Right Heart Clot-in-Transit: Endovascular Therapies

Abstract

Right heart thrombus is a challenging high mortality disease typically seen in the setting of pulmonary embolism. Traditional treatments have included anticoagulation, thrombolysis, and surgical embolectomy. Advances in recognition and treatment of clot-in-transit have led to the development of endovascular therapies increasingly becoming the preferred method of treatment due to rapid debulking and lower morbidity. Novel endovascular devices are large bore aspiration thrombectomy systems which mitigate the use of concomitant thrombolytics. The article reviews the disease process, relevant literature, and current endovascular devices and strategies for the treatment of right heart thrombus and clot-in-transit.

Right heart thrombus (RHT) presents a challenging clinical dilemma with potential associated mortality. An increasing number of devices and techniques for endovascular thrombectomy have been developed in the last 20 years with overlapping applications for treating deep vein thrombus, RHT, and pulmonary embolism (PE). This article reviews the epidemiology and treatment paradigm for RHT and clot-in-transit.

RHT is typically associated with PE from deep vein thrombosis (DVT) but may develop in situ in the setting of cardiac chamber dilatation or hypokinesis. Catheter-related atrial thrombus (CRAT) is distinct and associated with central venous catheters or electrical pacer wires. Valvular endocarditis with mass-like vegetations and catheter or wire-related septic thrombi can also occur. Right heart masses from primary tumors or metastases may similarly present with obstructive or embolic complications, and can be differentiated from thrombus based on location, morphology, and imaging findings.

The overall incidence of RHT in the general population is unclear. The incidence of RHT in the setting of PE is approximately 2 to 6% as reported by several large PE registries including the International Cooperative Pulmonary Embolism Registry (ICOPER) of 2,454 patients, a multicenter Japanese registry of 2,698 patients, and the world's largest database of 12,441 PE patients in the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE). ^{1 2 3}

Thrombus and Mass Morphology

RHT is best evaluated by transesophageal echocardiogram (TEE) or contrast-enhanced cardiac magnetic resonance imaging (MRI), but can be evaluated on transthoracic echocardiogram (TTE) and less reliably by contrast-enhanced computed tomography (CT) of the chest. ^{4 5} RHT on echo is characterized by shape, mobility, and size, and can be classified as: Type A—mobile and tubular usually due to lower extremity origin; Type B—nonmobile and thought to arise in situ from chamber hypokinesis or dilation; and Type C—mobile and nonmobile components. ^{6 7 8} An older observational study suggested significantly higher thrombus-related mortality with Type A thrombus; however, certain confounding factors including right heart failure and hemodynamic status were not fully evaluated. ⁶ A larger and more recent pooled analysis of 316 patients and a large European registry of 138 patients with RHT both noted a higher mortality associated with the presence of RHT but no significant mortality prognostication by thrombus morphology. ^{7 8} Hence, thrombus morphology alone does not necessarily predict mortality.

Regarding right heart tumors, metastatic disease is more common than primary cardiac tumors and is secondary to hematogenous dissemination (e.g., melanoma), lymphatic dissemination (e.g., lymphoma), direct invasion (e.g., lung cancer), or transvenous extension (e.g., renal cell carcinoma). ⁹ Tumor thrombus from transvenous extension is most amenable to endovascular intervention, but primary cardiac tumors and other metastases have been reported in the thrombectomy literature. ¹⁰ Endovascular thrombectomy of right heart tumors should be considered only after multidisciplinary case review under the full scope of the patient's clinical acuity, cardiopulmonary function and reserve, oncologic treatment plan, and overall prognosis.

