THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM By Rikkea Nelson, R.T. (R) (VI) A Thesis submitted to the School of Radiologic Sciences In partial fulfillment of the requirements for the degree of MASTER OF SCIENCE IN RADIOLOGIC SCIENCES (MSRS) WEBER STATE UNIVERSITY Ogden, Utah December 10, 2020 THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 2 THE WEBER STATE UNIVERSITY GRADUATE SCHOOL SUPERVISORY COMMITTEE APPROVAL of a thesis submitted by Rikkea Nelson, R.T. (R) (VI) This thesis has been read by each member of the following supervisory committee and by majority vote found to be satisfactory. ______________________________ Dr. Robert Walker, PhD Chair, School of Radiologic Sciences ______________________________ Dr. Tanya Nolan, EdD Director of MSRS ______________________________ Dr. Laurie Coburn, EdD Director of MSRS RA THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 3 Acknowledgments To Michael, my loving and supportive husband. I wouldn’t be here without you. THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 4 Table of Contents Abstract ....................................................................................................................................................... 6 Introduction ................................................................................................................................................ 7 Methods ..................................................................................................................................................... 12 Data Analysis ............................................................................................................................................ 13 Discussion ................................................................................................................................................. 15 References ................................................................................................................................................. 18 THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 5 List of Tables Table 1. Contraindications of Thrombolysis in a PE patient……………………………16 THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 6 Abstract Pulmonary embolism, whether massive or sub-massive, requires appropriate emergent treatment. This process needs to take the most effective course of treatment based on patient symptomology and hemodynamic stability status. Therefore, treatment options explored should be based on the patient’s clinical signs and symptoms, with specific contraindications for intervention, and a benefit versus risk assessment for each individual case. As mentioned, this process is required to take place in a timely manner due to the emergent nature of the condition. A systemic approach to therapy may assist medical professional in this process, such that timely treatment is initiated. A meta-analysis of current literature on treating PE, concludes that treatment options remain controversial and further research is needed for institutions to implement PE treatment algorithms. THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 7 Introduction Acute pulmonary embolism (PE) is when clot travels to the lungs and suddenly prevents the exchange of oxygen to occur. It is the third most common cardiovascular event, behind myocardial infarction and stroke (Giri et al., 2019). PE occurrence is on the rise and is one of the leading causes of in-hospital morbidity and mortality (Avgerinos et al., 2018). Hence, there is a need for improved understanding of course of treatment and the affected outcomes. How to intervene and proceed with treatment has been controversial and studies have attempted to understand outcomes and what treatment is best for each type of PE. This is important because mortality is substantial among patients with massive and sub-massive pulmonary embolism and when advanced treatments are used, a 61% reduction in mortality has been shown (Secemsky et al., 2018). Outcomes have been compared when analyzing the approach of the two most common courses of treatment: systemic thrombolysis (ST) and catheter directed thrombolysis (CDT), when compared to anti-coagulation alone. By analyzing the studies, we gain a better understanding of what the best treatment plan and intervention for the patient who presents with acute PE, based on their type of PE and their comorbidities. Literature Review Some research research researchresearchresearchresearch andand datadatadata reportreportreport the advantagesadvantages advantages advantagesadvantages advantages of usingusing cathetercathetercatheter catheter-directed directed directeddirected thrombolysis thrombolysisthrombolysis thrombolysis (CDT). (CDT). The Aggarwal AggarwalAggarwal AggarwalAggarwal et al.al. study