1. Thrombolysis for Acute Pulmonary Embolus Michael Tupper M4 Medical Therapeutics University of Michigan Medical School

2. Objectives To provide a brief overview of the mechanism of action of thrombolytics To provide a brief overview of the mechanism of action of thrombolytics To evaluate the use of thrombolytic therapy in following situations To evaluate the use of thrombolytic therapy in following situations Massive Pulmonary Embolism characterized by hemodynamic instability Massive Pulmonary Embolism characterized by hemodynamic instability Submassive Pulmonary Embolism characterized by right ventricular strain Submassive Pulmonary Embolism characterized by right ventricular strain When thrombolytic therapy may be traditionally contraindicated When thrombolytic therapy may be traditionally contraindicated

3. Fibrin Fibrin(ogen) Degradation Products Fibrinogen Thrombin Plasminogen Plasmin t-PA u-PA Streptokinase Coagulation Cascade + + ++ + +

4. Thrombolysis for PE Treatment of pulmonary embolism with thrombolytic therapy first described in 1969 (streptokinase) 1 Treatment of pulmonary embolism with thrombolytic therapy first described in 1969 (streptokinase) 1 Multiple randomized trials comparing streptokinase, urokinase, and t-PA (in combination with heparin*) to heparin alone since the 1970’s 2 Multiple randomized trials comparing streptokinase, urokinase, and t-PA (in combination with heparin*) to heparin alone since the 1970’s 2 Alteplase (recombinant t-PA) 100 mg IV over 2 hrs is the most commonly used protocol today and the only contemporary thrombolytic approved by the FDA for massive PE 3 Alteplase (recombinant t-PA) 100 mg IV over 2 hrs is the most commonly used protocol today and the only contemporary thrombolytic approved by the FDA for massive PE 3 Avoids antigenicity of streptokinase Avoids antigenicity of streptokinase Alteplase has more rapid administration than Urokinase Alteplase has more rapid administration than Urokinase In one randomized trial comparing alteplase vs. urokinase, alteplase was associated with improved arteriogram appearance at two hours after therapy (though studies were identical at 24 hours) and was less likely to have thrombolytic therapy ceased secondary to bleeding complications 4 In one randomized trial comparing alteplase vs. urokinase, alteplase was associated with improved arteriogram appearance at two hours after therapy (though studies were identical at 24 hours) and was less likely to have thrombolytic therapy ceased secondary to bleeding complications 4 *Administration note: Heparin is held during the infusion of the thrombolytic and then is typically resumed as a continuous infusion as dictated by the aPTT *Administration note: Heparin is held during the infusion of the thrombolytic and then is typically resumed as a continuous infusion as dictated by the aPTT

5. Circulation. 2004 Aug 10;110(6):744-9. Meta-analysis of 11 randomized controlled trials (748 patients - heterogeneous population); outcome is recurrent PE or death

6. This meta-analysis included trials of pts with both massive PE and unselected PE This meta-analysis included trials of pts with both massive PE and unselected PE Thrombolytic therapy was associated with a nonsignificant reduction in recurrent PE and death Thrombolytic therapy was associated with a nonsignificant reduction in recurrent PE and death There was a trend towards more major bleeding complications in patients receiving thrombolysis but this was not significantly different There was a trend towards more major bleeding complications in patients receiving thrombolysis but this was not significantly different 9.1% in patients receiving thrombolysis 6.1% in patients receiving heparin alone Circulation. 2004 Aug 10;110(6):744-9.

7. However, when a subgroup analysis of 5 trials that included only patients with massive PE (hemodynamically unstable) was performed, there was a statistically significant reduction in recurrent PE and death However, when a subgroup analysis of 5 trials that included only patients with massive PE (hemodynamically unstable) was performed, there was a statistically significant reduction in recurrent PE and death Conclusions: No benefit to thrombolytic therapy in unselected patients with PE, but there is a benefit demonstrated in patients selected at highest risk Conclusions: No benefit to thrombolytic therapy in unselected patients with PE, but there is a benefit demonstrated in patients selected at highest risk Clear indications and recommendations exist that thrombolytic therapy is a standard, first line treatment for patients with massive PE characterized by hemodynamic instability 5 Clear indications and recommendations exist that thrombolytic therapy is a standard, first line treatment for patients with massive PE characterized by hemodynamic instability 5 Are there other specific situations where thrombolytic therapy is warranted? Are there other specific situations where thrombolytic therapy is warranted? Circulation. 2004 Aug 10;110(6):744-9.