CRAT is due to repetitive catheter mechanical irritation of the venous endothelium leading to thrombus formation around the catheter tip. ¹¹ CRAT is distinct from DVT-related or in situ RAT and occurs in approximately 5 to 13% of patients with central catheters, with the higher end typically observed in oncologic populations. ^{11 12 13 14} In the absence of patent foramen ovale (PFO), CRAT generally has a more benign natural history. ^{14 15} However, embolic complications and death may still occur in the setting of CRAT in elderly patients with endocarditis and bacteremia. ¹⁴ The general treatment recommendation is catheter removal and/or systemic anticoagulation. ^{14 15} Thrombectomy is typically reserved but should be strongly considered in circumstances including failure of conservative treatment, poor cardiopulmonary reserve, and the presence of PFO. ^{14 15 16 17 18 19}

Treatment Considerations

Left untreated, RHT is associated with a very high mortality risk approaching 90 to 100%. ^{20 21} Patients with RHT present with more hemodynamic instability, have a higher risk of recurrent PE, and have higher PE-related and higher overall mortality. ^{1 3 8 20 22}

In the ICOPER subgroup of 1,135 patients with PE who had echocardiograms, outcomes of 42 patients with RHT were compared to that of 1,071 patients without RHT. ²² Patients with RHT had more hemodynamic instability at presentation, right bundle branch block on electrocardiogram, and right ventricle (RV) hypokinesis on echocardiogram ( p  < 0.05). Respectively, overall mortality in the RHT group compared to non-RHT groups was 21% compared to 11% at 2 weeks ( p  = 0.032), and 29% compared to 16% at 12 weeks ( p  = 0.036). Importantly, there was a significant difference in mortality in patients treated with heparin alone in the RHT group compared to the non-RHT group (23.5 vs. 8.0%, p  < 0.02), whereas mortality rates of thrombolysis and embolectomy treatment were similar among groups. The difference in mortality was unattributable to baseline hemodynamic status in the heparin group and suggests anticoagulation with heparin alone may be unsuitable for the treatment of RHT given the high mortality. ²²

In a multicenter PE registry in Japan of 2,698 patients with acute PE and echocardiograms, outcomes of 166 patients with RHT were compared to 2,532 patients without RHT. ³ There was a higher percentage of hemodynamically unstable patients included in the Japanese study cohort compared to the ICOPER cohort, and patients with RHT had significantly more hemodynamic instability (53 vs. 37.7%, p  < 0.001). Patients with RHT had a twofold higher mortality at 30 days (20.2 vs. 10.4%, p  < 0.001), particularly worse in submassive and massive PE subgroups. ³

In the RIETE registry of 12,441 patients with PE and echocardiograms, 325 patients with PE and RHT were compared to 12,116 patients with PE without RHT. ¹ Similar to the ICOPER results, patients with RHT who were treated with anticoagulation alone had a threefold higher 30-day all-cause mortality than patients with RHT treated with thrombolysis or surgical embolectomy.

The Right Heart Thrombi European Registry (RiHTER) evaluated 138 patients with PE and RHT compared to a propensity-matched group of 276 patients with PE without RHT. ⁸ PE-related mortality was higher in the RHT group and all-cause mortality in patients with RHT at 30 days was 21%, similar to ICOPER. Hemodynamic instability expressed by the simplified Pulmonary Embolism Severity Index (sPESI) in the clinical evaluation of PE was validated as a prognosticator of mortality in patients with RHT. ⁸

The investigations altogether conclude that RHT is a marker of hemodynamic instability and portends significantly higher mortality, though RHT as a direct cause of worse outcomes is still unclear. ^{1 3 8 22} Importantly, anticoagulation with heparin alone appears insufficient for the treatment of RHT, which requires a more invasive treatment approach. ^{1 3 8 20 22} Thrombolysis and surgical embolectomy were associated with better outcomes in patients with RHT in these registries, but these treatments are also associated with considerable risk including the perioperative morbidity of surgical embolectomy, and the 2 to 3% risk of intracranial hemorrhage and 6 to 11% major bleeding risk of thrombolysis. ^{1 2 3 7 8 20 22 23 24 25}

Endovascular Thrombectomy

While traditional therapies for RHT include anticoagulation, thrombolysis, and surgical embolectomy, there is a dearth of evidence in the registries regarding endovascular thrombectomy given its relative novelty. Endovascular aspiration thrombectomy systems have quickly become more favorable for right heart mass removal given their ability to rapidly debulk with faster procedure times and lower morbidity than operative embolectomy, and lesser risk of major hemorrhage than thrombolysis. Devices with application in treating right heart thrombi or clot-in-transit are the AngioVac system (Angiodynamics, Latham, NY), the FlowTriever system (INARI Medical, Irvine, CA), and the AlphaVac system (Angiodynamics; Table 1 ). Treatment decisions are heavily influenced by patient factors, operator's experience, and local resources.

