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

Thrombolysis for Acute Pulmonary Embolus

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Thrombolysis for Acute Pulmonary Embolus. Michael Tupper M4 Medical Therapeutics University of Michigan Medical School. Objectives. To provide a brief overview of the mechanism of action of thrombolytics To evaluate the use of thrombolytic therapy in following situations - PowerPoint PPT Presentation

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Page 1: Thrombolysis for Acute Pulmonary Embolus

Thrombolysis for Acute Thrombolysis for Acute Pulmonary EmbolusPulmonary Embolus

Michael TupperMichael Tupper

M4 Medical TherapeuticsM4 Medical Therapeutics

University of Michigan Medical SchoolUniversity of Michigan Medical School

Page 2: Thrombolysis for Acute Pulmonary Embolus

ObjectivesObjectives

To provide a brief overview of the To provide a brief overview of the mechanism of action of thrombolyticsmechanism of action of thrombolytics

To evaluate the use of thrombolytic To evaluate the use of thrombolytic therapy in following situationstherapy in following situationsMassive Pulmonary Embolism characterized Massive Pulmonary Embolism characterized

by hemodynamic instabilityby hemodynamic instabilitySubmassive Pulmonary Embolism Submassive Pulmonary Embolism

characterized by right ventricular straincharacterized by right ventricular strainWhen thrombolytic therapy may be When thrombolytic therapy may be

traditionally contraindicatedtraditionally contraindicated

Page 3: Thrombolysis for Acute Pulmonary Embolus

Fibrin

Fibrin(ogen) Degradation Products

Fibrinogen

Thrombin

Plasminogen

Plasmin

t-PA

u-PA

Streptokinase

CoagulationCascade

++

+ +

++

Page 4: Thrombolysis for Acute Pulmonary Embolus

Thrombolysis for PEThrombolysis for PE Treatment of pulmonary embolism with thrombolytic Treatment of pulmonary embolism with thrombolytic

therapy first described in 1969 (streptokinase)therapy first described in 1969 (streptokinase)11

Multiple randomized trials comparing streptokinase, Multiple randomized trials comparing streptokinase, urokinase, and t-PA (in combination with heparin*) to urokinase, and t-PA (in combination with heparin*) to heparin alone since the 1970’sheparin alone since the 1970’s22

Alteplase (recombinant t-PA) 100 mg IV over 2 hrs is the Alteplase (recombinant t-PA) 100 mg IV over 2 hrs is the most commonly used protocol today and the only most commonly used protocol today and the only contemporary thrombolytic approved by the FDA for contemporary thrombolytic approved by the FDA for massive PEmassive PE33

Avoids antigenicity of streptokinaseAvoids antigenicity of streptokinase Alteplase has more rapid administration than UrokinaseAlteplase has more rapid administration than Urokinase In one randomized trial comparing alteplase vs. urokinase, In one randomized trial comparing alteplase vs. urokinase,

alteplase was associated with improved arteriogram appearance alteplase was associated with improved arteriogram appearance at two hours after therapy (though studies were identical at 24 at two hours after therapy (though studies were identical at 24 hours) and was less likely to have thrombolytic therapy ceased hours) and was less likely to have thrombolytic therapy ceased secondary to bleeding complicationssecondary to bleeding complications44

*Administration note: Heparin is held during the infusion of the thrombolytic and then *Administration note: Heparin is held during the infusion of the thrombolytic and then is typically resumed as a continuous infusion as dictated by the aPTTis typically resumed as a continuous infusion as dictated by the aPTT

Page 5: Thrombolysis for Acute Pulmonary Embolus

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

Page 6: Thrombolysis for Acute Pulmonary Embolus

This meta-analysis included This meta-analysis included trials of pts with both massive trials of pts with both massive PE and unselected PEPE and unselected PE

Thrombolytic therapy was Thrombolytic therapy was associated with a associated with a nonsignificant reduction in nonsignificant reduction in recurrent PE and deathrecurrent PE and death

There was a trend towards There was a trend towards more major bleeding more major bleeding complications in patients complications in patients receiving thrombolysis but this receiving thrombolysis but this was not significantly differentwas not significantly different 9.1% in patients receiving 9.1% in patients receiving

thrombolysisthrombolysis 6.1% in patients receiving 6.1% in patients receiving

heparin aloneheparin alone

Circulation. 2004 Aug 10;110(6):744-9.

