Fibrinolysis for acute pulmonary embolism
Vascular Medicine 15(5) 419–428 © The Author(s) 2010 Reprints and permission: sagepub. co.uk/journalsPermissions.nav DOI: 10.1177/1358863X10380304 http://vmj.sagepub.com
Gregory Piazza and Samuel Z Goldhaber
Abstract Acute pulmonary embolism (PE) presents as a constellation of clinical syndromes with a variety of prognostic implications. Patients with acute PE who have normal systemic arterial blood pressure and no evidence of right ventricular (RV) dysfunction have an excellent prognosis with therapeutic anticoagulation alone. Normotensive acute PE patients with evidence of RV dysfunction are categorized as having submassive PE and comprise a population at intermediate risk for adverse events and early mortality. Patients with massive PE present with syncope, systemic arterial hypotension, cardiogenic shock, or cardiac arrest and have the highest risk for short-term mortality and adverse events. The majority of deaths from acute PE are due to RV pressure overload and subsequent RV failure. The goal of fibrinolysis in acute PE is to rapidly reduce RV afterload and avert impending hemodynamic collapse and death. Although generally considered to be a life-saving intervention in massive PE, fibrinolysis remains controversial for submassive PE. Successful administration of fibrinolytic therapy requires weighing benefit versus risk. Major bleeding, in particular intracranial hemorrhage, is the most feared complication of fibrinolysis. Alternatives to fibrinolysis for acute PE, including surgical embolectomy, catheter-assisted embolectomy, and inferior vena cava (IVC) filter insertion, should be considered when contraindications exist or when patients have failed to respond to an initial trial of fibrinolytic therapy. Patients with massive and submassive PE may be best served by rapid triage to specialized centers with experience in the administration of fibrinolytic therapy and the capacity to offer alternative advanced therapies such as surgical and catheter-assisted embolectomy. Keywords fibrinolysis; pulmonary embolism; right ventricular failure; thrombolysis; tissue plasminogen activator; treatment; venous thromboembolism
Introduction Venous thromboembolism (VTE), comprised of deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cardiovascular disorder in the USA after myocardial infarction (MI) and stroke. The mortality rate for acute PE exceeds 15% in the first 3 months after diagnosis, surpassing that of MI.1 In nearly 25% of patients, the initial manifestation of acute PE is sudden death.2 The majority of deaths from acute PE are due to right ventricular (RV) pressure overload and subsequent RV failure. 3 Survivors of acute PE may develop debilitating chronic thromboembolic pulmonary hypertension.4 Acute PE presents as a constellation of clinical syndromes with a variety of prognostic implications. Patients with acute PE who have normal systemic arterial blood pressure and no evidence of RV dysfunction have an excellent prognosis with therapeutic anticoagulation alone. Normotensive acute PE patients with evidence of RV dysfunction are categorized as having submassive PE and comprise a population at increased risk for adverse events and early mortality.5 Patients with massive PE present with syncope, systemic arterial hypotension, cardiogenic shock, or cardiac arrest. Fibrinolysis is considered a life-saving intervention in massive PE but remains controversial for submassive PE.6,7
In this article, we will discuss the pathophysiology of acute PE and the rationale for fibrinolysis. We will review the literature regarding fibrinolysis for acute massive and submassive PE. Finally, we will provide practical recommendations for the management of acute PE patients undergoing fibrinolysis and alternative therapies for patients who are not eligible for fibrinolytic administration.
Pathophysiology of acute PE Most pulmonary emboli originate from thrombus in the deep venous system of the lower extremities and pelvis. The frequency of PE in the setting of upper extremity DVT ranges broadly from 3% to 33%.8,9 These thrombi can
Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Corresponding author: Gregory Piazza Cardiovascular Division Brigham and Women’s Hospital 75 Francis Street Boston, MA 02115 USA Email:
[email protected]
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Figure 1. Two-dimensional and Doppler echocardiographic findings of right ventricular (RV) pressure overload in submassive pulmonary embolism (PE). Increased diastolic pressure results in RV dilatation and deviation of the interventricular septum (arrows) toward the left ventricle (LV) (Panel A). An abnormal transmitral Doppler flow pattern is observed with left atrial contraction, represented by the A wave on transmitral Doppler, making a greater contribution to LV diastole than passive filling, signified by the E wave (Panel B).
