Once a diagnosis of pulmonary embolism is made, prompt initiation of anticoagulation is imperative as it has been shown to reduced mortality [
12]. Similarly, conservative efforts to reduce the RV afterload, including oxygen supplementation and inhaled nitric oxide (iNO) to assist with pulmonary vasodilation can aid in preserving stability [
13]. In cases of severe RV dysfunction, an inotropic agent such as dobutamine, should be initiated [
14]. Supportive vasopressor therapy is required to keep mean arterial pressures (MAP) greater than 65 mmHg, with norepinephrine as the treatment of choice [
15]. However, once dobutamine or vasopressors are used, the patient has progressed to a high-risk pulmonary embolism category and treatment algorithms can change. In significant pulmonary embolism, high afterload leads the right ventricle to dilate further. The use of extraneous intravenous fluid therapy can lead to acute RV decompensation by worsening septal shift and impacting LV preload [
16]. In patients who are clinically deteriorating because of hypoxemia and respiratory distress, the decision to pursue invasive positive pressure ventilation is challenging due to concern for worsening RV afterload. The application of positive thoracic pressure can cause an acute decrease in RV preload. Therefore, an attempt to try conservative treatment, such as high flow nasal oxygen, should be considered prior to considering mechanical ventilation. If mechanical ventilation is pursued, hemodynamically neutral agents should be used for induction as the elevated PVR makes the right ventricle extremely preload sensitive. The use of propofol, a negative inotrope, has been associated with increased mortality in submassive pulmonary embolism and should be avoided [
17].
Systemic thrombolytic therapy
While the use of systemic thrombolytic therapy is recommended in high-risk pulmonary embolism, defined as hemodynamically unstable patients or in patients after the return of spontaneous circulation, application in intermediate-risk pulmonary embolism is less well defined [
15]. Patients with high-risk pulmonary embolism should undergo thrombolysis, in the absence of contraindications, as thrombolysis reduces mortality by almost 50% (3.9–2.2%) compared with anticoagulation alone [
18], yet this is counterbalanced by an increase in major bleeding (3.4–9.2%) and intracranial hemorrhage (0.2–1.5%). There is clear indication for use of systemic thrombolysis in the setting of rescue therapy for patients with submassive pulmonary embolism who have evidence of hemodynamic deterioration or who have not responded appropriately to anticoagulation [
15]. When to use systemic thrombolysis in intermediate-risk pulmonary embolism poses a complex clinical dilemma with careful weighing of the risk–benefit ratio needed. This is because patients with intermediate-low risk pulmonary embolism will do well without escalation of therapy, and the addition of thrombolysis only adds risk without benefit. Several studies addressed below have looked at various dosages for systemic therapy with mixed results.
The European Pulmonary Embolism Thrombolysis (PEITHO) trial, the largest randomized controlled trial (RCT) to date, randomized 1004 patients with normotensive, submassive pulmonary embolism who had RV strain to weight-based tenecteplase with standard parenteral anticoagulation or parenteral anticoagulation alone [
19]. Although the primary outcome was met, a decrease in the combination of death or decompensation, with decompensation making up most of the benefit, the study observed significant increases in major bleeding including intracranial hemorrhage in the tenecteplase group [
19]. Nevertheless, the results solidified the role of tenecteplase in rescue therapy.
Another trial, TOPCOAT (Tenecteplase Or Placebo: Cardiopulmonary Outcomes At Three months), examined outcomes in patients with submassive pulmonary embolism randomized to low-molecular-weight heparin plus tenecteplase or placebo and demonstrated improvement in cardiopulmonary outcomes at 90 days with respect to dyspnea, quality of life scores, echocardiographic measures of RV function, and walk distance, but was not powered for mortality [
20]. In meta-analysis, the stable hemodynamic subgroup has yet to show a clinically significant mortality benefit and given the increase in major bleeding, including intracranial hemorrhage, defining the exact subgroup that would benefit from more aggressive therapy remains elusive [
21]. This is perhaps because intermediate-risk pulmonary embolism encompasses a large heterogeneous group of patients including those with lowintermediate risk and intermediate-high risk. The appropriate phenotyping of a patient becomes paramount when enrolling in trials to assess the true benefit of systemic thrombolysis. Because of this there remains a knowledge gap in managing patients with intermediate-high risk pulmonary embolism; currently treatment is guided mostly by a multidisciplinary and individualized approach.
Given the bleeding complications observed with conventional thrombolysis dosage, consideration was given to a ‘half-dose’ thrombolytic therapy. The rationale was that the lower dose would have the ability to maximize benefit of acutely lowering PVR while minimizing bleeding complications. The MOderate Pulmonary Embolism Treated with Thrombolysis trial, (MOPETT), was a single center study that aimed to determine whether half-dose recombinant tissue plasminogen activator (rtPA) would reduce rates of pulmonary hypertension (on echocardiogram) at 28 months. The incidence of pulmonary hypertension on echo was 57% in the anticoagulation group compared to 16% in the rtPA group and there was no increased risk of bleeding. However, the 57% incidence of pulmonary hypertension in the control arm is disparate to known historical controls [
22]. Therefore, there has been little change in clinical practice based on this study. At the present time, there is no convincing evidence to support ubiquitous use of systemic thrombolysis at any dose in hemodynamically stable patients and current guidelines do not recommend its use [
15,
23,
24].
