A 49-year-old morbidly obese woman presented to the emergency department with shortness of breath and abdominal distention. On presentation, her blood pressure was 100/60 mm Hg with a heart rate of 110, respiratory rate of 24, and a pulse oximetric saturation (SpO2) of 86% on room air. Troponin T was elevated at 0.3 ng/mL. Computed tomography (CT) of the chest with intravenous contrast showed saddle pulmonary embolism (PE) with dilated right ventricle (RV). CT abdomen/pelvis revealed a very large uterine mass with diffuse lymphadenopathy.
Heparin infusion was started promptly. Echocardiogram demonstrated RV strain. Findings on duplex ultrasound of the lower extremities were consistent with acute deep vein thromboses (DVT) involving the left common femoral vein and the right popliteal vein. Biopsy of a supraclavicular lymph node showed high grade undifferentiated carcinoma most likely of uterine origin.
What, if any, therapeutic options should be considered beyond standard systemic anticoagulation? Is there a role for:
1. Systemic thrombolysis?
2. Catheter-directed thrombolysis (CDT)?
3. Inferior vena cava (IVC) filter placement?
What is the appropriate management of “submassive” PE?
In the case of massive PE, where the thrombus is located in the central pulmonary vasculature and associated with hypotension due to impaired cardiac output, systemic thrombolysis, embolectomy, and CDT are indicated as potentially life-saving measures. However, the evidence is less clear when the PE is large and has led to RV strain, but without overt hemodynamic instability. This is commonly known as an intermediate risk or “submassive” PE. Submassive PE based on American Heart Association (AHA) guidelines is:1
An acute PE without systemic hypotension (systolic blood pressure less than 90 mm Hg) but with either RV dysfunction or myocardial necrosis. RV dysfunction is defined by the presence of at least one of these following:
• RV dilation (apical 4-chamber RV diameter divided by LV diameter greater than 0.9) or RV systolic dysfunction on echocardiography;
• RV dilation on CT, elevation of BNP (greater than 90 pg/mL), elevation of N-terminal pro-BNP (greater than 500 pg/mL);
• Electrocardiographic changes (new complete or incomplete right bundle branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion).
Myocardial necrosis is defined as elevated troponin I (greater than 0.4 ng/mL) or elevated troponin T (greater than 0.1 ng/mL).
Why is submassive PE of clinical significance?
In 1999, analysis of the International Cooperative Pulmonary Embolism Registry (ICOPER) revealed that RV dysfunction in PE patients was associated with a near doubling of the 3-month mortality risk (hazard ratio 2.0, 1.3-2.9).2 Given this increased risk, one could draw the logical conclusion that we need to treat submassive PE more aggressively than PE without RV strain. But will this necessarily result in a better outcome for the patient given the 3% risk of intracranial hemorrhage associated with thrombolytic therapy?
In the clinical scenario above, the patient did meet the definition of submassive PE. While the patient did not experience systemic hypotension, she did have RV dilation on CT, RV systolic dysfunction on echo as well as an elevated Troponin T level. In addition to starting anticoagulant therapy, what more should be done to increase her probability of a good outcome?
The AHA recommends that systemic thrombolysis and CDT be considered for patients with acute submassive PE if they have clinical evidence of adverse prognosis, including worsening respiratory failure, severe RV dysfunction, or major myocardial necrosis and low risk of bleeding complications (Class IIB; Level of Evidence C).1
The 2016 American College of Chest Physicians (CHEST) guidelines update3 recommends systemically administered thrombolytic therapy over no therapy in selected patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk (Grade 2C recommendation).
Systemic thrombolysis is administered as an intravenous thrombolytic infusion delivered over a period of time. The Food and Drug Administration–approved thrombolytic drugs currently include tissue plasminogen activator (tPA)/alteplase, streptokinase and urokinase.
Efficacy of low dose thrombolysis was studied in MOPETT 2013,5 a single-center, prospective, randomized, open label study, in which 126 participants found to have submassive PE based on symptoms and CT angiographic or ventilation/perfusion scan data received either 50 mg tPA plus heparin or heparin anticoagulation alone. The composite endpoint of pulmonary hypertension and recurrent PE at 28 months was 16% in the tPA group compared to 63% in the control group (P less than .001). Systemic thrombolysis was associated with lower risk of pulmonary hypertension and recurrent PE, although no mortality benefit was seen in this small study.