Figure 2. The pathophysiology of right ventricular (RV) dysfunction due to acute pulmonary embolism (PE). PVR, pulmonary vascular resistance; LV, left ventricular.
embolize through the inferior vena cava (IVC) and right heart, thereby obstructing the pulmonary arterial tree and causing hemodynamic and gas exchange abnormalities. The severity of hemodynamic and gas exchange derangements caused by acute PE depends upon the extent of pulmonary arterial obstruction, the patient’s underlying
cardiopulmonary reserve, and the degree of compensatory neurohumoral adaptations. Direct physical obstruction of the pulmonary arteries, hypoxemia, and release of potent pulmonary arterial vasoconstrictors cause an increase in pulmonary vascular resistance and RV afterload.3,10 Sudden elevation in RV afterload may result in RV hypokinesis and dilation, tricuspid regurgitation and, ultimately, acute RV failure. Acute PE patients with RV failure may deteriorate and develop systemic arterial hypotension, cardiogenic shock, and cardiac arrest. Increased diastolic pressure causes deviation of the interventricular septum toward the left ventricle (LV) and impairs LV preload (Figure 1). Abnormal transmitral flow on Doppler echocardiography is observed because left atrial contraction, represented by the A wave on transmitral Doppler, makes a greater contribution to LV diastole than passive filling, signified by the E wave in the setting of RV dysfunction due to PE. RV pressure overload may also result in increased wall stress and ischemia by increasing myocardial oxygen demand while simultaneously limiting its supply (Figure 2). Mismatch between myocardial oxygen demand and supply due to RV pressure overload may lead to eventual RV infarction. Gas exchange abnormalities in patients with acute PE are most commonly due to a combination of ventilation-toperfusion mismatch, increases in total dead space, and right-to-left shunting.10 Arterial hypoxemia and an increased alveolar–arterial oxygen gradient are the most frequently observed abnormalities of gas exchange in patients with
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Piazza G and Goldhaber SZ Table 1. Rationale for fibrinolysis in acute pulmonary embolism • Provides a ‘head start’ in pulmonary reperfusion compared with standard therapy with anticoagulation alone • Rapidly reverses right ventricular (RV) failure due to pressure overload and prevents hemodynamic collapse due to worsening RV dysfunction • Restores systemic arterial perfusion pressure • Improves pulmonary capillary blood flow and gas exchange • Reduces thrombus burden in the pulmonary arteries and deep veins of the pelvis and lower extremities • Decreases the risk of developing chronic thromboembolic pulmonary hypertension
acute PE. Hyperventilation, especially in acute PE patients with normal underlying lung function, may cause hypocapnea and respiratory alkalosis. In massive PE, hypercapnea may result from increases in anatomical and physiological dead space and subsequent reduction in minute ventilation.
Rationale for fibrinolysis in acute PE The rationale for fibrinolysis in acute PE is to rapidly reverse hemodynamic compromise and gas exchange derangements (Table 1). In patients with massive PE, fibrinolysis improves systemic arterial perfusion pressure by relieving RV pressure overload. Fibrinolysis is administered to avert impending hemodynamic collapse and death due to progressive RV failure and to decrease the likelihood of developing chronic thromboembolic pulmonary hypertension. Short-term mortality rates for acute PE patients presenting in shock or requiring cardiopulmonary resuscitation range from 25% to 65%.11 Normotensive patients with acute PE and echocardiographic evidence of RV dysfunction have submassive PE, which confers an increased risk of systemic arterial hypotension, cardiogenic shock, and death compared with those with preserved RV function.5 Conceptualize successful fibrinolysis as a ‘medical embolectomy’ that reduces thrombus burden and more rapidly relieves RV afterload than could be achieved with standard anticoagulation alone. The rapid decrease in pulmonary vascular resistance allows for early recovery of RV function.12–14 In addition, restoration of pulmonary capillary blood flow improves gas exchange.15 Finally, fibrinolysis may help prevent the development of chronic thromboembolic pulmonary hypertension.16 In a follow-up study of patients from two randomized fibrinolysis trials, the Urokinase Pulmonary Embolism Trial (UPET) and the Urokinase-Streptokinase PE Trial (USPET), 23 of the 40 patients were studied after a mean of 7 years to evaluate hemodynamic parameters and response to exercise.17 At rest, mean pulmonary artery pressures and pulmonary vascular resistance were significantly higher in patients treated with heparin only compared with those receiving fibrinolytic therapy.17 After supine bicycle ergometry, both mean pulmonary artery pressures and pulmonary vascular resistance rose significantly in the heparin only group but not in the fibrinolytic group.17 These data suggest that fibrinolysis may preserve the normal hemodynamic response to exercise in the long-term after acute PE.
