Practice of Medicine
Is Thrombolysis Only for a Crisis?
December 19, 2017
Is Thrombolysis Only for a Crisis?
Indications for Thrombolytic Therapy in Patients with Acute Pulmonary Embolism
A 28 year old woman with a history of systemic lupus erythematosus (SLE) and recurrent miscarriages presented to the emergency department (ED) with right sided chest pain and shortness of breath (SOB). On examination she had a pulse of 132, blood pressure of 98/60 and an oxygen saturation of 90% on 3L/min of supplemental oxygen (administered via a nasal cannula). The ED attending suspected pulmonary embolism (PE) and ordered a stat chest CT angiography. The chest CT revealed a large acute PE in the right pulmonary artery (PA) extending to the descending branch of the right PA. The patient was given a bolus of IV heparin then started on a heparin drip and admitted to the medical floor. Doppler ultrasound of the lower extremities was ordered to assess for deep vein thrombosis (DVT). A routine transthoracic echocardiogram (TTE) was also ordered to assess for right ventricular (RV) dysfunction and evaluate for pulmonary hypertension.
Eight hours following admission, before the Doppler ultrasound or TTE were obtained, the patient experienced worsening SOB. The nurse assigned to the patient contacted the respiratory therapist on duty and the patient’s physician. Based on the nurse’s report of the patient’s condition, the admitting physician consulted the pulmonologist on call for his opinion regarding thrombolytic therapy. Twenty minutes later when the pulmonologist arrived, the patient’s breathing was labored, her oxygen saturation was 88% on a non re-breather face mask, her pulse was 146, and her blood pressure was 83/48. The pulmonologist immediately requested an intubation kit and placed a stat order for tissue plasminogen activator (tPA). While the team was setting up the intubation tray and just as the pharmacist was entering the room with the tPA, the patient coded. Cardiopulmonary resuscitation was initiated and tPA was started. The patient failed to respond to resuscitation and died ten hours after admission. The patient’s family sued, alleging that the admitting doctor failed to recognize the patient’s clinical severity and failed to consult the pulmonary specialist and give tPA in a timely manner.
Patients with PE vary from stable, with no need for supplemental oxygen, to critically unstable with significant oxygen requirements and imminent cardiac collapse. In some cases indications for thrombolytic use may be clear, with no contraindications, making the decision straight-forward. In many instances however, indications are weak or unclear and contraindications may be present, raising concerns.
In the case presented above, both the ED physician and the admitting physician assessed the patient as appropriate for anticoagulation with heparin alone as the initial therapy. A closer look at this case revealed that in addition to having tachycardia, commonly seen with PE, the patient’s BP was decreased on presentation and her clot burden was fairly large. Although the patient was not initially in shock, a more expeditious assessment of her RV function (via echocardiography) may have persuaded her doctors to consider administration of tPA at an earlier point in her clinical course. While her PE was diagnosed in a timely manner, the degree of her hemodynamic compromise was not fully appreciated.
Anticoagulation, the standard of care for venous thromboembolic disease, prevents propagation of an existing clot and formation of new clots but does not cause lysis of an existing thrombus. In cases where a thrombus causes significant vascular occlusion associated with cardiovascular collapse, thrombolytic therapy may be warranted to restore hemodynamic stability. Studies indicate that thrombolytic therapy results in early hemodynamic improvement among patients with PE but, unfortunately, is associated with an increased risk of major bleeding. In addition, the impact of thrombolytic therapy on PE related mortality or recurrence of thromboembolism is unclear. Thus, the decision to use thrombolytic therapy in patients with acute PE needs to be individualized and the benefits must always be weighed against the risks. Thrombolytic therapy is typically reserved for cases of confirmed PE, given the associated risk for major bleeding, and is avoided when PE is merely suspected.
Indications for Thrombolytic Therapy in patients with PE
The most consistently agreed upon indication for use of thrombolytic therapy in patients with acute PE is the presence of hemodynamic instability. Typically hemodynamic instability is associated with hypotension from obstructive shock. Less often, individuals may be able to maintain a blood pressure at the lower limit of normal in the face of significant right ventricular compromise. Echocardiography can be used to assess for right ventricular dysfunction and to identify the presence of septal deviation in persons with pulmonary embolism. Another echocardiographic parameter that has prognostic value in the setting of PE is the ratio of the right ventricular (RV) end-diastolic diameter to the left ventricular (LV) end-diastolic diameter. The mortality associated with PE three months after the event increases in a step-wise manner once the RV/LV is ≥ 1.0. Elevated troponin levels and/or significantly increased brain natriuretic peptide levels also portend a poor prognosis in individuals with PE.
In addition to the presence of hemodynamic instability, other possible indications for thrombolytic therapy in patients with PE include:
- Right ventricular (RV) dysfunction (identified on echocardiography)
- Large clot burden
- Cardiopulmonary arrest due to PE
- Free floating (intra-cardiac) thrombus
Management of obstructive shock in the setting of PE often warrants removal of the obstructive thrombus to restore hemodynamic stability. In cases where the risk of bleeding is unduly high or a contraindication to thrombolytic therapy exists, mechanical removal of the thrombotic material may be attempted via surgery or an endovascular approach. If a decision is made to give thrombolytic therapy, the thrombolytic agent may be administered systemically or via a catheter-directed approach.