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However, when a subgroup analysis of 5 trials that included only However, when a subgroup analysis of 5 trials that included only patients with massive PE (hemodynamically unstable) was patients with massive PE (hemodynamically unstable) was performed, there was a statistically significant reduction in recurrent performed, there was a statistically significant reduction in recurrent PE and deathPE and death

Conclusions: No benefit to thrombolytic therapy in unselected Conclusions: No benefit to thrombolytic therapy in unselected patients with PE, but there is a benefit demonstrated in patients patients with PE, but there is a benefit demonstrated in patients selected at highest riskselected at highest risk

Clear indications and recommendations exist that thrombolytic Clear indications and recommendations exist that thrombolytic therapy is a standard, first line treatment for patients with massive therapy is a standard, first line treatment for patients with massive PE characterized by hemodynamic instabilityPE characterized by hemodynamic instability55

Are there other specific situations where thrombolytic therapy is Are there other specific situations where thrombolytic therapy is warranted?warranted?

Circulation. 2004 Aug 10;110(6):744-9.

Page 8: Thrombolysis for Acute Pulmonary Embolus

256 patients with acute pulmonary embolism and pulmonary 256 patients with acute pulmonary embolism and pulmonary hypertension or right ventricular dysfunction but without arterial hypertension or right ventricular dysfunction but without arterial hypotension or shock randomly assigned to receive: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 criteriaInclusion criteria: echocardiographic detected RV dysfunction or pulmonary-artery : echocardiographic detected RV dysfunction or pulmonary-artery hypertension; new electrocardiographic signs of RV strain; or precapillary pulmonary hypertension; new electrocardiographic signs of RV strain; or precapillary pulmonary HTN on right heart catheterization – with confirmation of PE (VQ scan, spiral CT, or HTN on right heart catheterization – with confirmation of PE (VQ scan, spiral CT, or pulmonary angiography)pulmonary angiography)

Exclusion criteriaExclusion criteria: age >80; hemodynamic instability (SBP<90mmHg); onset of : age >80; hemodynamic instability (SBP<90mmHg); onset of symptoms >96hrs before dx; pregnancy/lactation; bleeding diathesis; GI bleeding w/in 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 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 monthsbiopsy w/in 7days; major trauma w/in 10 days; life expectancy < 6 months

Primary End Points:Primary End Points: In-hospital deathIn-hospital death Clinical deterioration that required escalation of treatment:Clinical deterioration that required escalation of treatment:

catecholamine infusion, rescue/secondary thrombolysis, endotracheal intubation, CPR, catecholamine infusion, rescue/secondary thrombolysis, endotracheal intubation, CPR, surgical embolectomy or thromus fragmentation by cathetersurgical embolectomy or thromus fragmentation by catheter

Secondary End PointsSecondary End Points Recurrent PE, major bleeding, and hemorrhagic or ischemic strokeRecurrent PE, major bleeding, and hemorrhagic or ischemic stroke

N Engl J Med. 2002 Oct 10;347(15):1143-50

Page 9: Thrombolysis for Acute Pulmonary Embolus

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

Page 10: Thrombolysis for Acute Pulmonary Embolus

Mortality was low and not Mortality was low and not statistically significant different statistically significant different between groupsbetween groups

Statistical significance obtained Statistical significance obtained when all primary end-points when all primary end-points considered in totalityconsidered in totality

In large part due to increased rate of secondary In large part due to increased rate of secondary thrombolysis in heparin plus placebo groupthrombolysis in heparin plus placebo group

Indications for secondary thrombolysis included Indications for secondary thrombolysis included worsening clinical symptoms (particularly worsening clinical symptoms (particularly dyspnea or worsening respiratory failure), arterial dyspnea or worsening respiratory failure), arterial hypotension or shock, and persistent or hypotension or shock, and persistent or worsening pulmonary HTN or RV dysfunctionworsening pulmonary HTN or RV dysfunction

