Special Feature: Thrombolytic Therapy for Pulmonary Embolism
October 1, 2002 11 minutes read
Thrombolytic Therapy for Pulmonary Embolism
By Esther Chen, MD, and Stephanie B. Abbuhl, MD
Most relevant to the emergency care of patients with pulmonary embolism (PE) is rapid diagnosis with risk stratification and initiation of appropriate therapy, with the goals of reducing mortality and improving clinical outcome. Despite improvements in the diagnosis and treatment over the past 30 years, PE still causes approximately 9% of in-hospital deaths and may represent up to 36% of unexplained cardiac arrests with pulseless electrical activity.1,2 In one prospective study of consecutive emergency department (ED) patients who presented with pleuritic chest pain, 21% were found to have PE as diagnosed on pulmonary angiogram or autopsy.3 One of the primary determinants of mortality from PE is right ventricular dysfunction (RVD) causing circulatory collapse and shock, resulting in a mortality rate of 59%.4 The use of thrombolytic therapy (TT) has been suggested in these patients, where the immediate goals are to normalize pulmonary vascular resistance, prevent recurrent embolism, and improve survival.5 The indications for TT remain controversial. Faced with the challenges of rapid decision-making, the ED physician quickly must determine the correct diagnosis and consider the use of TT along with other treatment options, while balancing the potential risks and benefits of therapy.
Pathophysiology of PE
The pulmonary circulation has a remarkable ability to accommodate small to moderate-sized blood clots because of its redundant vasculature. This excess in pulmonary vessels is necessary to accommodate the normal increase in blood flow that occurs during exercise. It is this reserve that allows post-pneumonectomy patients to maintain their ventilation/perfusion (V/Q) balance by opening up vascular beds in the unresected lung.6 This is also the reason why healthy patients with no underlying lung disease can have multiple PEs and present with little or no change in their pulse rate, respiratory rate, p02 , or A-a gradient.7
As clot burden increases, however, there is a limit to the lung’s ability to compensate for obliterated lung vessels, and pulmonary vascular resistance rises. The release of vasoactive substances such as serotonin and bradykinin can cause local bronchial constriction and pulmonary vascular redistribution. With increasing resistance, the right ventricle loses its capacity to increase stroke volume and becomes overloaded and dilated, leading to right heart failure with hemodynamic compromise. Major PEs almost always are associated with hypoxemia from the large areas of pulmonary deadspace and significant V/Q mismatch. In addition, the remaining limited areas of intact pulmonary perfusion are forced to accommodate the entire cardiac output and are overperfused, effectively creating a shunt.6
Mechanism of Action of Thrombolytic Agents
Effective pharmacologic regimens for the treatment of PE fall into two categories: drugs that inhibit coagulation (heparin, low molecular weight heparin, warfarin) and direct thrombolytic agents (streptokinase, urokinase, and tissue plasminogen activator [tPA]). Heparin exerts its effect by activating antithrombin III, which in turn inhibits thrombin, preventing further fibrin deposition on the thrombus. With clot stabilization, heparin enables the patient’s endogenous fibrinolytic mechanisms to take effect, but heparin itself does not lyse existing clot. This concept has been termed "secondary prevention" and is distinctly different from the "primary therapy" of TT and embolectomy.8
Thrombolytic agents dissolve thrombi by activating plasminogen to plasmin, which degrades fibrin to soluble peptides.9 The theoretic advantages of TT over anticoagulation are threefold. First, there should be rapid and complete clot lysis, leading to improvements in hemodynamics, gas exchange, and mortality; second, thrombolysis should dissolve the original venous thrombosis and reduce the risk of recurrent venous thromboembolism; third, the risk of chronic pulmonary hypertension and chronic venous stasis complications should be reduced.10 The TT agents approved for use in PE are streptokinase, urokinase, and tissue plasminogen activator (alteplase, tPA), although there have been several trials with others, such as reteplase and saruplase. In the few comparison studies, there have been no statistical differences in efficacy or safety among the approved agents.10
Evidence Comparing TT with Anticoagulation
In several small, randomized trials and in the larger Urokinase Pulmonary Embolism Trial (UPET), undifferentiated patients with PE were prospectively studied, comparing the effects of thrombolytic agents followed by heparin with heparin alone.11,12,13 These studies have been systematically reviewed in an excellent article by Arcasoy and Kreit.10 In general, these studies concluded that TT significantly increased pulmonary blood flow and improved hemodynamics in the immediate post-treatment period. However, between two hours to seven days, depending on the design of the trial, these differences disappeared. None of these studies revealed a significant difference in mortality or recurrent PE between the two groups. It was not clear if there was truly no difference, or if larger studies would reveal a difference in outcome.