comparescompares comparescompares the outcomeoutcome of 110,731 patients patients patientspatientspatients that were were admittedadmitted admitted admittedadmitted to the hospital hospital with PulmonaryPulmonary Pulmonary Pulmonary Embolism Embolism (PE). SomeSome received receivedreceivedreceived thrombolysis thrombolysis as pa rt of their treatment treatmenttreatment treatmenttreatment plan andand others others were were treated treatedtreatedtreated with cathetercathetercatheter cathetercatheter-direct directdirect thrombolysis, thrombolysis, thrombolysis, addressingaddressing addressing addressing the risks with systemic systemicsystemic systemic thrombolysis; thrombolysis;thrombolysis; thrombolysis; bleeding bleeding and/orand/or hemorrhagic hemorrhagic hemorrhagic hemorrhagic stroke. stroke.stroke. This study demonstrated demonstrated demonstrated demonstrated that CDTCDT allowedallowed allowed allowed more efficientefficient efficient efficientefficient dissolution dissolution dissolution of clot,clot, clot, therefor therefortherefor therefor therefore, creatingcreating creatingcreating creating shorter shorter timestimes timestimes of infusion andand lowering lowering the overall overalloveralloverall risk of bleeding bleeding complicationcomplication complication complication complication (Aggarwal, (Aggarwal, (Aggarwal, (Aggarwal,(Aggarwal, Nicolais, Nicolais, Lee Lee & Bashir,Bashir,Bashir, 2017). 2017). THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 8 The first listed Averginos et al. study analyzed catheter-directed interventions (CDIs) and the effect on a patient presenting with acute pulmonary embolism (PE). This study compared the outcomes of patients receiving CDI or systemic thrombolysis (ST). The data found that CDIs improve the right ventricular function when recovery was compared to those who received ST. CDIs are believed to be a complimentary treatment to ST and that recommended use of the treatments should be based on clinical presentation and risk factors (Avgerinos et al., 2018). The second listed Averginos study analyzed patients who received suction thrombolytic (ST) catheter intervention for massive and sub-massive PE against a matching patient who received catheter directed thrombolysis (CDT). The matching of patients was based on PE type, age, gender, presence of acute deep vein thrombosis (DVT), pulmonary disease, and date of the procedure. Thrombolytic therapy was found to help prevent the hemodynamic decompensation of the patient (Avgerinos et al., 2019). Dudzinski, Giri, Rosenfield & Dudzinski address the poor outcomes of massive and submissive pulmonary embolism and the controversial clinical benefits to using thrombolysis. The study ultimately found that clinical outcomes were similar, when comparing the systemic thrombolysis and catheter-directed thrombolysis. Rate of bleeding complications were found to not be significantly different between the two groups. The effectiveness of thrombolysis in patients that are hemodynamically stable is still considered controversial (Dudzinski, Giri, Rosenfield, & Dudzinski, 2017). A person’s person’s person’s hemodynamic hemodynamic hemodynamichemodynamic hemodynamic stability stability is one considerationconsideration consideration considerationconsiderationconsideration consideration in management, management, management, treatment treatmenttreatment treatmenttreatment andand outcomes outcomes in those with PE.PE. Many Many studies studiesstudies have have analyzedanalyzedanalyzedanalyzed analyzed the hemodynamichemodynamichemodynamic stability stability patients, patients, patients,patients, including the strain strain that PE can causecausecause cause the right ventricle. ventricle. ventricle. The ValerioValerioValerio Valerio 2019 2019 study found that if a patient’s patient’s patient’s patient’s hemodynamics hemodynamics areare stable, stable, including includingincluding including ventricular ventricular ventricular heart heartheart strain, strain, systemic systemicsystemic systemic thrombolysis thrombolysis THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 9 should should not be a treatment treatmenttreatment treatmenttreatment option option because becausebecausebecause the substa substantial ntialntial bleeding bleeding risk outweighs outweighsoutweighs the benefit benefit benefit (Valerio, (Valerio,(Valerio, (Valerio, 2019). 