Table 1. Endovascular devices.

Device	Specifications	System components	Advantages	Disadvantages
AngioVac	- 20°, 85°, or 180° angled tip - 22-Fr Proprietary Funnel Tip Design with radiopaque nitinol reinforced funneled tip - Y-adapter Touhy for working wire or up to 17 Fr adjunct device	- Venous drainage cannula - Extracorporeal circuit - Venous reinfusion cannula (18 Fr) - ECMO pump and filter - Requires large bore dry seal	- Largest-volume aspiration - Excellent results in CTE and RHT	- Cost/resources - Procedure complexity and need for ECMO - Less suitable for PE
FlowTriever	- 16, 20, 24 Fr catheter - Curved 20 Fr catheter - 120 cm working length - 6–25 mm disk diameters	- T20 and T24 catheters - Nitinol mesh disks - Flush port stopcock and syringe - Requires large bore dry seal	- Ease of use - Angiography through device lumen - Excellent for DVT, CTE, PE	- Unclear role for RHT (no large registry/trial)
AlphaVac	- 20°, 85°, or 180° angled tip - 22 Fr balloon actuated expandable funnel-shaped cannula - Semiautomatic actuations with 10 cc (thrombus hunting) or 30 cc (thrombus engaged) settings - Y-adapter Touhy for working wire or up to 9 Fr adjunct device	- Endovascular catheter with expandable infusion basket - Requires large bore dry seal sheath	- Large-volume aspiration with advantages of AngioVac without ECMO	- New device - Limited operator experience

Abbreviations: CTE, caval thromboemboli; DVT, deep vein thrombosis; ECMO, extracorporeal membrane oxygenation; PE, pulmonary embolism; RHT, right heart thrombus.

Notes: AngioVac, Angiodynamics—Latham, NY; FlowTriever, INARI Medical—Irvine, CA; AlphaVac, Angiodynamics.

AngioVac

The AngioVac is a mechanical aspiration thrombectomy system capable of removing large-volume thrombus or masses with very high-volume aspiration requiring venovenous extracorporeal membrane oxygenation for filtered blood reinfusion.

The Registry of AngioVac Procedures in Detail (RAPID) is the largest current multicenter prospective registry of 234 patients having undergone AngioVac thrombectomy treatments for caval thromboemboli (CTE) (35.9%, n  = 84), right heart thrombi/masses (48.3%, n  = 113), catheter-related thrombi (8.5%, n  = 20), and PE (1.7%, n  = 4). Successful thrombectomy, defined as 70 to 100% thrombus removal, was obtained in 73.6% of patients with CTE, 58.5% with right heart mass, 60% with catheter-related thrombus, and 57.1% with PE. ²⁶ Additional smaller studies have shown similar safety and efficacy profiles of AngioVac thrombectomy in the treatment of RHT and CTE. ^{10 27 28 29} Treatment of PE with the AngioVac device has been less successful likely due to limited device steerability. ^{26 27 30}