While a lower dosage may be ideal for some cases of pulmonary embolism, there are questions surrounding whether this approach is equivalent to higher doses in reducing PVR. We know that systemic thrombolytic therapy in patients with high- risk pulmonary embolism can be unsuccessful, as defined by persistent clinical instability or RV dysfunction up to 36 h after therapy, and accordingly the rate of inadequate response may increase as the thrombolysis dosage is lowered [
25]. Analysis of a prospective single-center registry demonstrated higher mortality and higher recurrent pulmonary embolism in patients who had repeat-dose thrombolysis compared to surgical embolectomy, with similar bleeding risk. The study also noted that bleeding events in repeat dose therapy were all fatal [
25]. To add to the discussion, the timing of the thrombolytic therapy can affect efficacy; thrombolysis is known to be most effective within 48 h of thrombosis generation. Early dosing offers the greatest benefit in reducing pulmonary artery pressure and RV dilation, yet delayed use for up to 2 weeks after symptoms has also shown some benefit [
26]. Therefore, all applications of systemic thrombolysis may not be equal. With the advent of catheter-directed therapies, determining when to use systemic thrombolysis in intermediate-high risk PE has become further complicated. Catheter- directed therapies use less fibrinolytics but take longer to employ than systemic fibrinolytics.
Catheter-directed therapies
Percutaneous catheter-directed therapies offer an alternative to systemic thrombolysis, as well as a minimally invasive alternative to surgical thrombectomy for patients with high-intermediate risk pulmonary embolism at increased risk for decompensation. Several catheter-based treatment strategies have been utilized in clinical practice; however where catheter-directed therapies fit in the treatment algorithm for intermediate risk pulmonary embolism is still controversial.
Catheter-directed therapy can mean mechanical removal of clot alone or in conjunction with catheter-based thrombolysis. Mechanical therapies are good treatment options when a patient cannot tolerate fibrinolysis but has a physiologically significant thrombosis. The location of the clot dictates the utility of catheter-directed therapies as the pulmonary embolus must be proximal for the therapy to be effective. While there are larger vacuum-based therapies that require placement on extra-corporeal oxygenation prior to their use, we will not review those as they would be unlikely to be used in intermediate-risk pulmonary embolism. Rheolytic thrombectomy, with devices such as AngioJet
®, removes the thrombus by injecting a saline jet from the distal port under a high-pressure, thus creating a negative pressure force, while a separate catheter helps evacuate the thrombus [
27]. Rheolytic thrombectomy has become less popular, because as the thrombus breaks down there can sometimes be a sudden release of adenosine causing hemodynamic decompensation mostly evidenced by hypotension and bradycardia [
28].
The FlowTriever
® device has a suction catheter alongside three nitinol mesh disks that help remove residual clot after the initial thrombus is removed using suction. The advantage of the FlowTriever
® device is that it offers a complete evacuation of proximal thrombi. The nitinol mesh disks are available in several sizes, allowing the proceduralist to choose an optimal size for each patient. The FLARE study demonstrated that the FlowTriever
® results in significant improvement in the right ventricle to left ventricle ratio at 48 h. While no major bleeding or deaths were noted, the adverse event rate was 3.8%, including one pulmonary hemorrhage and three procedure-related clinical deteriorations [
29]. The clinical use of FlowTriever
® is often limited by the blood removed with the thrombus.
Mechanical catheter-directed therapy can be used in conjunction with catheter-directed thrombolysis or thrombolysis can occur on its own. Catheter-directed thrombolysis is when low-dose fibrinolytic agents are directly injected into the pulmonary artery at a slow infusion rate, often over the course of 12–24 h. The theoretical advantage of this technique is that the fibrinolytic infusion is at the site of thrombosis and a lower dose of fibrinolytics can be given despite longer exposure. There is conflicting evidence as to whether catheter-directed thrombolysis has less bleeding risk compared to systemic thrombolysis [
30,
31].
Catheter-based therapies can help normalize the pressure in the right side of the heart more quickly than anticoagulation. The ULTIMA (ULTrasound Accelerated ThrombolysIs of PulMonAry Embolism) trial reported improvement in the right ventricle to left ventricle dimension ratio when ultrasound-assisted catheter-directed thrombolysis was used with unfractionated heparin compared to unfractionated heparin alone [
32]. Although the study included only 59 patients, only three minor bleeding complications were noted in the ultrasound-assisted catheter-directed thrombolysis group compared to one in the heparin-only group. Similar results of reduced RV strain by decreasing pulmonary artery pressure, and no major bleeding complications were noted in two prospective single-armed studies: SEATTLE-II (A Prospective, Single-arm, Multi-center Trial of EkoSonic
® Endovascular System and Activase for Treatment of Acute Pulmonary Embolism) and PERFECT (Pulmonary Embolism Response to Fragmentation, Embolectomy, & Catheter Thrombolysis) trials [
33,
34]. The OPTALYSE (Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Intermediate-Risk Pulmonary Embolism) trial reported that a shorter duration of 6–12 h of ultrasound-guided assisted catheter-directed thrombolysis with a lower dose of the fibrinolytic agent was also able to improve RV strain and decrease in RV afterload compared to longer durations and higher doses [
35]. Given these studies, it seems like the optimal patient for catheter-directed therapies would be an intermediate risk patient with pulmonary embolism who is on the cusp of hemodynamic compromise; however, identification of this cohort remains a challenge.
The field of catheter-based treatment of intermediate-high risk pulmonary embolism continues to evolve. Its utility depends on the availability of an expert proceduralist and the institution’s access to use of an extracorporeal bypass circuit in the case of hemodynamic decompensation. The benefits, risks, and alternatives of the selected procedure must be discussed in a multidisciplinary manner and with the patient to improve outcomes and minimize complications.