In the randomized, double-blind PEITHO trial (n = 1,006) of 20146 comparing tenecteplase plus heparin versus heparin in the submassive PE patients, the primary outcomes of death and hemodynamic decompensation occurred in 2.6% of the tenecteplase group, compared to 5.6% in the placebo group (P = .02). Thrombolytic therapy was associated with 2% rate of hemorrhagic stroke, whereas hemorrhagic stroke in the placebo group was 0.2% (P = .03). In this case, systemic thrombolysis was associated with a 3% lower risk of death and hemodynamic instability, but also a 1.8% increased risk of hemorrhagic stroke.
Catheter-directed thrombolysis (CDT)
CDT was originally developed to treat arterial, dialysis graft and deep vein thromboses, but is now approved by the FDA for the treatment of acute submassive or massive PE.
A wire is passed through the embolus and a multihole infusion catheter is placed, through which a thrombolytic drug is infused over 12-24 hours. The direct delivery of the drug into the thrombus is thought to be as effective as systemic therapy but with a lower risk of bleeding. If more rapid thrombus removal is indicated due to large clot burden and hemodynamic instability, mechanical therapies, such as fragmentation and aspiration, can be used as an adjunct to CDT. However, these mechanical techniques carry the risk of pulmonary artery injury, and therefore should only be used as a last resort. An ultrasound-emitting wire can be added to the multihole infusion catheter to expedite thrombolysis by ultrasonically disrupting the thrombus, a technique known as ultrasound-enhanced thrombolysis (EKOS).7,10
The ULTIMA 2014 trial,8 a small, randomized, open-label study of Ultrasound-Assisted Catheter Directed Thrombolysis (USAT, the term can be used interchangeably with EKOS) versus heparin anticoagulation alone in 59 patients, was designed to study if the former strategy was better at improving the primary outcome measure of RV/LV ratio in submassive PE patients. The mean reduction in RV/LV ratio was 0.30 +/– 0.20 in the USAT group compared to 0.03 +/– 0.16 in the heparin group (P less than .001). However, no significant difference in mortality or bleeding was observed in the groups at 90-day follow up.
The PERFECT 2015 Trial,9 a multicenter registry-based study, prospectively enrolled 101 patients who received CDT as first-line therapy for massive and submassive PE. Among patients with submassive PE, 97.3% were found to have “clinical success” with this treatment, defined as stabilization of hemodynamics, improvement in pulmonary hypertension and right heart strain, and survival to hospital discharge. There was no major bleeding or intracranial hemorrhage. Subgroup analyses in this study comparing USAT against standard CDT did not reveal significant difference in average pulmonary pressure changes, average thrombolytic doses, or average infusion times.
A prospective single-arm multicenter trial, SEATTLE II 2015,10 evaluated the efficacy of EKOS in a sample of 159 patients. Patients with both massive and submassive PE received approximately 24 mg tPA infused via a catheter over 12-24 hours. The primary efficacy outcome was the chest CT-measured RV/LV ratio decrease from the baseline compared to 48 hours post procedure. The pre- and postprocedure ratio was 1.55 versus 1.13 respectively (P less than .001), indicating that EKOS decreased RV dilation. No intracranial hemorrhage was observed and the investigators did not comment on long-term outcomes such as mortality or quality of life. The study was limited by the lack of a comparison group, such as anticoagulation with heparin as monotherapy, or systemic thrombolysis or standard CDT.
Treatment of submassive PE varies between different institutions. There simply are not adequate data comparing low dose systemic thrombolysis, CDT, EKOS, and standard heparin anticoagulation to make firm recommendations. Some investigators feel low-dose systemic thrombolysis is probably as good as the expensive catheter-based thrombolytic therapies.11,12 Low-dose thrombolytic therapy can be followed by use of oral direct factor Xa inhibitors for maintenance of antithrombotic activity.13
In our institution, the interventional radiology team screens patients who meet criteria for submassive PE on a case-by-case basis. We use pulmonary angiographic data (nature and extent of the thrombus), clinical stability, and analysis of other comorbid conditions to decide the best treatment modality for an individual patient. Our team prefers EKOS for submassive PE patients as well as for massive PE patients and as a rescue procedure for patients who have failed systemic thrombolysis.