2019). Treatment TreatmentTreatmentTreatment TreatmentTreatment of PE has has other other treatment treatmenttreatment treatmenttreatment options. options. The option option of surgical surgicalsurgical pulmonary pulmonary pulmonary embolectomyembolectomy embolectomyembolectomyembolectomy embolectomy (SPE), (SPE), (SPE), which which until until recently, recently,recently,recently, recently, was was known known to be a controversialcontroversial controversialcontroversial controversial treatment treatmenttreatment treatmenttreatment (QiMan (QiMan et al.,al., 2020) is currentlycurrently currentlycurrently currently anotheranotheranother treatment treatmenttreatment treatmenttreatment option. option. Historically, Historically, Historically,Historically, Historically, SPE was was given as a final finalfinal option option andand last resort resort for unstable unstableunstable PE patients, patients, patients,patients, which which couldcould explainexplain the high mortality mortality mortality rate rate associatedassociated associatedassociated with SPE (QiMan (QiMan et al.,al., 2020). 2020). BeingBeingBeing ableable to get get the unstableunstable PE patient patient patientpatient to the OR is challengingchallenging challenging challengingchallenging andand the use of anesthesiaanesthesiaanesthesiaanesthesia is complicatedcomplicated complicated complicated with the unfavorable unfavorable unfavorable hemodynamics hemodynamics (QiMan(QiMan (QiMan et al.,al., 2019), 2019), addingadding to the low utilization utilization utilizationutilizationutilization utilization of this this option option for treatment. treatment.treatment. treatment.treatment. Recently, Giri et al. (2019) sought to understand the treatment options for acute PE from an endovascular interventional therapy standpoint. They also considered the use of new therapeutic devices and the evidence of their contributions. Active assessment of patient-specific bleeding risks and the associated harm of thrombolytics and thrombus removal devices was studied. Giri et al. (2019) describes 3 categories of Pulmonary Embolism (PE): Massive, Sub-Massive and Low Risk. With those 3 categories in mind, they further addressed current stratification schemes and the attempt of predicting patient outcomes and mortality chances. Intermediate risk patients appear to have similar outcomes when receiving systemic thrombolysis versus catheter-directed thrombolysis. Giri et al. (2019) found there is uncertainty of optimal dose and duration of thrombolytics. Finally, they describe the formation of Pulmonary Embolism Response Teams (PERT) in the hospital setting to be able to assess and quickly designate the appropriate method of care (Giri et al., 2019). Jain Jain et al.al. (2017) (2017) similarly similarly similarlysimilarly similarly comparedcompared comparedcompared massive andand sub -massive pulmonary pulmonary pulmonary embolismembolism embolism location location location with practice practicepractice practicepractice patternspatternspatternspatterns patterns andand patient patient patientpatient outcomes. outcomes.outcomes. This study performed performed performed performed analysisanalysis analysis analysis on a larger larger larger THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 10 list list of therapies therapiestherapies including anticoagulation,anticoagulation, anticoagulation,anticoagulation, anticoagulation, IVCIVC filter placement, placement,placement, systemic systemicsystemic systemic thrombolysis thrombolysis given intravenously intravenously intravenously intravenously intravenously (IV),(IV),(IV),(IV), cathetercathetercatheter catheter -directed directeddirected thrombolysis thrombolysis (CDT), (CDT), the suction suction suction thrombectomy thrombectomy thrombectomy thrombectomy method, extracorporealextracorporeal extracorporealextracorporealextracorporeal extracorporealextracorporealextracorporeal membrane membranemembranemembrane oxygenation oxygenation oxygenation oxygenation andand surgical surgicalsurgicalsurgical embolectomy.embolectomy. embolectomy.embolectomy.embolectomy. embolectomy. Jain Jain et al.al. (2017) (2017) found that clotclot burden, burden, sub -massive or massive, did not have have an effecteffect effecteffecteffect on mortality mortality mortality at 90 days. days. Further,Further, Further, they describedescribed escribed escribed patientpatientpatient patientpatient clinicalclinical clinical clinical presentation presentation presentation as more more indicative indicativeindicativeindicative indicative of how to proceed proceedproceedproceedproceed andand treat treattreat the pulmonary pulmonary pulmonary embolism,embolism, embolism, embolism, when when comparedcompared comparedcompared to treatment treatmenttreatment treatmenttreatment planning based based based on radiographic radiographic radiographic radiographic appearanceappearance appearanceappearanceappearanceappearanceappearance appearance of the PE (Jain (Jain et al.,al., 2017). 