Table 2. ‘Pros’ and ‘cons’ of fibrinolysis in submassive pulmonary embolism ‘Pros’
‘Cons’
• Reverses right ventricular (RV) failure which may progress to cardiovascular collapse • Reduces the need for escalation of therapy (catecholamine infusion, rescue fibrinolysis, mechanical ventilation, cardiopulmonary resuscitation, or emergency surgical embolectomy) • Decreases the frequency of chronic thromboembolic pulmonary hypertension
• Has limited clinical trial data supporting routine use • Has not been shown to reduce mortality after acute pulmonary embolism (PE) • Increases the risk of major bleeding, including intracranial hemorrhage
Massive PE For patients with massive PE, fibrinolysis is considered a life-saving intervention.6,18 The 2008 American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines recommend fibrinolysis for patients with evidence of hemodynamic compromise unless there are major contraindications owing to bleeding risk (Grade 1B).19 Furthermore, the Guidelines caution against delays in administration of fibrinolysis in massive PE patients and warn that procrastination may lead to irreversible cardiogenic shock.19 In a small randomized controlled clinical trial, patients with acute PE and cardiogenic shock were randomized to fibrinolysis with peripherally administered streptokinase (1,500,000 units over 1 hour) plus anticoagulation with unfractionated heparin versus anticoagulation with unfractionated heparin alone.20 The trial was terminated early after only eight patients of a planned 40 patients were enrolled because of ethical reasons.20 The first four patients treated with heparin alone died within a few hours of arrival to the emergency departments.20 All four patients treated with streptokinase demonstrated rapid hemodynamic improvement within the first hour and survived.20 Three of the four patients treated with heparin underwent postmortem examination and were found to have RV infarction as a result of massive PE.20 A meta-analysis of 11 randomized controlled trials comparing fibrinolysis with heparin anticoagulation alone for acute PE demonstrated that fibrinolytic therapy reduced the risk of recurrent PE or death (9.4% versus 19%; odds ratio 0.45, 95% confidence interval 0.22–0.92; number needed to treat = 10) in the five trials that included patients with massive PE. Despite these data and general consensus guidelines19,21 supporting fibrinolysis in massive PE, an analysis of the International Cooperative Pulmonary Embolism Registry (ICOPER) found that only one-third of patients with massive PE received fibrinolytic therapy.22 In addition, the magnitude of the clinical benefit of fibrinolysis in patients with massive PE remains unclear.22
Submassive PE Use of fibrinolysis in submassive PE remains controversial because of a lack of conclusive randomized controlled trials (Table 2). The 2008 ACCP Guidelines include
422 administration of fibrinolytic therapy as an option for normotensive patients with acute PE and RV dysfunction who are judged to have a low risk of bleeding (Grade 2B).19 However, the Guidelines recommend that the decision to administer fibrinolysis depends on a clinical assessment of PE severity, prognosis, and bleeding risk.19 The largest clinical trial of fibrinolysis in submassive PE to date, Management Strategies and Prognosis of Pulmonary Embolism Trial-3 (MAPPET-3), randomized 256 hemodynamically stable patients with acute PE and either pulmonary hypertension or RV dysfunction to receive recombinant tissue plasminogen activator (t-PA) 100 mg over 2 hours followed by unfractionated heparin infusion or placebo plus heparin anticoagulation.23 The primary study end point was in-hospital death or clinical deterioration requiring escalation of therapy (defined as catecholamine infusion, rescue fibrinolysis, mechanical ventilation, cardiopulmonary resuscitation, or emergency surgical embolectomy).23 Compared with heparin anticoagulation alone, fibrinolysis resulted in a significant reduction in the primary end point.23 The difference was attributable to a higher frequency of escalation of therapy in patients randomized to anticoagulation with heparin alone compared with those treated with fibrinolysis (24.6% versus 10.2%, p = 0.004).23 Specifically, the heparin-alone group received more frequent administration of open-label fibrinolysis due to ‘clinical deterioration’ (a decision which was made by the treating clinician, not the trial investigators). The rate of major bleeding was low in both treatment groups.23 In a prospective study of 200 patients with submassive PE, echocardiography was performed at the time of diagnosis and after 6 months to document the frequency of pulmonary hypertension.16 Of 180 survivors, 162 (90%) patients returned for follow-up, including 144 who had been treated with heparin alone and 18 who had been treated with t-PA plus heparin.16 Among the heparin-only patients, pulmonary hypertension, defined as an estimated pulmonary artery systolic pressure in excess of 39 mmHg, was present in 35% of patients at time of diagnosis, compared with 7% in follow-up.16 If a more widely