8. 256 patients with acute pulmonary embolism and pulmonary hypertension or right ventricular dysfunction but without arterial hypotension or shock randomly assigned to receive: 256 patients with acute pulmonary embolism and pulmonary hypertension or right ventricular dysfunction but without arterial hypotension or shock randomly assigned to receive: Heparin plus t-PA (alteplase)100mg (n=118) Heparin plus t-PA (alteplase)100mg (n=118) Heparin plus placebo (n=138) Heparin plus placebo (n=138) Inclusion criteria: echocardiographic detected RV dysfunction or pulmonary-artery hypertension; new electrocardiographic signs of RV strain; or precapillary pulmonary HTN on right heart catheterization – with confirmation of PE (VQ scan, spiral CT, or pulmonary angiography) Inclusion criteria: echocardiographic detected RV dysfunction or pulmonary-artery hypertension; new electrocardiographic signs of RV strain; or precapillary pulmonary HTN on right heart catheterization – with confirmation of PE (VQ scan, spiral CT, or pulmonary angiography) Exclusion criteria: age >80; hemodynamic instability (SBP 96hrs before dx; pregnancy/lactation; bleeding diathesis; GI bleeding w/in 6 months; stroke, TIA, craniocerebral trauma, neurosurgery w/in 6 months; surgery or biopsy w/in 7days; major trauma w/in 10 days; life expectancy 80; hemodynamic instability (SBP 96hrs before dx; pregnancy/lactation; bleeding diathesis; GI bleeding w/in 6 months; stroke, TIA, craniocerebral trauma, neurosurgery w/in 6 months; surgery or biopsy w/in 7days; major trauma w/in 10 days; life expectancy < 6 months Primary End Points: Primary End Points: In-hospital death In-hospital death Clinical deterioration that required escalation of treatment: Clinical deterioration that required escalation of treatment: catecholamine infusion, rescue/secondary thrombolysis, endotracheal intubation, CPR, surgical embolectomy or thromus fragmentation by catheter catecholamine infusion, rescue/secondary thrombolysis, endotracheal intubation, CPR, surgical embolectomy or thromus fragmentation by catheter Secondary End Points Secondary End Points Recurrent PE, major bleeding, and hemorrhagic or ischemic stroke Recurrent PE, major bleeding, and hemorrhagic or ischemic stroke N Engl J Med. 2002 Oct 10;347(15):1143-50

9. RV Strain Defined (one of the following) : Complete or incomplete right bundle branch block Inverted T waves in precordial leads V1, V2, V3 S waves in lead I combined with Q waves in lead III

10. Mortality was low and not statistically significant different between groups Mortality was low and not statistically significant different between groups Statistical significance obtained when all primary end-points considered in totality Statistical significance obtained when all primary end-points considered in totality In large part due to increased rate of secondary thrombolysis in heparin plus placebo group Indications for secondary thrombolysis included worsening clinical symptoms (particularly dyspnea or worsening respiratory failure), arterial hypotension or shock, and persistent or worsening pulmonary HTN or RV dysfunction Recurrent PE, major bleeding, and ischemic stroke not significantly different Recurrent PE, major bleeding, and ischemic stroke not significantly different Conclusion: Alteplase can prevent clinical deterioration requiring escalation of treatment in stable patients with acute submassive PE Conclusion: Alteplase can prevent clinical deterioration requiring escalation of treatment in stable patients with acute submassive PE N Engl J Med. 2002 Oct 10;347(15):1143-50

11. Contraindications to Thrombolytics Absolute: History of hemorrhagic stroke History of hemorrhagic stroke Active intracranial neoplasm Active intracranial neoplasm Recent (<2 months) intracranial surgery or trauma Recent (<2 months) intracranial surgery or trauma Active or recent internal bleeding in prior 6 months Active or recent internal bleeding in prior 6 monthsRelative: Bleeding diathesis Bleeding diathesis Uncontrolled severe hypertension Uncontrolled severe hypertension Cardiopulmonary resuscitation Cardiopulmonary resuscitation Nonhemorrhagic stroke within prior 2 months Nonhemorrhagic stroke within prior 2 months Surgery within the previous 10 days Surgery within the previous 10 days Thrombocytopenia (plts < 100,000) Thrombocytopenia (plts < 100,000) From UpToDate “Contraindications lysis in PE”

12. BUT… if your patient is dying (from massive PE) Resuscitation. 2007 Jan;72(1):154-7. Epub 2006 Nov 2 J Intensive Care Med. 2006 Jul-Aug;21(4):240-5