2017). RecentRecentRecentRecentRecent research researchresearchresearchresearchresearchresearch in Germany, Germany, Germany,Germany, studied studiedstudied the potent ially lifesaving lifesaving lifesaving lifesaving abilitiesabilities abilities abilities of systemic systemicsystemic systemic thrombolysis thrombolysis andand measured measured measured the trend trend of when when it waswaswas used used andand the outcomes outcomesoutcomes was was of patients patients patientspatients presenting presenting presenting presenting with PE (Keller (Keller(Keller (Keller(Keller et al.,al., 2019). 2019). Acute Acute PE was was associatedassociated associatedassociatedassociated with a high in -hospital hospital mortality mortality mortality rate rate andand the overall overalloverall overall risk was found to be based based based on patient’s patient’s patient’s patient’s presenting presentingpresenting presenting presenting clinicalclinical clinical clinical status, co -morbidities morbidities morbiditiesmorbidities andand treatment treatmenttreatment treatmenttreatment plan. WhenWhen When there there areare no contraindications,contraindications, contraindications,contraindications, contraindications,contraindications,contraindications, contraindications, the use of systemic systemicsystemicsystemic thrombolysis thrombolysis was was the recommended recommendedrecommended recommendedrecommended recommended coursecourse of treatment treatmenttreatment treatmenttreatment to assistassist assist in re -perfusing perfusing perfusingperfusing patients patients patientspatients with hemodyna hemodyna mically micallymicallymically mically unstable unstableunstableunstable PE (Keller (Keller(Keller (Keller(Keller et al.,al., 2019). 2019). The Patel et al. (2015) study also compared outcomes of systemic thrombolysis (ST) and catheter directed thrombolysis (CDT). Specifically, they compared a primary outcome of in-hospital mortality and a secondary combined outcome of in-hospital mortality with intra-cranial hemorrhage (ICH). This study found catheter directed thrombolysis had significantly lower primary and secondary outcomes when compared to systemic thrombolysis (Patel et al., 2015). The Emergency Emergency EmergencyEmergencyEmergency Medicine Medicine Medicine journal journal comparedcompared compared compared clinicalclinical clinical clinicalclinical outcomes outcomes of pulmonary pulmonary pulmonarypulmonary embolismembolismembolism embolism (PE) patients patients patientspatients when when eithereither either either systemic systemicsystemicsystemic thrombolysis thrombolysis (ST) or cathetercathetercatheter catheter directed directeddirected thrombolysisthrombolysis thrombolysis (CDT) (CDT) was was used used as treatment treatmenttreatmenttreatment treatmenttreatment options. options. options. BleedingBleeding Bleeding complicationscomplications complications complications complications (minor (minor andand major), major), mortalities mortalities mortalities mortalitiesmortalities of patients, patients, patients,patients, hospital hospital stays, length of time in the ICU,ICU,ICU, andand need needneed for intubation intubation intubation intubation were were allall categoriescategoriescategories categories used used in this this THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 11 study. study. This study claimsclaims similar similar similarsimilar clinicalclinical clinical clinical outcomes outcomes between between betweenbetween CDTCDT andand ST treatments treatmentstreatments treatmentstreatments in patients patients patientspatients with PE.PE. (9). (9). The Henneman Henneman HennemanHenneman study found that CDTCDT treatment, treatment,treatment, treatment,treatment, fo r acuteacuteacute massive massive massive andand submassive submassivesubmassive submassive PE,PE, “significantly significantly significantlysignificantly significantly improves improves improves RV/LVRV/LV ratio ratio ratio at 24 -48 hours comparedcompared comparedcompared with anticoagulationanticoagulation anticoagulationanticoagulation anticoagulation alonealone andand may lower lower hospital hospital readmissionreadmissionreadmissionreadmission readmission readmission rates” rates” (Henneman,(Henneman, (Henneman, (Henneman,(Henneman, 2018). 2018). The journal, “A metametameta -analysis analysis of outcomes outcomesoutcomes of cathetercatheter catheter-directed directed thrombolys thrombolysthrombolysis for high - and intermediate intermediateintermediate intermediate intermediate-risk risk pulmonary pulmonary embolismembolism embolism”, provides a meta-analysis highlighting the benefit of CDT in both high risk (massive) PE and intermediate risk (sub-massive) PE (Avgerinos et al., 2018). However, the study also concluded that there is an increased risk of bleeding and a higher mortality rate with massive PE patients (Avgerinos et al., 2018). To reduce bleeding risk, Bhatt, Al-Hakim, & Benenati described absolute and relative contraindications. (See Table 1) The Liang et al. (2016) study concluded that clinical and hemodynamic