accepted definition of pulmonary hypertension is used (estimated pulmonary artery systolic pressure greater than 30 mmHg), an even greater proportion of heparin-only patients had pulmonary hypertension at 6 months.16 Estimated pulmonary artery systolic pressure at the 6-month follow-up increased in 27% of patients receiving heparin alone and nearly half of these patients were moderately symptomatic, with a New York Heart Association class of at least III or exercise intolerance on a 6-minute walk test.16 The median decrease in pulmonary artery systolic pressure was only 2 mmHg in patients treated with heparin alone compared with 22 mmHg in those treated with t-PA plus heparin.16 Among patients treated with t-PA and heparin, pulmonary hypertension was present in 61% at time of diagnosis, compared with 11% in follow-up.16 Estimated pulmonary artery systolic pressure at follow-up did not increase in any of the patients treated with t-PA.16 No study has as yet shown a mortality reduction with fibrinolysis in patients with submassive PE. A large
Vascular Medicine 15(5) randomized controlled trial of submassive PE fibrinolysis began in Europe in 2007 aimed at evaluating the impact of fibrinolysis on mortality in submassive PE. The Pulmonary Embolism International Thrombolysis Trial (PEITHO) plans to enroll 1000 patients in 12 countries and will evaluate a primary clinical end point of all-cause mortality or hemodynamic collapse within 7 days in patients treated with the fibrinolytic agent tenecteplase, followed by heparin versus heparin alone. Secondary end points include death within 7 days, hemodynamic collapse within 7 days, objectively confirmed symptomatic PE recurrence within 7 days, death within 30 days, stroke (hemorrhagic or ischemic) within 7 days, major bleeding within 7 days, and serious adverse events within 30 days. As of 31 March 2010, 453 patients have been randomized. Results are expected in 2013. Until then, fibrinolysis for submassive PE should remain a clinical decision made on a case-bycase basis.
Risk stratification While the clinical presentation of hemodynamic instability distinguishes massive from non-massive PE, detection of RV dysfunction is required to identify patients with submassive PE. The presence of RV dysfunction has been associated with an increased 30-day mortality5 and risk of VTE recurrence.24 Clinical examination, electrocardiography, cardiac biomarker determination, chest computed tomography (CT) and echocardiography are key instruments in the detection of RV dysfunction and risk stratification of patients with acute PE (Table 3). The history and physical examination often provide important clinical clues for the risk stratification. An analysis of the International Cooperative Pulmonary Embolism Registry (ICOPER) identified several clinical predictors of increased 30-day mortality, including heart failure, chronic lung disease, cancer, systolic blood pressure ≤ 100 mmHg, age greater than 70 years, and heart rate > 100 beats per minute.5 A risk stratification model combining prognostic variables of age, sex, comorbid conditions including cancer, heart failure, and chronic lung disease, as well as physical examination findings can accurately classify patients with acute PE into categories of increasing risk for death, recurrent VTE, and major bleeding.25 The electrocardiogram is often one of the earliest indicators of RV dysfunction in the setting of acute PE.26 Incomplete or complete right bundle branch block (RBBB), T wave inversions in leads V1-V4, and the combination of an S wave in lead I, Q wave in lead III, and T wave inversion in lead III (S1Q3T3), suggest RV strain in patients with acute PE.10 In an analysis of the Management Strategies and Prognosis in Pulmonary Embolism Trial (MAPPET-1) registry, the presence of any electrocardiographic abnormality (atrial arrhythmias, complete RBBB, low voltage in the limb leads, Q waves in leads III and aVF, or ST segment changes across the precordium) correlated with an increased risk of in-hospital mortality.11 Elevations in cardiac biomarkers, including troponin, brain-type natriuretic peptide (BNP) and heart-type fatty
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Piazza G and Goldhaber SZ Table 3. Instruments for risk stratification of patients with acute pulmonary embolism Clinical signs associated with increased mortality • Heart failure • Chronic lung disease/pneumonia • Malignancy • Systolic blood pressure ≤ 100 mmHg • Age > 70 years • Heart rate > 100 beats per minute Electrocardiographic findings suggestive of right ventricular (RV) dysfunction • Sinus tachycardia • Incomplete or complete right bundle branch block (RBBB) • T wave inversions in leads V1–V4 • S wave in lead I, Q wave in lead III, and T wave inversion in lead III (S1Q3T3) Cardiac biomarker elevation suggestive of RV dysfunction • Cardiac troponins • Brain-type natriuretic peptide (BNP) • Heart-type fatty acid-binding protein (H-FABP)
Figure 3. An algorithm for risk stratification of patients with acute pulmonary embolism. RV, right ventricular; CT, computed tomography; IVC, inferior vena cava.