Until more data are available to support firm guidelines, we feel establishing multidisciplinary teams composed of interventional radiologists, intensivists, cardiologists, and vascular surgeons is prudent to make individualized decisions and to achieve the best outcomes for our patients.14
Since the patient in this case already has a submassive PE, can she tolerate additional clot burden should her remaining DVT embolize again? Is there a role for IVC filter?
The implantation of IVC filters has increased significantly in the past 30 years, without quality evidence justifying their use.15
The 2016 Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report states clearly: In patients with acute DVT of the leg or PE who are treated with anticoagulants, the use of an IVC filter is not recommended (Grade 1B).3 This recommendation is based on findings of the Prevention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) randomized trial,16 and the recently published PREPIC 2 randomized trial,17 both showing that in anticoagulated patients with PE and DVT, concurrent placement of an IVC filter for 3 months did not reduce recurrent PE, including fatal PE.
CHEST guidelines state that an IVC filter should not be routinely placed as an adjunct in patients with PE and DVT. However, what about in the subgroup of patients with submassive or massive PE in whom another PE would be catastrophic? Clinical data are lacking in this area.
Deshpande et al. reported on a series of six patients with massive PE and cardiopulmonary instability; patients all received an IVC filter with anticoagulation. The short-term outcome was excellent, but long-term follow-up was not done.18 Kucher and colleagues reported that from the ICOPER in 2006, out of the 108 massive PE patients with systolic arterial pressure under 90 mm Hg, 11 patients received adjunctive IVC filter placement. None of these 11 patients developed recurrent PE in 90 days and 10 of them survived at least 90 days; IVC filter placement was associated with a reduction in 90-day mortality. In this study, the placement of an IVC filter was entirely decided by the physicians at different sites.19 In a 2012 study examining case fatality rates in 3,770 patients with acute PE who received pulmonary embolectomy, the data showed that in both unstable and stable patients, case fatality rates were lower in those who received an IVC filter.20
Although the above data are favorable for adjunctive IVC filter placement in massive PE patients, at least in short-term outcomes, the small size and lack of randomization preclude establishment of evidence-based guidelines. The 2016 CHEST guidelines point out that as it is uncertain if there is benefit to place an IVC filter adjunctively in anticoagulated patients with severe PE, in this specific subgroup of patients, the recommendation against insertion of an IVC filter in patients with acute PE who are anticoagulated may not apply.3
There is no evidence-based guideline as to whether IVC filters should be placed adjunctively in patients with submassive or massive PE; however, based on expert consensus, it may be appropriate to place an IVC filter as an adjunct to anticoagulation in patients with severe PE. The decision should be individualized based on each patient’s characteristics, preferences, and institutional expertise.
In our case, in hope of preventing further embolic burden, the patient received an IVC filter the day after presentation. Despite the initiation of anticoagulation with heparin, she remained tachycardic and tachypneic, prompting referral for CDT. The interventional radiology team did not feel that she was a good candidate, given her persistent vaginal bleeding and widely metastatic uterine carcinoma. She was switched to therapeutic enoxaparin after no further invasive intervention was deemed appropriate. Her respiratory status did not improve and bilevel positive airway pressure was initiated. Taking into consideration the terminal nature of her cancer, she ultimately elected to pursue comfort care and died shortly afterward.
The authors would like to thank Benjamin A. Hohmuth, MD, A. Joseph Layon, MD, and Luis L. Nadal, MD, for their review of the article and invaluable feedback.
Dr. Wenqian Wang, Dr. Vedamurthy, and Dr. Wang are based in the department of hospital medicine at The Medicine Institute, Geisinger Health System, Danville, Penn. Contact Dr. Wenqian Wang at [email protected].
• Use pulmonary angiographic data, clinical stability, and analysis of other comorbid conditions to decide the best treatment modality.
• Our team prefers ultrasound-enhanced thrombolysis (EKOS) for submassive PE patients, massive PE patients, and as a rescue procedure for patients who fail systemic thrombolysis.
• Establishing multidisciplinary teams composed of interventional radiologists, intensivists, cardiologists, and vascular surgeons is prudent to make individualized decisions.
• It may be appropriate to place an IVC filter as an adjunct to anticoagulation in patients with severe PE.
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