Pulmonary embolism (PE) is the third most common acute cardiovascular event after myocardial infarction and stroke1 and is a potentially life-threatening condition that requires urgent intervention. Sudden death is the first symptom in about 25% of people with PE, and 10–30% of people will die within one month of diagnosis.2,3 Acute PE puts a considerable strain on emergency departments, and efficient diagnosis and risk assessment is needed to manage the condition appropriately. Despite the prevalence and severity of PE, there is not a large body of robust clinical trial evidence on which to base the choice of appropriate therapeutic strategies.
PE is commonly classified as massive (high-risk), submassive (intermediate-risk), and low-risk to help determine the appropriate treatment. Massive PE is defined as suspected or confirmed PE with shock, sustained hypotension, the absence of a pulse, or persistent profound bradycardia.4 Submassive PE is defined as suspected or confirmed PE with right ventricular dysfunction but no shock.5,6 In all cases, European and US guidelines recommend the use of anticoagulants with the aim of preventing migration of the blood clot.5,7 Subsequent treatment depends on the level of risk.
In massive acute PE, thrombolytic therapy, which employs tissue plasminogen activator (tPA), and aims to dissolve the clot, may be used. However, many patients cannot receive systemic thrombolysis (ST), which involves placement of a catheter into one or both pulmonary arteries, due to contraindications and the risk of major haemorrhage.8 Furthermore, there may be insufficient time in the acute setting to infuse full-dose thrombolytic agent. A 2015 Cochrane review concluded that thrombolytic therapy may be helpful in reducing the recurrence of PE but may cause more major and minor haemorrhagic events and stroke.9
Direct administration using catheter-directed thrombolysis (CDT), which infuses thrombolytic drugs within the thrombus, offers a safer alternative.5,7 Some CDT catheters such as EkoSonic® (EKOS, Bothell, WA), employ ultrasound to aid in dispersing the thrombolytic drug within the clot, maximizing drug distribution and minimizing mechanical damage of the venous wall.10 In addition to high-risk patients, the use of thrombolytic therapy has also been shown to be safe and more effective than anticoagulants in intermediate-risk patients with PE.11
Following a number of small studies demonstrating the safety and efficacy of CDT in acute massive PE,12 two more recent studies have provided strong evidence in favor of ultrasound-assisted CDT. The Ultrasound Accelerated Thrombolysis of PE (ULTIMA) study, a phase II randomized controlled trial investigating the efficacy and safety of ultrasound-assisted CDT in intermediate risk PE, proved that CDT reduced pulmonary pressures and improved right ventricular (RV) function compared with heparin, with no evidence of major bleeding in the CDT group.13 Doses used in ULTIMA were 10 and 20% of typical ST doses, minimizing the risk of adverse events. A larger, single-arm study (A Prospective, Single-arm, Multi-center Trial of EkoSonic Endovascular System and Activase for Treatment of Acute Pulmonary Embolism [SEATTLE II]) was a prospective multicenter trial in patients with acute massive or submassive PE. CDT rapidly relieved pulmonary artery obstruction and reduced pulmonary hypertension, with a low incidence of major bleeding events.10
Despite this growing body of clinical evidence, a recent study has found that many patients are not receiving these potentially lifesaving therapies. The retrospective study collected data from a US national commercial insurance claims database and identified 100,744 patients who had been hospitalized with PE during the period 2004–2014. Results were presented at the American College of Cardiology 66th Annual Scientific Session and showed that only 2,175 patients, around 2%, received either CDT or ST. During this period, the number of hospitalizations for PE increased by 306%.14 These findings support those of a 2012 study that found that ST was underused in acute unstable PE although its use was associated with a lower fatality rate.15
The study also raised the question about whether the appropriate patients are receiving CDT and ST, since the side effects can be devastating. At present, there are a lack of data comparing the efficacy of CDT compared with ST in different risk groups. Unfortunately, there is no validated tool for predicting the risk of bleeding in patients undergoing thrombolysis. Standard assessment tools, such as the Pulmonary Embolism Severity Index (PESI), can help identify patients who may benefit from thrombolytic therapy.16
A Pulmonary Embolism Response Team (PERT) Consortium17 has been created to ensure that high-risk patients with PE are receiving the most appropriate therapies at the optimal time. This involves a multidisciplinary team consisting of representatives from vascular medicine, interventional cardiology, cardiothoracic surgery, pulmonology, echocardiography, and radiology, which convene to evaluate the patient’s case and review imaging studies.
In conclusion, PE is a major cause of death. Further research on CDT for acute PE is needed to refine existing protocols and to evaluate long-term outcomes. However, with careful risk stratification involving a multidisciplinary team, clinicians should be able to perform ST and CDT safely and effectively in patients with PE. In patients with haemodynamically unstable PE, their potential benefits will almost certainly outweigh the risk of a life-threatening bleed.
1. Huang W, Goldberg RJ, Anderson FA, et al., Secular trends in occurrence of acute venous thromboembolism: the Worcester VTE study (1985–2009), Am J Med, 2014;127:829–39 e5.
2. Centers for Disease Control and Prevention (CDC), Venous thromboemblism: data and statistics, Available at: www.cdc.gov/ncbddd/dvt/data.html (accessed April 24, 2017).
3. Douma RA, Kamphuisen PW, Buller HR, Acute pulmonary embolism. Part 1: epidemiology and diagnosis, Nat Rev Cardiol, 2010;7:585–96.
4. Wood KE, Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism, CHEST, 2002;121:877–905.
5. Konstantinides SV, Torbicki A, Agnelli G, et al., 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism, Eur Heart J, 2014;35:3033–69, 69a–69k.
6. Jaff MR, McMurtry MS, Archer SL, et al., Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association, Circulation, 2011;123:1788–830.
7. Kearon C, Akl EA, Ornelas J, et al., Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report, CHEST, 2016;149:315–52.
8. Goldhaber SZ, Visani L, De Rosa M, Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER), Lancet, 1999;353:1386–9.
9. Hao Q, Dong BR, Yue J, et al., Thrombolytic therapy for pulmonary embolism, Cochrane Database Syst Rev, 2015;CD004437.
10. Piazza G, Hohlfelder B, Jaff MR, et al., A prospective, single-arm, multicenter trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism: the SEATTLE II study, JACC Cardiovasc Interv, 2015;8:1382–92.
11. Chatterjee S, Chakraborty A, Weinberg I, et al., Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis, JAMA, 2014;311:2414–21.
12. Kuo WT, Gould MK, Louie JD, et al., Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques, J Vasc Interv Radiol, 2009;20:1431–40.
13. Kucher N, Boekstegers P, Muller OJ, et al., Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism, Circulation, 2014;129:479–86.
14. Adusumalli S, et al, presentation at the American College of Cardiology 66th Annual Scientific Session, Washington DC, US, March 17–19, 2017.
15. Stein PD, Matta F, Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused, Am J Med, 2012;125:465–70.
16. Vedantham S, Piazza G, Sista AK, et al., Guidance for the use of thrombolytic therapy for the treatment of venous thromboembolism, J Thromb Thrombolysis, 2016;41:68–80.
17. National Pulmonary Embolism Response Team (PERT) Consortium. Available at: //pertconsortium.org/ (accessed April 24, 2017).