Chest computed tomography (CT) evidence of RV enlargement Echocardiographic findings in patients with RV pressure overload • RV hypokinesis and dilatation • Interventricular septal flattening and paradoxical motion toward the left ventricle (LV) • Left atrial contraction (A wave) makes a greater contribution to LV diastole than passive filling (E wave), resulting in abnormal transmitral Doppler flow pattern • Tricuspid regurgitation • Pulmonary hypertension as identified by a peak tricuspid regurgitant jet velocity of greater than 2.6 m/s • Loss of inspiratory collapse of the inferior vena cava (IVC) • Patent foramen ovale
acid-binding protein (H-FABP), are associated with RV dysfunction and are important tools for risk stratification. RV pressure overload results in release of cardiac troponin due to RV microinfarction and secretion of BNP in response to increased RV shear stress.27 Also released as a result of myocardial injury, H-FABP diffuses more quickly than troponin and is detectable earlier.28 Elevations in levels of cardiac troponins and BNP signify increased short-term mortality and adverse outcomes among normotensive patients with acute PE.29,30 Acute PE patients with normal H-FABP levels have an excellent prognosis regardless of echocardiographic findings, while those with increased levels have a higher rate of adverse events even if echocardiography is normal.28 In normotensive patients with confirmed PE, increased levels of H-FABP (≥ 6 ng/ml) on admission indicated a marked increase in the risk of death or major adverse events by 30 days, including hemodynamic collapse, respiratory failure, or cardiac arrest, and a nearly fourfold increase in long-term mortality.31 RV enlargement on chest CT is defined by an RV-to-LV diameter ratio of greater than 0.9.32 Presence of RV enlargement on chest CT predicts increased 30-day mortality.32,33 Detection of RV enlargement by chest CT is an especially convenient risk stratification tool because it utilizes data acquired from the initial diagnostic scan.
Echocardiography is the best imaging study to detect RV dysfunction in the setting of acute PE and constitutes the core of risk stratification algorithms (Figure 3). While normotensive patients with acute PE and preserved RV function generally have a benign clinical course, patients with normal systolic blood pressure and echocardiographic evidence of RV dysfunction have an elevated risk of systemic arterial hypotension, cardiogenic shock, cardiac arrest, and death.5,34 Typical echocardiographic findings in patients with acute PE and RV pressure overload include RV hypokinesis and dilatation, interventricular septal flattening and paradoxical motion toward the left ventricle, abnormal transmitral Doppler flow profile, tricuspid regurgitation, pulmonary hypertension as identified by a peak tricuspid regurgitant jet velocity greater than 2.6 m/s, and loss of inspiratory collapse of the inferior vena cava (IVC).34 The finding of regional RV dysfunction with severe free wall hypokinesis and apical sparing (McConnell sign) is specific for acute PE.35 Echocardiography for risk stratification should be performed in patients with acute PE and clinical evidence of RV failure, elevated levels of cardiac biomarkers, and unexpected clinical decompensation.3
Administration of fibrinolysis for PE The U.S. Food and Drug Administration (FDA) has approved recombinant t-PA 100 mg administered as a continuous intravenous infusion over 2 hours for fibrinolysis of acute PE. Optimal administration of fibrinolytic therapy requires careful consideration of the indications and contraindications in order to maximize benefit and minimize risk. The goals of fibrinolysis are rapid reduction in RV pressure overload, stabilization of hemodynamics, and normalization of gas exchange. The biggest risk is intracranial hemorrhage. Fibrinolysis is indicated for the treatment of patients presenting with acute PE and syncope, systemic arterial hypotension, cardiogenic shock, or cardiac arrest (massive PE).