A study by Goldhaber in 1993 was one of the first to suggest that important advantages to TT may exist.14 A total of 101 hemodynamically stable patients were randomized to receive either heparin or tPA and evaluated for right ventricular (RV) function by echocardiogram at baseline, three, and 24 hours. Pulmonary blood flow was measured by perfusion scan at baseline and at 24 hours. The patients who received tPA showed significantly greater improvements in RV function and pulmonary perfusion than the heparinized group. The improvement in RV function was greatest in patients with baseline RVD (89% improvement in the tPA group vs 44% in the heparin alone group; p = 0.03). No patient in the tPA group had a recurrent PE at 14 days, compared to a 9% clinically suspected recurrence rate (two fatal and three non-fatal) in the heparin group, although this did not reach statistical significance (p = 0.06). All recurrences occurred in patients with RVD. Despite showing hemodynamic improvement with TT, this study was not powered to evaluate a survival advantage.
A similar improvement in cardio-pulmonary function in TT-treated patients was reported by Dalla-Volta et al in 1992.15 Thirty-six hemodynamically stable patients with PE were assigned to either alteplase (n = 20) or heparin (n = 16). Improvements in vascular obstruction and pulmonary artery pressures were significantly greater in the TT group vs. the heparin group at two hours post-treatment. However, there were no differences between the two groups when comparing follow-up lung scans done on days seven and 30. Major bleeding episodes occurred in 15% of the alteplase group and in 12.5% of the heparin group.
The first randomized trial to show a decrease in mortality using TT involved only eight patients with major PE and shock who were randomized to receive either TT (bolus streptokinase) or heparin.16 All patients in the heparin group died, whereas all patients who received TT survived. On postmortum examination, all three patients who were autopsied died of RV infarct. This study originally was designed to include 40 patients, but was prematurely terminated because of the significant survival advantage shown with TT. While the study has been criticized for a longer time delay from onset of symptoms to treatment in the heparin group, the results are impressive.
Konstantinides et al published a study from the MAPPET registry that provided insight into the use of TT in patients with RVD, but without shock.17 In the subgroup of 719 patients with moderate or severe RVD and normal systemic blood pressure, the group that received TT had a significantly lower mortality at 30 days when compared to the heparin group (4.7% vs 11.1%). Patients treated with TT also had significantly less frequent recurrent PE than the heparin alone group (7.7% vs 18.7%). Major bleeding complications were significantly higher in the TT group (21.9% vs 7.8%), but cerebral hemorrhage occurred in only two patients in each group. The major limitation of this study was its non-randomized design and inevitable selection bias, in that older patients with underlying co-morbid conditions were selected to receive heparin instead of TT.
Risk Stratification
Along with basic clinical parameters, echocardiography has emerged as a key tool in determining the risk of adverse outcomes in patients with PE. Abnormalities on transthoracic echo (TTE) that predict a large PE include right ventricular dilatation and hypokinesis, paradoxical motion of the interventricular septum with septal flattening, tricuspid regurgitation, and lack of collapse of the inferior vena cava during inspiration.18 Studies that have attempted to define the relationship between RVD and the size of the PE have found that approximately 30% of non-perfused lung predicts most patients with right ventricular hypokinesis.18 While TTE rarely will show actual thrombus, transesophageal echo (TEE) often can directly visualize the extent of the thrombus and its accessibility for surgical embolectomy. However, TEE is limited by the expertise required, the conscious sedation needed, and the fact that a left pulmonary artery embolism can be obscured by the left main bronchus.
