Pulmonary embolism (PE) is the third leading cause of cardiovascular mortality behind acute myocardial infarction and stroke and a leading cause of in-hospital mortality. Up to 40% of patients are classified as intermediate risk (submassive) PE, defined by the presence hemodynamic stability with significant right ventricular (RV) dysfunction and/or cardiac injury.¹ Patients with intermediate-risk PE have up to 21% mortality at 3 months. Unfortunately, the optimal treatment for most patients with intermediate-risk PE is unknown.

Catheter-directed thrombectomy with the FlowTriever system (Inari Medical; Irvine, CA) was recently shown to reduce early RV strain in patients with acute intermediate-risk PE.² The FlowTriever catheter system consists of a large aspiration guide catheter that is placed through the right heart into the pulmonary artery (PA) through which the FlowTriever device is advanced (Figure 1). The FlowTriever device has three self-expanding nitinol disks that are unsheathed to engage, disrupt, and extract the thrombus while simultaneously aspirating and withdrawing this through the 20 Fr guide catheter.³

Figure 1: The FlowTriever Catheter Embolectomy

In the multicenter single-arm FLARE (FlowTriever Pulmonary Embolectomy Clinical Study), presented as a late-breaking trial at the 2018 Society of Cardiac Angiography and Interventions Annual Scientific Sessions, 106 patients with intermediate-risk PE underwent catheter embolectomy using the FlowTriever catheter.² Patients were enrolled if they presented with acute PE within 14 days of symptom onset and were noted to have evidence of RV strain by right-to-left ventricular (RV/LV) ratio ≥0.9 on computed topographic angiography. The mean age was 55.6 ± 13.6 years; 54.7% were male; 50.9% presented with bilateral PE; and concurrent deep vein thrombosis was noted in 68.9%. The cardiac troponin and B-natriuretic peptide were elevated in 59.4% and 73%, respectively. Patients were excluded if they had shock, recent thrombolytic use, systolic PA pressures over 70 mmHg, hypoxia requiring more than 40% fraction of inspired oxygen, hematocrit less than 28%, platelet count less than 100,000, creatinine more than 1.8 mg/dL, international normalized ratio more than 3, recent cardiac or pulmonary surgery, or active cancer.

The primary endpoint was change in RV/LV ratio at 48 hours, which was significantly reduced with FlowTriever embolectomy by 0.39 (1.53-1.15, p < 0.0001) from baseline (Figure 2). Importantly, there were no cases of intracranial hemorrhage, access-site major bleeding, device-related cardiac or pulmonary injury, or device-related deaths. The adverse event rate was 3.8% and included 1 bleeding event (coughing up blood) and 3 treatment-related clinical deterioration events. The mean procedural time was about 1 hour and 39 minutes, and 95% were performed using right common femoral venous access. The mean intensive care unit stay was about 1 day, and 42% of patients spent no time in the intensive care unit.

Figure 2: Comparison of Studies on RV/LV Ratio and Major Bleeding

StudyREF	N	Treatment	Tissue Plasminogen Activator	Reduction in RV/LV Ratio	Major Bleeding
FLARE2	104	FlowTriever embolectomy	0 mg	0.39 (25%)	0.9%
SEATTLE II (A Prospective, Single-arm, Multi-center Trial of EkoSonic® Endovascular System and Activase for Treatment of Acute Pulmonary Embolism)9	150	Ultrasound-assisted catheter-directed thrombolysis	24 mg	0.42 (24%)	11.4%
ULTIMA (Ultrasound Accelerated Thrombolysis of Pulmonary Embolism)10	30	Ultrasound-assisted catheter-directed thrombolysis	10-20 mg	0.29 (22%)	0.0%
Becattini et al.11	23	Systemic thrombolysis	30-50 mg Bolus (Tenecteplase)	0.31 (24%)	8.7%
Fasullo et al.12	37	Systemic thrombolysis	100 mg (Alteplase)	0.38 (27%)	5.4%
Mi et al.13	79	Systemic thrombolysis	50 mg (Alteplase)	0.11 (8%)	6.3%
ULTIMA10	29	Anticoagulation	0 mg	0.03 (2.5%)	0.0%
Becattini et al.11	28	Anticoagulation	0 mg	0.1 (8%)	3.6%
Fasullo et al.12	35	Anticoagulation	0 mg	0.2 (14%)	2.9%
Mi et al.13	57	Anticoagulation	0 mg	0.04 (2.9%)	1.8%

To put the results of the FLARE trial into context, the change in RV/LV ratio with FlowTriever embolectomy is similar to that noted with other trials investigating catheter-directed thrombolysis and systemic thrombolysis and better than that of anticoagulation alone (Figure 2). Importantly, there was a low rate of adverse events with FlowTriever, similar to that of anticoagulation. This is exciting because the procedure requires no thrombolytic drug and now offers an option for many patients with relative and absolute contraindications to thrombolysis. Though limited by its single-arm nature and lack of long-term outcome data, the FLARE trial demonstrates that mechanical thrombectomy using the FlowTriever is feasible and safe. Based on the results of the FLARE trial, the catheter received US Food and Drug Administration 510(k) clearance for the treatment of PE and makes it the first and only thrombectomy device cleared by the US Food and Drug Administration for the treatment of PE.

