Thrombolysis for Acute Pulmonary Embolus

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 evaluate the use of thrombolytic therapy in following situations • Massive Pulmonary Embolism characterized by hemodynamic instability • Submassive Pulmonary Embolism characterized by right ventricular strain • When thrombolytic therapy may be traditionally contraindicated

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

4. Thrombolysis for PE • 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’s2 • 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 PE3 • Avoids antigenicity of streptokinase • 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 complications4 • *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. Meta-analysis of 11 randomized controlled trials (748 patients - heterogeneous population); outcome is recurrent PE or death Circulation. 2004 Aug 10;110(6):744-9.

6. 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 • 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 • 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 instability5 • 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: • Heparin plus t-PA (alteplase)100mg (n=118) • 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) • Exclusion criteria: age >80; hemodynamic instability (SBP<90mmHg); onset of symptoms >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: • In-hospital death • Clinical deterioration that required escalation of treatment: • catecholamine infusion, rescue/secondary thrombolysis, endotracheal intubation, CPR, surgical embolectomy or thromus fragmentation by catheter • Secondary End Points • 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 • 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 • 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. Absolute: History of hemorrhagic stroke Active intracranial neoplasm Recent (<2 months) intracranial surgery or trauma Active or recent internal bleeding in prior 6 months Relative: Bleeding diathesis Uncontrolled severe hypertension Cardiopulmonary resuscitation Nonhemorrhagic stroke within prior 2 months Surgery within the previous 10 days Thrombocytopenia (plts < 100,000) Contraindications to Thrombolytics From UpToDate “Contraindications lysis in PE”

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

13. What about pregnancy? • 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 • Seven case reports of pregnant women receiving rt-PA for severe pulmonary embolus • All 7 women had good outcomes • 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 • 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 • Two mothers died, three suffered from complications that were managed conservatively • 4/19 fetuses from surviving mothers did not survive • 3/4 fetal demise due to induced abortion for maternal reasons • 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

14. Recommendations • 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 • 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 • Proverbially, more studies are needed to further evaluate these issues and identify other patients that may benefit from thrombolytic therapy

15. References • Miller GA, Gibson RV, Honey M, Sutton GC. Treatment of Pulmonary embolism with streptokinase. A preliminary report. Br Med J 1969; 1:812. • 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. • Kucher N, Goldhaber SZ. Management of Massive Pulmonary Embolism. Circulation 2005; 112: e28-e32. • 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. • 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. • 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. • Tapson, VF. Thrombolytic therapy in venous thromboembolism. UpToDate. 2006. • 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. • 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. • Leonhardt G, Gaul C, Nietsch H, Buerke M, Schleussner E. Thrombolytic therapy in pregnancy. J Thromb Thrombolysis 2006; 21(3): 271-276.