outcomes in treating acute PE had no statistical difference or complication rates when patient outcomes were compared using Ultrasound Assisted Thrombolysis (USAT) and catheter directed thrombolysis (Liang et al., 2016). (Kolkailah et al., 2018). Contradictory to the Liang et al. (2016), the Chatterjee et al. (2017) discovered that 1.8% of the patients hospitalized from PE, and received thrombolytics, developed an intracranial hemorrhage (ICH) (Chatterjee et al., 2017). It was also determined that certain factors put individuals at higher risk; pre-existing peripheral vascular disease, those 65 years and older, history of cerebrovascular accident, and prior myocardial infarction (Chatterjee et al., 2017). Each one of these conditions that an individual had, increased their chances of ICH (Chatterjee et al., 2017). Further, others report low risks of both treatment options. Data from Furfaro, Stephens, Streiff, & Brower (2018) shows that there is a low mortality rate for both catheter-directed THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 12 thrombolysis and only anticoagulation treatment options; catheter directed thrombolysis is associated with slightly higher bleeding risks (Furfaro, Stephens, Streiff, & Brower, 2018). Methods A broad and thorough literary search was conducted through January 2020 through November 2020 to locate relevant articles to help define appropriate PE treatment options. The search was primarily conducted via Google Scholar, as well as through PubMed and UpToDate. In each of these databases, multiple articles were to be found on individuals presenting with pulmonary embolism and how to clinically treat pulmonary embolism. Google Scholar The Google Scholar database yielded many articles on pulmonary embolism. Using “pulmonary embolism” and “thrombolysis” as key words and using a filter that articles must be from 2016 to present day, presented with 22,900 articles. Adding “catheter directed” to the current search, the large database found 10,300 articles. By removing “catheter directed” and adding “systemic”, the search yielded 20,200 articles. When the search was conducted using “pulmonary embolism”, “thrombolysis”, “catheter directed” and “systemic”, 7,900 articles were found to be relevant. PubMed Searching “pulmonary embolism” and “thrombolysis” in PubMed, with the filter only allowing 2016 to current day articles, the database search led to 896 articles. Adding the word “systemic” to the current search, yielded 228 articles. Deleting “systemic” from the search and THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 13 adding “catheter directed”, a total of 324 articles were found. Searching the original search with both words, “systemic” and “catheter directed”, resulted in 128 articles. UpToDate UpToDate isn’t a search database but is a resource for clinicians where the information is authored, thoroughly edited and reviewed by other competent physicians. The most current evidence based medical information and recommendations are available to search and implement. Searching UpToDate with “pulmonary embolism treatment” provided the most current methods of treating pulmonary embolism, being practiced and accepted by physicians in the current medical setting, including multiple subcategories of types of pulmonary embolism and possible treatments. Data Analysis Most methods of treating pulmonary embolism will encompass a certain level of risk. Understanding those risks and associated comorbidities while taking into consideration the type of pulmonary embolism, will help guide healthcare providers with the best course of treatment for each individual patient. The meta-analysis of PE treatment options, dependent on the comorbidities of the patient, revealed a shift of data and evidence-based practice, using the articles and data from 2016 to present. Population groups were often small for comparing systemic thrombolysis against catheter directed thrombolysis and results were often inconclusive and comorbidities rarely were taken into consideration, when deciding the course of treatment. More current articles and information, 2019-2020, show a pattern of determination of the course of treatment for PE based on the hemodynamic stability of the presenting patient. Hemodynamically stable patients are found to have the best clinical outcomes from systemic THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 14 thrombolysis. Hemodynamically unstable patients are shown to benefit from much more aggressive interventions; catheter directed thrombolysis, embolectomy, or surgical embolectomy. Dudzinski et al. (2017) concluded that in conditions of high-risk PE, categorized as hemodynamically unstable PE, systemic thrombolysis is the most appropriate course of treatment. However, the UpToDate site recommended the best