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Table 4. Principal contraindications to fibrinolysis in patients with acute pulmonary embolism
Table 5. Clinical pearls for fibrinolysis in acute pulmonary embolism
• Intracranial malignancy or mass • History of intracranial hemorrhage • Cerebrovascular event or neurosurgical procedure within the prior 2 months • Surgery, invasive procedure, or internal organ biopsy • Recent major trauma • Active or recent respiratory tract, gastrointestinal, or genitourinary bleeding • Severe uncontrolled hypertension • Recent prolonged cardiopulmonary resuscitation • Thrombocytopenia with < 50,000 platelets/μl • Acute pericarditis or pericardial effusion • Ongoing suspicion for aortic dissection
• While considering fibrinolysis, high-dose intravenous unfractionated heparin should be administered as soon as massive pulmonary embolism (PE) is suspected • Unfractionated heparin is preferred in patients undergoing fibrinolysis because it can be discontinued and reversed rapidly • High doses of unfractionated heparin are often necessary because standard doses frequently fail to achieve adequate therapeutic anticoagulation in patients with massive PE • Stop heparin infusion when issuing the order to administer fibrinolysis • Obtain immediate post-fibrinolytic infusion-activated partial thromboplastin time (aPTT) • After the fibrinolytic infusion has concluded, do not restart heparin until the aPTT is < 80 seconds
Although consensus is lacking, fibrinolysis may be considered in appropriately selected patients with acute PE, normal systemic arterial blood pressure, and RV dysfunction or enlargement combined with biomarker elevation (submassive PE). We believe that the overall available evidence supports use of fibrinolysis for submassive PE in patients at low risk for major bleeding complications. All patients being considered for fibrinolytic therapy require meticulous screening for contraindications that make the bleeding risk prohibitive (Table 4). Fibrinolysis has the highest success when administered within several days of acute PE. Although the efficacy of fibrinolytic therapy appears to be inversely proportional to the duration of symptoms, effective fibrinolysis can be achieved up to 2 weeks after an acute PE.36,37 Patients with anatomically extensive PE achieve a greater response to fibrinolysis than those with smaller and often peripherally located thrombi.37 Local, catheter-directed delivery of the fibrinolytic agent directly into the pulmonary artery can be undertaken. This is in contradistinction to catheter-assisted embolectomy which combines local fibrinolysis with mechanical thrombectomy and which we discuss later. Catheter-directed delivery of the fibrinolytic agent may result in more rapid and complete fibrinolysis than systemic fibrinolytic therapy because of higher local drug concentrations and may have fewer bleeding complications.38 Small clinical series have demonstrated success with local administration of fibrinolytic therapy.39–42 In one historical study comparing catheter-directed with peripherally administrated fibrinolysis, local therapy with outdated techniques for drug delivery did not improve efficacy or safety.43 Based upon available data, peripherally administered fibrinolytic therapy is ordinarily preferred to catheter-directed fibrinolysis.
rapidly. In patients with massive PE, standard doses of unfractionated heparin frequently fail to achieve adequate therapeutic anticoagulation, with potentially fatal consequences.18 The majority of massive PE patients will require a minimum 10,000-unit intravenous bolus of unfractionated heparin followed by a continuous infusion of at least 1250 units per hour with a target activated partial thromboplastin time (aPTT) of at least 80 seconds.18 In contrast to fibrinolysis in MI, intravenous unfractionated heparin is withheld (in the USA but not throughout Europe) during the infusion of t-PA in patients with acute PE.13 At the conclusion of the fibrinolytic infusion, the aPTT should be checked. Unfractionated heparin infusion should be restarted without a bolus when the aPTT has fallen to less than 80 seconds. If still greater than 80 seconds, the aPTT should be rechecked every 4 hours until it falls into the range at which heparin can be safely restarted. The adjunctive therapy for patients with massive PE is challenging. While a common initial reaction to systemic arterial hypotension is to augment RV preload with bolus administration of intravenous fluids such as normal saline, care must be taken to avoid excessive volume resuscitation which may worsen RV failure.18 In the setting of RV pressure overload, volume loading may overdistend the RV, increase wall stress, worsen RV ischemia, decrease contractility, and cause further interventricular septal deviation toward the LV, thereby worsening LV filling and reducing systemic cardiac output.3,18 An initial intravenous volume trial of 500 ml is most likely to be successful in acute PE patients without signs of increased RV preload such as those with central venous pressures of less than 12–15 mmHg.3,18 In patients with central venous pressures of greater than 12–15 mmHg, volume loading should be avoided, and the administration of vasopressors and inotropes should be used for hemodynamic support.3 The optimal agent for hemodynamic support of patients with massive PE should augment RV function through positive inotropic effects while also maintaining systemic arterial perfusion pressure.3 Dopamine, norepinephrine, and epinephrine function as both inotropes and vasopressors