Recurrent PE, major bleeding, Recurrent PE, major bleeding, and ischemic stroke not and ischemic stroke not significantly differentsignificantly different

Conclusion: Alteplase can Conclusion: Alteplase can prevent clinical deterioration prevent clinical deterioration requiring escalation of treatment requiring escalation of treatment in stable patients with acute in stable patients with acute submassive PEsubmassive PE

N Engl J Med. 2002 Oct 10;347(15):1143-50

Page 11: Thrombolysis for Acute Pulmonary Embolus

Contraindications to ThrombolyticsContraindications to Thrombolytics

Absolute:Absolute: History of hemorrhagic History of hemorrhagic

strokestroke Active intracranial Active intracranial

neoplasmneoplasm Recent (<2 months) Recent (<2 months)

intracranial surgery or intracranial surgery or traumatrauma

Active or recent internal Active or recent internal bleeding in prior 6 bleeding in prior 6 monthsmonths

Relative:Relative: Bleeding diathesisBleeding diathesis Uncontrolled severe Uncontrolled severe

hypertensionhypertension Cardiopulmonary Cardiopulmonary

resuscitationresuscitation Nonhemorrhagic stroke Nonhemorrhagic stroke

within prior 2 monthswithin prior 2 months Surgery within the Surgery within the

previous 10 daysprevious 10 days Thrombocytopenia (plts < Thrombocytopenia (plts <

100,000)100,000)

From UpToDate “Contraindications lysis in PE”

Page 12: Thrombolysis for Acute Pulmonary Embolus

BUT… if your patient is dying (from BUT… if your patient is dying (from massive PE)massive PE)

Resuscitation. 2007 Jan;72(1):154-7. Epub 2006 Nov 2

J Intensive Care Med. 2006 Jul-Aug;21(4):240-5

Page 13: Thrombolysis for Acute Pulmonary Embolus

What about pregnancy?What about pregnancy? Pregnancy procoagulant state with increased risk of DVT and PEPregnancy procoagulant state with increased risk of DVT and PE Not a contraindication for treatment with alteplase, but pregnant women Not a contraindication for treatment with alteplase, but pregnant women

were excluded from phase II and phase III trials were excluded from phase II and phase III trials Seven case reports of pregnant women receiving rt-PA for severe Seven case reports of pregnant women receiving rt-PA for severe

pulmonary emboluspulmonary embolus All 7 women had good outcomesAll 7 women had good outcomes 5/7 children were delivered healthy5/7 children were delivered healthy

One child died due to spontaneous abortion 24hrs after thrombolytic therapy, believed One child died due to spontaneous abortion 24hrs after thrombolytic therapy, believed secondary to severe hemodynamic failure during PA occlusion rather than adverse secondary to severe hemodynamic failure during PA occlusion rather than adverse reaction to rt-PAreaction to rt-PA

Second child died due to neonatal RDS and had multiple intracerebral and Second child died due to neonatal RDS and had multiple intracerebral and subarachnoidal hemorrhages on autopsy that were classified as sequelae of RDSsubarachnoidal hemorrhages on autopsy that were classified as sequelae of RDS

Case reports of twenty-one other pregnant women that received rt-PA for Case reports of twenty-one other pregnant women that received rt-PA for other indicationsother indications Two mothers died, three suffered from complications that were managed Two mothers died, three suffered from complications that were managed

conservativelyconservatively 4/19 fetuses from surviving mothers did not survive4/19 fetuses from surviving mothers did not survive

3/4 fetal demise due to induced abortion for maternal reasons3/4 fetal demise due to induced abortion for maternal reasons 1/4 fetal demise due to spontaneous abortion secondary thrombolysis1/4 fetal demise due to spontaneous abortion secondary thrombolysis

Recommendation: Limited data available but thrombolytic therapy should Recommendation: Limited data available but thrombolytic therapy should not be withheld in pregnant patients in the event of life-threatening PEnot be withheld in pregnant patients in the event of life-threatening PE

