Thrombolysis for Acute Pulmonary EmbolusMichael TupperM4 Medical TherapeuticsUniversity of Michigan Medical School
ObjectivesTo provide a brief overview of the mechanism of action of thrombolyticsTo evaluate the use of thrombolytic therapy in following situationsMassive Pulmonary Embolism characterized by hemodynamic instabilitySubmassive Pulmonary Embolism characterized by right ventricular strainWhen thrombolytic therapy may be traditionally contraindicated
FibrinFibrin(ogen) Degradation ProductsFibrinogenThrombinPlasminogenPlasmint-PAu-PAStreptokinaseCoagulationCascade++++++
Thrombolysis for PETreatment of pulmonary embolism with thrombolytic therapy first described in 1969 (streptokinase)1Multiple randomized trials comparing streptokinase, urokinase, and t-PA (in combination with heparin*) to heparin alone since the 1970s2Alteplase (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 PE3Avoids antigenicity of streptokinaseAlteplase has more rapid administration than UrokinaseIn 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
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
This meta-analysis included trials of pts with both massive PE and unselected PEThrombolytic therapy was associated with a nonsignificant reduction in recurrent PE and deathThere was a trend towards more major bleeding complications in patients receiving thrombolysis but this was not significantly different9.1% in patients receiving thrombolysis6.1% in patients receiving heparin alone
Circulation. 2004 Aug 10;110(6):744-9.
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 deathConclusions: No benefit to thrombolytic therapy in unselected patients with PE, but there is a benefit demonstrated in patients selected at highest riskClear indications and recommendations exist that thrombolytic therapy is a standard, first line treatment for patients with massive PE characterized by hemodynamic instability5Are there other specific situations where thrombolytic therapy is warranted?
Circulation. 2004 Aug 10;110(6):744-9.
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 (SBP96hrs 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 monthsPrimary End Points:In-hospital deathClinical deterioration that required escalation of treatment:catecholamine infusion, rescue/secondary thrombolysis, endotracheal intubation, CPR, surgical embolectomy or thromus fragmentation by catheterSecondary End PointsRecurrent PE, major bleeding, and hemorrhagic or ischemic strokeN Engl J Med. 2002 Oct 10;347(15):1143-50
RV Strain Defined (one of the following):Complete or incomplete right bundle branch blockInverted T waves in precordial leads V1, V2, V3S waves in lead I combined with Q waves in lead III
Mortality was low and not statistically significant different between groupsStatistical significance obtained when all primary end-points considered in totalityIn large part due to increased rate of secondary thrombolysis in heparin plus placebo groupIndications 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 dysfunctionRecurrent PE, major bleeding, and ischemic stroke not significantly differentConclusion: Alteplase can prevent clinical deterioration requiring escalation of treatment in stable patients with acute submassive PEN Engl J Med. 2002 Oct 10;347(15):1143-50
- Contraindications to ThrombolyticsAbsolute:History of hemorrhagic strokeActive intracranial neoplasmRecent (
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
What about pregnancy?Pregnancy procoagulant state with increased risk of DVT and PENot 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 embolusAll 7 women had good outcomes5/7 children were delivered healthyOne 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-PASecond child died due to neonatal RDS and had multiple intracerebral and subarachnoidal hemorrhages on autopsy that were classified as sequelae of RDSCase reports of twenty-one other pregnant women that received rt-PA for other indicationsTwo mothers died, three suffered from complications that were managed conservatively4/19 fetuses from surviving mothers did not survive3/4 fetal demise due to induced abortion for maternal reasons1/4 fetal demise due to spontaneous abortion secondary thrombolysisRecommendation: Limited data available but thrombolytic therapy should not be withheld in pregnant patients in the event of life-threatening PE
RecommendationsThrombolysis is of no benefit in unselected patients with pulmonary embolusThrombolysis has been demonstrated to decrease mortality and PE recurrence in a subgroup of patients with massive PE characterized by hemodynamic instabilityThe contraindications to thrombolysis should be considered in these patients, but also weighed against the severity of the patients conditionIn 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 recurrenceProverbially, more studies are needed to further evaluate these issues and identify other patients that may benefit from thrombolytic therapy
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Leonhardt G, Gaul C, Nietsch HH, Buerke M, Schleussner E. Thrombolytic therapy in pregnancy. J Thromb Thrombolysis. 2006 Jun;21(3):271-6.