Management of patients undergoing fibrinolysis for PE Intravenous unfractionated heparin is the preferred agent for immediate systemic anticoagulation in patients undergoing fibrinolysis or embolectomy (Table 5). Intravenous unfractionated heparin can be discontinued and reversed
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Piazza G and Goldhaber SZ and are favorable agents for the initial support of patients with massive PE.3 Inotropes such as dobutamine may be necessary to augment cardiac output but may result in systemic arterial hypotension.3 In such cases, the addition of a vasopressor such as phenylephrine may be required in order to maintain systemic perfusion.3 Phenylephrine may also be useful in massive PE with tachycardia because it will not further accelerate the heart rate.3
Complications of fibrinolysis The most feared complication of fibrinolysis is bleeding, in particular intracranial hemorrhage. An analysis of data from five clinical trials of fibrinolysis for acute PE reported a risk of intracranial hemorrhage of 1.9%.44 A subsequent analysis from the International Cooperative Pulmonary Embolism Registry (ICOPER) reported that the risk of intracranial hemorrhage may be as high as 3%.1 A study from a center with particular expertise in fibrinolysis for acute PE suggested that the overall major bleeding rate may approach 20%.45 Data from these studies emphasize the importance of careful patient selection before administration of fibrinolytic therapy. Advancing age appears to amplify the risk of hemorrhagic complications, with one study demonstrating a 4% incremental increase in bleeding risk with each year of age.46 Increasing body mass index and use of pulmonary angiography were also significant predictors of major bleeding.46 In another study, diastolic blood pressure was significantly elevated among patients who suffered intracranial hemorrhage compared with those who did not.44 Additional predictors of bleeding complications include the administration of vasopressors for systemic arterial hypotension, cancer, diabetes mellitus, and an elevated international normalized ratio (INR) prior to the administration of fibrinolytic therapy.45 In one prospective multicenter registry, women undergoing fibrinolysis for PE experienced a threefold increase in the frequency of major hemorrhage.47 If a patient develops major bleeding during or after fibrinolysis, the fibrinolytic infusion or heparin should be discontinued immediately.48 In the case of intracranial hemorrhage, neurosurgical consultation should be obtained emergently.48 Clinicians should maintain a high index of suspicion for retroperitoneal hemorrhage, especially in patients with unexplained hypotension or decreases in hematocrit, because bleeding may be sustained, brisk, and difficult to treat.48 Retroperitoneal hemorrhage may result from inadvertent arterial puncture during femoral vein cannulation for pulmonary angiography.48 In the event of a potentially life-threatening bleed, administration of cryoprecipitate may be necessary.48 In general, cryoprecipitate is used when fibrinogen levels are less than 100 mg/dl in the setting of severe bleeding. Recombinant factor VIIa has been used anecdotally offlabel to reverse bleeding associated with excessive or therapeutic fibrinolysis. In a randomized controlled trial of 841 patients with spontaneous intracerebral hemorrhage, recombinant factor VIIa reduced the volume of the hematoma but
did not improve survival or functional outcome.49 Use of recombinant factor VIIa to reverse bleeding after fibrinolysis in the prothrombotic setting of acute PE may exacerbate the underlying condition and increase the risk of other thromboembolic events. Protamine sulfate may be required if the patient has received intravenous unfractionated heparin. Protamine is given as a slow infusion in a dose of 1 mg for every 100 units of heparin administered over the preceding 4 hours (up to a maximum of 50 mg). Clinicians should be aware of a potentially severe allergic reaction to protamine that may develop in patients who have been exposed to neutral protamine Hagedorn (NPH) insulin. Other types of bleeding such as gross hematuria can generally be managed by discontinuing the fibrinolytic infusion or heparin.48 Control minor superficial oozing at venipuncture or arterial catheter sites with manual compression and, if necessary, a pressure dressing.48
Alternatives to fibrinolysis Consider alternatives to fibrinolysis when contraindications exist or when patients have failed to respond to an initial trial of fibrinolytic therapy. Major contraindications to fibrinolytic therapy are present in up to 30% of patients presenting with massive PE.11 Alternative options include surgical embolectomy, catheter-assisted embolectomy, and IVC filter insertion. Each strategy has distinct strengths and limitations (Table 6). Surgical embolectomy is considered for select patients with massive or submassive PE in whom fibrinolysis has failed or is contraindicated. Rescue surgical embolectomy after failed fibrinolysis is preferred over repeat admini stration of fibrinolytic therapy because of a reduced incidence of in-hospital adverse events.50 Additional indications for surgical embolectomy include paradoxical embolism, persistent right heart thrombi, ‘clot-in-transit’, and hemodynamic or respiratory compromise requiring cardiopulmonary resuscitation. The best results with surgical embolectomy are achieved in patients with large centrally located thrombi. Surgical embolectomy requires a median sternotomy and is performed under cardiopulmonary bypass. Perioperative mortality for patients undergoing surgical embolectomy has declined over the last two decades.51 In specialized centers with experience in the performance of the surgery and perioperative management of these patients, surgical embolectomy has been shown to be a safe and effective technique in the treatment of massive PE.52,53 In an analysis of hemodynamically unstable patients with severe pulmonary hypertension and RV dysfunction due to acute PE, surgical embolectomy was associated with reduced in-hospital mortality compared with fibrinolysis.54 However, this comparison was not randomized. Catheter-assisted embolectomy is an emerging technique for advanced therapy when full-dose fibrinolysis has failed or is contraindicated.55–59 In general, catheter-assisted techniques, such as low-dose ‘local’ fibrinolysis and thrombus fragmentation or aspiration, have the highest success