Page 14: Thrombolysis for Acute Pulmonary Embolus

RecommendationsRecommendations Thrombolysis is of no benefit in unselected patients with pulmonary Thrombolysis is of no benefit in unselected patients with pulmonary

embolusembolus Thrombolysis has been demonstrated to decrease mortality and PE Thrombolysis has been demonstrated to decrease mortality and PE

recurrence in a subgroup of patients with massive PE characterized recurrence in a subgroup of patients with massive PE characterized by hemodynamic instabilityby hemodynamic instability The contraindications to thrombolysis should be considered in these The contraindications to thrombolysis should be considered in these

patients, but also weighed against the severity of the patients conditionpatients, but also weighed against the severity of the patients condition In stable patients with submassive PE and pulmonary hypertension In stable patients with submassive PE and pulmonary hypertension

or RV strain, thrombolysis prevented clinical deterioration requiring or RV strain, thrombolysis prevented clinical deterioration requiring escalation of treatment in one randomized controlled trial, but has escalation of treatment in one randomized controlled trial, but has not been demonstrated to reduce mortality or PE recurrencenot been demonstrated to reduce mortality or PE recurrence

Proverbially, more studies are needed to further evaluate these Proverbially, more studies are needed to further evaluate these issues and identify other patients that may benefit from thrombolytic issues and identify other patients that may benefit from thrombolytic therapytherapy

Page 15: Thrombolysis for Acute Pulmonary Embolus

ReferencesReferences1.1. Miller GA, Gibson RV, Honey M, Sutton GC. Treatment of Pulmonary embolism with Miller GA, Gibson RV, Honey M, Sutton GC. Treatment of Pulmonary embolism with

streptokinase. A preliminary report. Br Med J 1969; 1:812.streptokinase. A preliminary report. Br Med J 1969; 1:812.2.2. Wan S, Quinlan DJ, Agenlli G, Eikeboom JW. Thrombolysis compared with heparin for the 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. initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 2004 Aug 10; 110(6): 744-9.Circulation 2004 Aug 10; 110(6): 744-9.

3.3. Kucher N, Goldhaber SZ. Management of Massive Pulmonary Embolism. Circulation 2005; Kucher N, Goldhaber SZ. Management of Massive Pulmonary Embolism. Circulation 2005; 112: e28-e32.112: e28-e32.

4.4. Goldhaber SZ, Kessler CM, Heit J, et al. A randomized controlled trial of recombinant tissue 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. plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988; 2:293.Lancet 1988; 2:293.

5.5. Buller HR, Agenlli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for 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 venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 401S-428S.Thrombolytic Therapy. Chest 2004; 126: 401S-428S.

6.6. Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin 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): alone in patients with submassive pulmonary embolism. N Engl J Med 2002 Oct 10; 347(15): 1143-50.1143-50.

7.7. Tapson, VF. Thrombolytic therapy in venous thromboembolism. UpToDate. 2006.Tapson, VF. Thrombolytic therapy in venous thromboembolism. UpToDate. 2006.8.8. Koroneos A, Koutsoukou A, Zervakis D, Politis P, Sourias S, Pagoni E, Roussos C. Koroneos A, Koutsoukou A, Zervakis D, Politis P, Sourias S, Pagoni E, Roussos C.

Successful resuscitation with thrombolysis of a patient suffering fulminant pulmonary Successful resuscitation with thrombolysis of a patient suffering fulminant pulmonary embolism after recent intracerbral hemorrhage. Resuscitation 2007; 72: 154-157.embolism after recent intracerbral hemorrhage. Resuscitation 2007; 72: 154-157.

9.9. Han S. Chaya C, Soo Hoo GW. Thrombolytic therapy for massive pulmonary embolism in a 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.patient with a known intracranial tumor. J Intensive Care Med 2006; 21:240-245.

10.10. Leonhardt G, Gaul C, Nietsch H, Buerke M, Schleussner E. Thrombolytic therapy in Leonhardt G, Gaul C, Nietsch H, Buerke M, Schleussner E. Thrombolytic therapy in pregnancy. J Thromb Thrombolysis 2006; 21(3): 271-276.pregnancy. J Thromb Thrombolysis 2006; 21(3): 271-276.