conventional treatment with anticoagulant only, either enoxaparin or heparin plus warfarin. The other patients received thrombolytic treatment with an infusion of TPA at half the standard dosage, starting in patients who weighed at least 50 kg with a loading dose of 10 mg delivered in 1 minute, and followed by a 40-mg total additional dose administered over 2 hours. Patients who weighed less received the same 10-mg initial dose, but their total dose including the subsequent 2-hour infusion was limited to 0.5 mg/kg. The patients treated with TPA also received concomitant anticoagulation, with either enoxaparin given at 1 mg/kg but not to exceed 80 mg as an initial dose, or heparin at an initial dose of 70 U/kg but capped at 6,000 U, followed by heparin maintenance at 10 U/kg per hour during the TPA infusion (but not exceeding 1,000 U/hour), and then rising to 18 U/kg per hour starting 1 hour after TPA treatment stopped. About 80% of all patients in the study received enoxaparin, and about 20% received heparin.

At 48 hours after starting treatment, average pulmonary artery systolic pressure dropped by 16 mm Hg in the TPA group and by 5 mm Hg in the control patients. By the end of the average 28-month follow-up, average pulmonary artery systolic pressure was 28 mm Hg in the TPA patients and 43 mm Hg in the controls. Dr. Sharifi attributed the efficacy of reduced-dose TPA to the "exquisite sensitivity" of blood clots lodged in a patient’s lungs to the drug, a consequence of all the infused TPA passing through the lung’s arterial circulation.

In addition to showing a statistically significant benefit from TPA for the study’s primary end point, the average duration of hospitalization in the TPA recipients was 2.2 days, compared with an average of 4.9 days in the control patients, a statistically significant difference. And at the end of the average 28 months of follow-up, three patients in the control arm had a recurrent PE and another three had died, significantly more than the no recurrent PEs and one death in the TPA arm.

Dr. Sharifi and Dr. Crawford said that they had no relevant disclosures.

CHICAGO – A reduced-dose regimen of tissue plasminogen activator and parenteral anticoagulant safely led to improved outcomes in hemodynamically stable patients with a pulmonary embolism in a pilot study with a total of 121 patients treated at one U.S. center.

None of the 61 patients treated with the regimen, which halved the standard dosage of tissue plasminogen activator (TPA) and cut the dosage of enoxaparin or heparin by about 20%-30%, had an intracranial hemorrhage or a major bleeding event, compared with a historic 2%-6% incidence of intracranial hemorrhage and a 6%-20% incidence of major bleeds in hemodynamically unstable pulmonary embolism patients who receive the standard, full dose of both the thrombolytic and anticoagulant, Dr. Mohsen Sharifi said at the meeting.

Mitchel L. Zoler/IMNG Medical Media

While he acknowledged that the results need confirmation in a larger study, "in our experience treating deep vein thrombosis [with a similarly low dosage of TPA], we are comfortable that this amount of TPA can be given safely," said Dr. Sharifi, an interventional cardiologist who practices in Mesa, Ariz.

The findings also showed that applying this reduced-dose intervention to hemodynamically stable patients with a pulmonary embolism (PE), who are typically not treated, substantially improved their long-term prognosis by reducing their development of pulmonary hypertension. After an average of 28 months follow-up, 9 of the 58 patients (16%) followed long term and treated with the reduced-dose regimen had pulmonary hypertension, defined as a pulmonary artery systolic pressure greater than 40 mm Hg, compared with pulmonary hypertension in 32 of the 56 control patients (57%) managed by standard treatment with anticoagulation only.

Current guidelines from the American Heart Association call for fibrinolytic treatment only in patients with a massive, acute PE, or in patients with a submassive PE who are hemodynamically unstable or have other clinical evidence of an adverse prognosis (Circulation 2011;123:1788-830). According to Dr. Sharifi, about 5% of all PE patients fall into this category. He estimated that broadening thrombolytic treatment to hemodynamically stable patients who met his study’s inclusion criteria could broaden TPA treatment to an additional 70% of PE patients currently seen in emergency departments.