Use of thrombolytic therapy for acute PE with RV dysfunction in the absence of shock remains controversial since few studies have examined the benefit of thrombolysis in this group. The largest randomized study looking at use of thrombolytic therapy in normotensive patients with acute PE and RV dysfunction, the “Pulmonary Embolism Thrombolysis” (PEITHO) trial, revealed that fibrinolysis prevented hemodynamic decompensation in patients with intermediate-risk PE but increased the risk of major hemorrhage and stroke. Hence, while thrombolytic therapy may seem appropriate for individuals with severe RV dysfunction, given the bleeding risks involved, the decision gets complicated when RV dysfunction is only mild to moderate in severity. To justify the use of thrombolytics the benefits should clearly outweigh any risks involved. Presence of other poor prognostic clinical indicators, such as high oxygen requirements, elevated troponin levels and/or highly elevated brain natriuretic peptide (BNP) levels, may lend support to a decision to use thrombolytic therapy in the setting of RV dysfunction without shock.
Patients with PE who have a significant clot burden but are hemodynamically stable are sometimes given thrombolytic therapy due to concerns that they will experience pulmonary hypertension (PH) and RV dysfunction. Evidence to support this practice is lacking. A single study comparing use of heparin alone to use of heparin in combination with “lower-dose” tissue plasminogen activator (tPA) among patients with “moderate” PE showed lower rates of PH, faster resolution of PH and similar risk of bleeding in the group that received combination therapy. The trial, titled “Moderate Pulmonary Embolism Treated with Thrombolysis” (MOPETT), defined moderate PE as signs and symptoms of PE PLUS >70 percent embolism in ≥2 lobar arteries or main PA on CT pulmonary angiogram OR a high probability ventilation/perfusion (V/Q) scan showing V/Q mismatch in ≥ 2 lobes. Despite the significant findings noted in the MOPPETT trial, the sample size was small (121) thus this one study cannot be used to guide clinical practice.
Decisions regarding use of fibrinolytic therapy to treat PE in patients who experience cardiopulmonary arrest or who have a free floating intra-cardiac clot should be made on an individual basis as there is no clear evidence against or in support of this practice.
Contraindications to Thrombolytic Therapy for PE
The relative and absolute contraindications to thrombolytic therapy in patients with acute PE are listed below.
- Severe uncontrolled hypertension on presentation (SBP >180 mmHg or DBP >110 mmHg)
- History of chronic, severe, poorly controlled hypertension
- History of ischemic stroke more than three months prior
- Traumatic or prolonged (>10 minute) CPR or major surgery less than three weeks prior
- Recent (within two to four weeks) internal bleeding
- Non-compressible vascular punctures
- Recent invasive procedure
- For streptokinase/anistreplase - Prior exposure (more than five days ago) or prior allergic reaction to these agents
- Active peptic ulcer
- Pericarditis or pericardial fluid
- Current use of anticoagulant (eg, warfarin sodium) that has produced an elevated international normalized ratio (INR) >1.7 or prothrombin time (PT) >15 seconds
- Age >75 years
- Diabetic retinopathy
- Known intracranial neoplasm
- Intracranial or spinal surgery or trauma
- History of intracranial hemorrhage
- Known structural cerebral vascular lesion
- Ischemic stroke within three months (excluding stroke within three hours*)
- Suspected aortic dissection
- Active bleeding or bleeding diathesis (excluding menses)
- Significant closed-head trauma or facial trauma within three months
* The American College of Cardiology (ACC) suggests that select stroke patients may benefit from thrombolytic therapy within 4.5 hours of symptom onset.
Concluding Remarks/Key Points
The benefit of thrombolytic therapy in the setting of acute PE complicated by shock has been widely accepted however, there are many cases of acute PE where the indication for thrombolytic therapy remains unclear, thus additional studies are needed to determine which other patient populations with PE would benefit from thrombolytics. The risks and benefits of thrombolytic therapy should be carefully weighed in each patient before a decision is made to administer a thrombolytic agent. When the indication for thrombolytic therapy is unclear, it is prudent to obtain the opinion of a specialist (with experience in treating PE and knowledge of the current PE guidelines) early in the patient’s clinical course.
Clinical scenarios where thrombolytics could be considered for treating PE:
- Cases where the individual has a high clot burden and evidence of RV dysfunction on echocardiography even if the individual does not demonstrate hemodynamic instability
- Cases where an individual has cardiac arrest secondary to PE
Several references and resources are provided below.
References and Resources
Chatterjee S, Chakraborty A, Weinberg I, et. al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun;311(23):2414-21.
Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. 2004 Aug;110(6):744-9.
Meyer G, Vicaut E, Danays T. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11.
Sharifi M1, Bay C, Skrocki L, et. al. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol. 2013 Jan 15;111(2):273-7.
Sista AK, Kearon C. Catheter-Directed Thrombolysis for Pulmonary Embolism: Where Do We Stand? JACC Cardiovasc Interv. 2015 Aug 24;8(10):1393-5.
Kearon C, Akl EA, Comerota AJ, et. al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e419S.
Victor F. Tapson. Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis. UpToDate (Accessed December 19, 2016
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