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Table 6. Alternative options for patients with massive or submassive pulmonary embolism (PE) and contraindications to fibrinolytic therapy or in whom fibrinolysis has failed Alternative
Strengths
Limitations
Surgical embolectomy
• Effective in patients with large centrally located thrombi • Preferred after failed fibrinolysis • Preferred for patients with paradoxical embolism, persistent right heart thrombi, ‘clot-in-transit’, or hemodynamic or respiratory compromise requiring cardiopulmonary resuscitation • Effective in patients with large centrally located thrombi • Useful in patients with contraindications to fibrinolysis and surgical embolectomy • Useful if surgical embolectomy is unavailable
• May not be effective for smaller peripherally located thrombi • May not be widely available • Requires median sternotomy and cardiopulmonary bypass
Catheter-assisted embolectomy
Inferior vena cava filter insertion
• Effective for the prevention of recurrent PE • Useful in patients with contraindications to fibrinolysis and surgical or catheter-assisted embolectomy • Retrievable filters offer temporary protection from recurrent PE
when applied to large, centrally located thrombi within the first 5 days of symptoms. The combination of local fibrinolysis and mechanical thrombectomy is called ‘pharmacomechanical therapy’. In a systematic review of 594 patients from 35 studies, the clinical success rate from catheter-assisted embolectomy was 86.5% with relatively low rates of minor and major procedural complications.60 Catheter-assisted embolectomy remains an exciting area of ongoing development and research and holds promise for the management of acute PE. IVC filter insertion is considered for patients with massive or submassive PE in whom fibrinolysis and embolectomy are contraindicated or unavailable. IVC filters are also routinely placed in patients undergoing surgical embolectomy. IVC filter insertion reduces the incidence of recurrent PE but has not been shown to lower long-term mortality.61 However, in an observational analysis of patients with massive PE, IVC filter insertion was associated with decreased 90-day mortality (hazard ratio, 0.12; 95% confidence interval 0.02–0.85).22 Further prospective studies are needed to validate this finding. IVC filters do not arrest the ongoing thrombotic process, and their insertion may be associated with vascular access site complications, including hematoma, arteriovenous fistula, and pseudoaneurysm. In addition, IVC filters appear to increase the risk of DVT.61 Retrievable IVC filters provide a safe and effective alternative to permanent filters and may be removed up to several months after insertion.62
• Requires the administration of iodinated contrast • Volume of contrast administered may worsen right ventricular failure • Associated with risk of pulmonary hemorrhage due to arterial dissection or rupture, especially in smaller caliber pulmonary arteries • Associated with vascular access site complications • Data are lacking in patients with hemodynamically stable PE • Hemolysis • Associated with an increased incidence of deep vein thrombosis • Does not address the initial PE or its hemodynamic effects • May be associated with vascular access site complications
Randomized clinical trials have not been done to determine whether retrievable filters can provide a short-term reduction in recurrent PE or mortality.63
Conclusion Despite current options for the management of patients with acute PE, especially those with hemodynamic insta bility and RV dysfunction, mortality rates remain high. Significant concerns regarding the risk of bleeding and a paucity of adequately powered randomized controlled trials evaluating safety and efficacy continue to limit the application of fibrinolysis in the treatment of patients with acute PE. Clinical trials designed to evaluate clinical end points, including mortality, recurrent PE, and bleeding, are critical to better define the benefits of fibrinolysis. Novel fibrinolytic agents hold promise for more site-specific fibrinolysis and improved safety profiles.64 Patients with massive and submassive PE may be best served by rapid triage to specialized centers with experience in the administration of fibrinolytic therapy and the capacity to offer alternative advanced therapies such as surgical and catheter-assisted embolectomy. Funding Dr Piazza is supported by a Research Career Development Award (K12 HL083786) from the National Heart, Lung, and Blood Institute (NHLBI).
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Piazza G and Goldhaber SZ Conflicts of Interest Dr Piazza has no conflicts of interest to disclose. Dr Goldhaber receives consulting fees from sanofi-aventis, Eisai, Bristol-Myers Squibb, Boehringer Ingelheim, and Medscape. Dr Goldhaber receives grant support from sanofi-aventis, Eisai, Bristol-Myers Squibb, Boehringer Ingelheim, and Johnson & Johnson.
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