"I think that, based on the results of this pilot study, you won’t get broad acceptance of treating hemodynamically stable PE patients with thrombolysis," commented Dr. Michael Crawford, chief of general cardiology at the University of California, San Francisco. Two larger studies nearing completion are both examining the efficacy and safety of thrombolysis in patients with submassive PE.

Dr. Sharifi said that despite the small study size, he and his associates were convinced enough by their findings to use the reduced TPA dosage tested in this study on a routine basis when they see patients who meet their enrollment criteria.

The MOPETT (Moderate Pulmonary Embolism Treated with Thrombolysis) study enrolled patients with a PE affecting at least two lobar segments, pulmonary artery systolic pressure greater than 40 mm Hg; right ventricular hypokinesia and enlargement; and at least two symptoms, which could include chest pain, tachypnea greater than 22 respirations/min, tachycardia with a resting heart rate of more than 90 beats/min, dyspnea, cough, oxygen desaturation, and jugular venous pressure more than 12 mm H₂O. The average age of the patients was about 59 years, and slightly more than half were women. Their average pulmonary artery systolic pressure at entry was about 50 mm Hg.

Dr. Sharifi and his associates randomized half the patients to receive conventional treatment with anticoagulant only, either enoxaparin or heparin plus warfarin. The other patients received thrombolytic treatment with an infusion of TPA at half the standard dosage, starting in patients who weighed at least 50 kg with a loading dose of 10 mg delivered in 1 minute, and followed by a 40-mg total additional dose administered over 2 hours. Patients who weighed less received the same 10-mg initial dose, but their total dose including the subsequent 2-hour infusion was limited to 0.5 mg/kg. The patients treated with TPA also received concomitant anticoagulation, with either enoxaparin given at 1 mg/kg but not to exceed 80 mg as an initial dose, or heparin at an initial dose of 70 U/kg but capped at 6,000 U, followed by heparin maintenance at 10 U/kg per hour during the TPA infusion (but not exceeding 1,000 U/hour), and then rising to 18 U/kg per hour starting 1 hour after TPA treatment stopped. About 80% of all patients in the study received enoxaparin, and about 20% received heparin.

At 48 hours after starting treatment, average pulmonary artery systolic pressure dropped by 16 mm Hg in the TPA group and by 5 mm Hg in the control patients. By the end of the average 28-month follow-up, average pulmonary artery systolic pressure was 28 mm Hg in the TPA patients and 43 mm Hg in the controls. Dr. Sharifi attributed the efficacy of reduced-dose TPA to the "exquisite sensitivity" of blood clots lodged in a patient’s lungs to the drug, a consequence of all the infused TPA passing through the lung’s arterial circulation.

In addition to showing a statistically significant benefit from TPA for the study’s primary end point, the average duration of hospitalization in the TPA recipients was 2.2 days, compared with an average of 4.9 days in the control patients, a statistically significant difference. And at the end of the average 28 months of follow-up, three patients in the control arm had a recurrent PE and another three had died, significantly more than the no recurrent PEs and one death in the TPA arm.

Dr. Sharifi and Dr. Crawford said that they had no relevant disclosures.

CHICAGO – A reduced-dose regimen of tissue plasminogen activator and parenteral anticoagulant safely led to improved outcomes in hemodynamically stable patients with a pulmonary embolism in a pilot study with a total of 121 patients treated at one U.S. center.

None of the 61 patients treated with the regimen, which halved the standard dosage of tissue plasminogen activator (TPA) and cut the dosage of enoxaparin or heparin by about 20%-30%, had an intracranial hemorrhage or a major bleeding event, compared with a historic 2%-6% incidence of intracranial hemorrhage and a 6%-20% incidence of major bleeds in hemodynamically unstable pulmonary embolism patients who receive the standard, full dose of both the thrombolytic and anticoagulant, Dr. Mohsen Sharifi said at the meeting.

Mitchel L. Zoler/IMNG Medical Media

While he acknowledged that the results need confirmation in a larger study, "in our experience treating deep vein thrombosis [with a similarly low dosage of TPA], we are comfortable that this amount of TPA can be given safely," said Dr. Sharifi, an interventional cardiologist who practices in Mesa, Ariz.