course of action for high risk/hemodynamically unstable PE is best treated more aggressively; an intervention of catheter directed thrombolysis or embolectomy would be indicated in the same scenario (Tapson & Weinberg, 2020). Dudzinksi et al. (2017) recognized that the treatment model for PE appears to be ever evolving and changing and that the risk of bleeding should be taken into serious consideration (Dudzinski, Giri, & Rosenfield, 2017). A previous meta-analysis, analyzing the data from 11 randomized trials of massive and sub-massive, found no difference between PE reoccurrence or death, when treating with heparin vs heparin and thrombolysis (Averginos & Chaer, 2016). This indicates that treatment options are similar; adding thrombolysis adds a high risk of internal bleeding and if the outcome is the same, treating with only heparin would be the safest method of treatment. This being said, the same article analyzed a subgroup for the massive PE population that displayed substantially improved results in combined PE reoccurring and death (19% vs. 9.4%) when treating with thrombolysis, compared to treating with heparin alone (Averginos & Chaer, 2016). Submassive PE is more difficult to compare because the mortality rate is much less, compared to massive PE (Averginos & Chaer, 2016). However, there is a mortality reduction with thrombolytic therapy and, unfortunately, a higher incidence of significant bleeding complications, especially in the 75 year and older population (Averginos & Chaer, 2016). THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 15 The inconclusive study by Winters et al. (2019) found that both surgical pulmonary embolectomy (SPE) and catheter directed intervention (CDI) could be beneficial to patients with life threatening PE but that more research would be necessary to further outline which patients would need which course of treatment (Winters et al., 2019). Furfaro et al. (2018) describes catheter-directed thrombolysis as a treatment option that can lower pulmonary artery pressures and improve heart strain in the right ventricle in individuals that present with an intermediate-risk pulmonary embolism (Furfaro, Stephens, Streiff, & Brower, 2018). It also suggests that pulmonary pressures are comparable to patients treated with catheter directed thrombolysis and those that are treated with anticoagulation only, when they are measured 3 months post treatment (Furfaro, Stephens, Streiff, & Brower, 2018). Furfaro et al. claims that catheter directed thrombolysis (CDT) carries a lower bleeding risk than systemic thrombolysis, yet CDT does come with a larger risk of bleeding issues when compared to only anticoagulating the patient (Furfaro, Stephens, Streiff, & Brower, 2018). Discussion In consideration of the information provided in this review of literature, the data suggested treatment options for PE are still controversial. The finding of this study suggests that perhaps the reason treatment of PE is varied, is due to the fact that there are many scholarly publications suggesting various treatments as being the most effective. The general consensus is that PE patients that are hemodynamically unstable should be treated aggressively and quickly; Catheter-directed thrombolysis often being the course of treatment for this type of PE patient. THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 16 Because various treatment options were favored by different institutions, the absolute and relative contraindications should be factored into the treatment plan and a generalized protocol may be to implement across treatment centers. However, each institution does have the opportunity to develop a systematic approach to treat patients seeking care. By outlining the various treatment options, medical professional in each institution may review the data and choose the treatment plan in their institution. See table 1. Table 1. Contraindications of Thrombolysis in a PE patient. ABSOLUTE CONTRAINDICATIONS RELATIVE CONTRAINDICATIONS INTRACRANIAL NEOPLASM Severe, uncontrolled hypertension RECENT INTRACRANIAL OR SPINAL SURGERY/TRAUMA Non-hemorrhagic stroke > 3 months HISTORY OF HEMORRHAGIC STROKE OR ANY STROKE WITHIN 3 MONTHS Recent surgery (<14 days) ACTIVE BLEEDING OR BLEEDING DIATHESIS Recent vascular punctures Age > 75 years (Bhatt, Al-Hakim, & Benenati, 2017) THE APPROPRIATE COURSE OF TREATMENT FOR PULMONARY EMBOLISM 17 Limitations The primary limitation of this study was the study design. The meta-analysis of the literature did not favor a specific treatment for acute PE. This outcome suggests that future opportunities for research should include a randomized clinical trial, testing various treatment options in an effort to determine best practices and treatment algorithms for acute PE. 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