Several studies reliably have established RVD on transthoracic echo as a predictor of mortality from PE.14,17,19,20,21,22 In the Konstantinides study, the overall 30-day mortality in patients with RVD and those with normal RV function was 10% and 4.1% (p = 0.018), respectively.17 In another MAPPET registry study, Kasper et al reported 1001 consecutive patients with acute PE who were divided into four groups: 1) RVD or pulmonary HTN on echo without arterial hypotension, 2) arterial hypotension without shock, 3) arterial hypotension with shock, 4) cardiogenic shock requiring CPR.19 The overall mortality was 22%, but highest in group 4 (65% vs 8.1% in group 1). In a second study by Kasper et al, 317 patients studied echocardiographically were subsequently divided into two groups, either with RVD (n = 87) or without RVD (n = 230).20 Patients with RVD had a significantly higher mortality than those without (19% vs 5.7%).
Most recently, in a study by Grifoni et al, 209 patients diagnosed with acute PE by either high probability pulmonary perfusion scan, positive CT scan, or pulmonary angiogram were categorized into four groups: 1) patients with shock or cardiac arrest, 2) hypotensive patients without shock, 3) patients with RVD but normotensive, 4) patients without RVD.22 PE-related mortality was 32% in patients with shock, 5% in normotensive patients with RVD, and 0% in patients without RVD.15
Complications of Thrombolysis
The most important complication of TT is hemorrhage, and the risk of significant bleeding must be carefully weighed against the potential benefits. In contemporary studies the outcome of "major hemorrhage" often is defined as including fatal, intracranial, and/or bleeding requiring surgery or transfusion.10 Given this definition, the average incidence of major hemorrhage is 6.3% with TT and 1.8% with heparin, although the range is wide and depends on numerous patient factors, including age, co-morbidities, and presence of hyper- and hypotension.10 The frequency of major bleeding complications has been as high as 15-27% in some studies.13,15 The rates often are higher in older studies where venous cutdowns routinely were done for angiography and when transfusions were given more readily. In a review of pooled data, the overall incidence of intracranial hemorrhage was found to be 1.2%, with fatal bleeding in about half of these patients.10
Intrapulmonary Thrombolysis
Potential advantages of intrapulmonary over systemic thrombolysis are three-fold. First, local delivery of TT may lead to more rapid and complete clot lysis; second, delivery of the medication directly near the clot may require a smaller amount of the drug to achieve the same result; third, if lower doses are used, there may be an associated lower risk of bleeding.10 There is evidence from the interventional radiology literature that intrapulmonary administration of TT with or without mechanical fragmentation is successful in treating PE; however, these are mainly small case series.23 Verstraete et al published a small pilot study that enrolled 34 patients with angiographically diagnosed PE who were randomized to receive systemic tPA (n = 15) or intrapulmonary tPA (n = 19).24 A post-infusion angiogram showed a decrease in clot burden by 38% from baseline in both groups. There was no significant benefit of intrapulmonary over systemic TT administration. Furthermore, there was no difference in bleeding complications.
In addition to the small size, a significant criticism of the study by Verstraete et al is that the technique that was studied is no longer the standard of care. Intrapulmonary thrombolysis now almost always is coupled with mechanical fragmentation, which is thought to accelerate clot lysis due to the increase in surface area from the fragmentation of the clot. To our knowledge, there have been no randomized trials comparing this new technique with systemic fibrinolysis.23
Conclusion
Three risk stratification categories emerge to assist in acute decision making for the potential use of TT in PE patients:
• In patients with circulatory collapse or shock secondary to PE, TT appears to decrease mortality and recurrence rate as compared to heparin alone;
• In normotensive patients without evidence of RVD on echocardiogram, TT confers no benefit over anticoagulation;
• In normotensive patients with evidence of RVD but without shock, TT may decrease mortality and recurrent PE as compared to heparin alone. A careful assessment of the potential risks and benefits must be made on an individual basis. Furthrer randomized trials are needed to better assess the outcomes measures of both short- and long-term mortality with TT as compared to heparin alone.
(Dr. Chen is Assistant Professor of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia. Dr. Abbuhl, Medical Director, Department of Emergency Medicine, The Hospital of the University of Pennsylvania; Associate Professor of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, is on the Editorial Board of Emergency Medicine Alert.)
References
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