Although increased RV/LV ratio is an independent predictor of 30-day mortality in acute PE, the impact of change in RV/LV ratio at 24-48 hours on long-term mortality and morbidity in intermediate-risk PE remains unresolved. As such, the optimal treatment for most patients with intermediate-risk PE in 2018 is still unknown. Unfortunately, society guidelines differ in treatment recommendations because there is a paucity of randomized trials to guide clinical practice. Currently, the 2014 European Society of Cardiology and 2016 American College of Chest Physicians PE guidelines recommend anticoagulation alone with rescue full-dose systemic thrombolysis for most patients with intermediate-risk PE.^1,4 However, randomized trials and meta-analyses suggest a higher incidence of in-hospital adverse events and mortality as well as poor function status at follow-up in patients with intermediate-risk PE with such an approach.^5-7 In contrast, the American Heart Association guidelines recommend full-dose systemic thrombolysis for patients with high- to intermediate-risk PE.⁸ However, full-dose systemic thrombolysis is limited by an extremely high incidence of major bleeding complications. In a meta-analysis of 8 randomized trials in intermediate-risk PE, major bleeding (odds ratio 3.19; 95% confidence interval, 2.07-4.92) and intracranial hemorrhage (odds ratio 4.63; 95% confidence interval, 1.78-12.04) were significantly more common with systemic thrombolysis compared with anticoagulation alone.⁷

Given this poor efficacy of anticoagulation alone and the high bleeding complications with full-dose systemic thrombolysis, many believe more moderate therapies such as reduced-dose systemic thrombolysis, catheter-directed thrombolysis, and catheter embolectomy better balance efficacy and safety in intermediate-risk PE. However, there are no studies comparing these novel treatment options in this population. Given this dilemma, multidisciplinary PE response teams have been developed at many hospitals to help select between these various treatment options. These PE teams are modeled on the heart team approach with structural heart disease and coronary revascularization and aim to provide a multidisciplinary approach to patients with acute higher-risk PE. PE response teams vary by institution but usually have a single activation by an on-call physician who gathers information and then facilitates a real-time discussion between consultants to generate risk-stratification and shared decision-making recommendations. The optimal use of the FlowTriever catheter today may be as part of a multidisciplinary PE response team's approach to higher-risk PE. For clinicians and hospital systems interested in learning more about PE response teams, please visit The Pulmonary Embolism Response Team Consortium at www.pertconsortium.com.

References

1. Konstantinides SV. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35:3145-6.
2. Tu T. A Prospective, Singe-Arm, Multicenter Trial of Catheter-Directed Mechanical Thrombectomy for Intermediate-Risk Acute Pulmonary Embolism: The FLARE Study. Presented 04/27/2018 at the Society of Angiography and Interventions Annual Scientific Sessions 2018.
3. Tukaye DN, McDaniel M, Liberman H, Burkin Y, Jaber W. Percutaneous Pulmonary Embolus Mechanical Thrombectomy. JACC Cardiovasc Interv 2017;10:94-5.
4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-52.
5. Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost 2014;12:459-68.
6. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402-11.
7. 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.
8. 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.
9. 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.
10. Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014;129:479-86.
11. Becattini C, Agnelli G, Salvi A, et al. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. Thromb Res 2010;125:e82-6.
12. Fasullo S, Scalzo S, Maringhini G, et al. Six-month echocardiographic study in patients with submassive pulmonary embolism and right ventricle dysfunction: comparison of thrombolysis with heparin. Am J Med Sci 2011;341:33-9.
13. Mi YH, Liang Y, Lu YH, Li YM, Liu WX, Qian W. Recombinant tissue plasminogen activator plus heparin compared with heparin alone for patients with acute submassive pulmonary embolism: one-year outcome. J Geriatr Cardiol 2013;10:323-9.

Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Vascular Medicine, Interventions and Imaging, Interventions and Vascular Medicine, Angiography, Nuclear Imaging

Keywords: Creatinine, Hospital Mortality, International Normalized Ratio, Pulmonary Artery, Platelet Count, Hematocrit, Lung Injury, Embolectomy, Thrombectomy, Pulmonary Embolism, Fibrinolytic Agents, Intracranial Hemorrhages, Venous Thrombosis, Thrombosis, Stroke, Angiography, Myocardial Infarction, Heart Diseases, Neoplasms, Natriuretic Peptides, Hemodynamics, Troponin, Oxygen

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