13. What about pregnancy? Pregnancy procoagulant state with increased risk of DVT and PE Pregnancy procoagulant state with increased risk of DVT and PE Not a contraindication for treatment with alteplase, but pregnant women were excluded from phase II and phase III trials Not a contraindication for treatment with alteplase, but pregnant women were excluded from phase II and phase III trials Seven case reports of pregnant women receiving rt-PA for severe pulmonary embolus Seven case reports of pregnant women receiving rt-PA for severe pulmonary embolus All 7 women had good outcomes All 7 women had good outcomes 5/7 children were delivered healthy 5/7 children were delivered healthy One child died due to spontaneous abortion 24hrs after thrombolytic therapy, believed secondary to severe hemodynamic failure during PA occlusion rather than adverse reaction to rt-PA One child died due to spontaneous abortion 24hrs after thrombolytic therapy, believed secondary to severe hemodynamic failure during PA occlusion rather than adverse reaction to rt-PA Second child died due to neonatal RDS and had multiple intracerebral and subarachnoidal hemorrhages on autopsy that were classified as sequelae of RDS Second child died due to neonatal RDS and had multiple intracerebral and subarachnoidal hemorrhages on autopsy that were classified as sequelae of RDS Case reports of twenty-one other pregnant women that received rt-PA for other indications Case reports of twenty-one other pregnant women that received rt-PA for other indications Two mothers died, three suffered from complications that were managed conservatively Two mothers died, three suffered from complications that were managed conservatively 4/19 fetuses from surviving mothers did not survive 4/19 fetuses from surviving mothers did not survive 3/4 fetal demise due to induced abortion for maternal reasons 3/4 fetal demise due to induced abortion for maternal reasons 1/4 fetal demise due to spontaneous abortion secondary thrombolysis 1/4 fetal demise due to spontaneous abortion secondary thrombolysis Recommendation: Limited data available but thrombolytic therapy should not be withheld in pregnant patients in the event of life-threatening PE Recommendation: Limited data available but thrombolytic therapy should not be withheld in pregnant patients in the event of life-threatening PE

14. Recommendations Thrombolysis is of no benefit in unselected patients with pulmonary embolus Thrombolysis is of no benefit in unselected patients with pulmonary embolus Thrombolysis has been demonstrated to decrease mortality and PE recurrence in a subgroup of patients with massive PE characterized by hemodynamic instability Thrombolysis has been demonstrated to decrease mortality and PE recurrence in a subgroup of patients with massive PE characterized by hemodynamic instability The contraindications to thrombolysis should be considered in these patients, but also weighed against the severity of the patients condition The contraindications to thrombolysis should be considered in these patients, but also weighed against the severity of the patients condition In stable patients with submassive PE and pulmonary hypertension or RV strain, thrombolysis prevented clinical deterioration requiring escalation of treatment in one randomized controlled trial, but has not been demonstrated to reduce mortality or PE recurrence In stable patients with submassive PE and pulmonary hypertension or RV strain, thrombolysis prevented clinical deterioration requiring escalation of treatment in one randomized controlled trial, but has not been demonstrated to reduce mortality or PE recurrence Proverbially, more studies are needed to further evaluate these issues and identify other patients that may benefit from thrombolytic therapy Proverbially, more studies are needed to further evaluate these issues and identify other patients that may benefit from thrombolytic therapy

15. References 1. Miller GA, Gibson RV, Honey M, Sutton GC. Treatment of Pulmonary embolism with streptokinase. A preliminary report. Br Med J 1969; 1:812. 2. Wan S, Quinlan DJ, Agenlli G, Eikeboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 2004 Aug 10; 110(6): 744-9. 3. Kucher N, Goldhaber SZ. Management of Massive Pulmonary Embolism. Circulation 2005; 112: e28-e32. 4. Goldhaber SZ, Kessler CM, Heit J, et al. A randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988; 2:293. 5. Buller HR, Agenlli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 401S-428S. 6. 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 Oct 10; 347(15): 1143-50. 7. Tapson, VF. Thrombolytic therapy in venous thromboembolism. UpToDate. 2006. 8. Koroneos A, Koutsoukou A, Zervakis D, Politis P, Sourias S, Pagoni E, Roussos C. Successful resuscitation with thrombolysis of a patient suffering fulminant pulmonary embolism after recent intracerbral hemorrhage. Resuscitation 2007; 72: 154-157. 9. Han S. Chaya C, Soo Hoo GW. Thrombolytic therapy for massive pulmonary embolism in a patient with a known intracranial tumor. J Intensive Care Med 2006; 21:240-245. 10. Leonhardt G, Gaul C, Nietsch H, Buerke M, Schleussner E. Thrombolytic therapy in pregnancy. J Thromb Thrombolysis 2006; 21(3): 271-276.