The findings also showed that applying this reduced-dose intervention to hemodynamically stable patients with a pulmonary embolism (PE), who are typically not treated, substantially improved their long-term prognosis by reducing their development of pulmonary hypertension. After an average of 28 months follow-up, 9 of the 58 patients (16%) followed long term and treated with the reduced-dose regimen had pulmonary hypertension, defined as a pulmonary artery systolic pressure greater than 40 mm Hg, compared with pulmonary hypertension in 32 of the 56 control patients (57%) managed by standard treatment with anticoagulation only.

Current guidelines from the American Heart Association call for fibrinolytic treatment only in patients with a massive, acute PE, or in patients with a submassive PE who are hemodynamically unstable or have other clinical evidence of an adverse prognosis (Circulation 2011;123:1788-830). According to Dr. Sharifi, about 5% of all PE patients fall into this category. He estimated that broadening thrombolytic treatment to hemodynamically stable patients who met his study’s inclusion criteria could broaden TPA treatment to an additional 70% of PE patients currently seen in emergency departments.

"I think that, based on the results of this pilot study, you won’t get broad acceptance of treating hemodynamically stable PE patients with thrombolysis," commented Dr. Michael Crawford, chief of general cardiology at the University of California, San Francisco. Two larger studies nearing completion are both examining the efficacy and safety of thrombolysis in patients with submassive PE.

Dr. Sharifi said that despite the small study size, he and his associates were convinced enough by their findings to use the reduced TPA dosage tested in this study on a routine basis when they see patients who meet their enrollment criteria.

The MOPETT (Moderate Pulmonary Embolism Treated with Thrombolysis) study enrolled patients with a PE affecting at least two lobar segments, pulmonary artery systolic pressure greater than 40 mm Hg; right ventricular hypokinesia and enlargement; and at least two symptoms, which could include chest pain, tachypnea greater than 22 respirations/min, tachycardia with a resting heart rate of more than 90 beats/min, dyspnea, cough, oxygen desaturation, and jugular venous pressure more than 12 mm H₂O. The average age of the patients was about 59 years, and slightly more than half were women. Their average pulmonary artery systolic pressure at entry was about 50 mm Hg.

Dr. Sharifi and his associates randomized half the patients to receive conventional treatment with anticoagulant only, either enoxaparin or heparin plus warfarin. The other patients received thrombolytic treatment with an infusion of TPA at half the standard dosage, starting in patients who weighed at least 50 kg with a loading dose of 10 mg delivered in 1 minute, and followed by a 40-mg total additional dose administered over 2 hours. Patients who weighed less received the same 10-mg initial dose, but their total dose including the subsequent 2-hour infusion was limited to 0.5 mg/kg. The patients treated with TPA also received concomitant anticoagulation, with either enoxaparin given at 1 mg/kg but not to exceed 80 mg as an initial dose, or heparin at an initial dose of 70 U/kg but capped at 6,000 U, followed by heparin maintenance at 10 U/kg per hour during the TPA infusion (but not exceeding 1,000 U/hour), and then rising to 18 U/kg per hour starting 1 hour after TPA treatment stopped. About 80% of all patients in the study received enoxaparin, and about 20% received heparin.

At 48 hours after starting treatment, average pulmonary artery systolic pressure dropped by 16 mm Hg in the TPA group and by 5 mm Hg in the control patients. By the end of the average 28-month follow-up, average pulmonary artery systolic pressure was 28 mm Hg in the TPA patients and 43 mm Hg in the controls. Dr. Sharifi attributed the efficacy of reduced-dose TPA to the "exquisite sensitivity" of blood clots lodged in a patient’s lungs to the drug, a consequence of all the infused TPA passing through the lung’s arterial circulation.

In addition to showing a statistically significant benefit from TPA for the study’s primary end point, the average duration of hospitalization in the TPA recipients was 2.2 days, compared with an average of 4.9 days in the control patients, a statistically significant difference. And at the end of the average 28 months of follow-up, three patients in the control arm had a recurrent PE and another three had died, significantly more than the no recurrent PEs and one death in the TPA arm.

Dr. Sharifi and Dr. Crawford said that they had no relevant disclosures.