AngioVac Technique

The procedure is performed under general anesthesia. All patients are anticoagulated with therapeutic heparin (or argatroban in the case of heparin-induced thrombocytopenia). Ultrasound-guided percutaneous access of the bilateral common femoral veins is obtained with standard micropuncture technique. Alternatively, right common femoral and right internal jugular venous access may be used. The right common femoral vein is typically used for the aspiration cannula, and the left common femoral vein or right internal jugular vein accessed for the reinfusion cannula. Following vascular access, the first venotomy is serially dilated over a stiff 0.035-inch working wire to accommodate placement of a 26-Fr Gore Dry Seal sheath through which the 22-Fr aspiration cannula is inserted and advanced under fluoroscopic guidance. The device is available in 20-, 85-, and 180-degree tip angulations which are selected on a case-by-case basis depending on target location and anatomy. The AngioVac F22 cannula technology is AngioDynamics' Proprietary Funnel Tip Design that allows for potentially easier navigation and placement throughout the patient's venous system. Additional features of the F22 cannula technology include radiopaque nitinol tip for visibility, funneled tip to enhance venous drainage flow, and a shaft supported by a flat stainless steel coiled wire within the catheter body to support kink resistance, and column strength. The second access is then serially dilated to accommodate the 18-Fr reinfusion cannula. The tubing is flushed and cleared of air. The aspiration cannula is attached to a filter canister to collect the aspirated thrombus, and blood is recirculated through the reinfusion venous cannula by the pump. After the cannula of the AngioVac aspiration catheter is confirmed to be in good position with apposition to the thrombus, the pump circulation is slowly increased until approximately 2,500 to 3,500 rotations per minute. The AngioVac device is slowly moved to-and-fro under TEE (or TTE) and fluoroscopic guidance until the thrombus is successfully aspirated. The Y-adapter allows for placement of adjunct devices up to 17 Fr such as balloons, snares, or forceps which may be used at the discretion of the operator. After successful aspiration, all devices are removed and the venotomies are closed with purse-string sutures.

AngioVac Case

A septuagenarian man with a history of lung adenocarcinoma and endoscopic myotomy presented with acute high-risk PE and was found to have an atrial lead associated 4.8 × 2.8 cm mobile thrombus extending across the tricuspid valve. Aspiration thrombectomy with the AngioVac 180-degree tip system was performed with assistance in clot removal using an endovascular snare through the side-arm adapter ( Fig. 1 ).

Fig. 1.

( a ) Transesophageal echocardiogram (TEE) demonstrating mobile right atrial thrombus (arrow); ( b ) intraoperative images of the AngioVac aspiration cannula (dashed arrow) advanced under continuous fluoroscopic and TEE guidance (solid arrow) for treatment of atrial lead associated thrombus (arrowhead); ( c ) aspiration filter with large-volume thrombus after thrombectomy with venovenous extracorporeal membrane oxygenation cannula in the background; ( d ) diagram courtesy of Angiodynamics demonstrating the procedure components and setup.

FlowTriever

The FlowTriever system (Inari Medical, Irvine, CA) is a mechanical aspiration thrombectomy device designed to rapidly aspirate clot through a large bore catheter with the use of a proprietary locking aspiration syringe.

The FLARE trial was the first prospective multicenter trial studying the use of the FlowTriever device for pulmonary thrombectomy in 106 patients with intermediate-risk submassive PE. ³¹ At 48 hours, there was a 25% reduction in the primary endpoint RV:LV (left ventricle) ratio, an established correlate for mortality, with a less than 1% risk of major bleeding and nonexistent risk of intracranial hemorrhage. ³¹ In addition to the device trials in PE, there are several retrospective studies and case reports of the use of the FlowTriever device for successful thrombus debulking in large venous beds for caval, portomesenteric, and RHT removal. ^{32 33 34 35}

FlowTriever Technique

The procedure is performed under moderate sedation or general anesthesia, keeping in mind that in the setting of acute submassive PE, general sedation with propofol is associated with increased mortality. All patients are anticoagulated with therapeutic heparin (or argatroban in the case of heparin-induced thrombocytopenia). Ultrasound-guided percutaneous access of the right common femoral vein or right internal jugular vein is obtained with standard micropuncture technique. Following vascular access, the venotomy is serially dilated over a stiff 0.035-inch working wire to accommodate placement of a 24-Fr Gore Dry Seal sheath through which the FlowTriever device will be inserted. The device is available in 16, 20, and 24 Fr sizes including a curved tip catheter with 260-degree rotational ability; device selection is based on target location and anatomy. Nitinol mesh disks are also available for clot extraction with variable diameters from 6 to 25 mm. In the case of IVC thrombus, venography or intravascular ultrasound via a second venous access can be used as an adjunct to visualize thrombus. In the setting of RHT, TEE is necessary for visualization. The device is then advanced under fluoroscopy until apposed with the clot. The proprietary locking syringe is aspirated and locked for maximum suction and the valve is then opened, referred to as a “Whoosh.” In the case of refractory or tip adherent thrombus not aspirated with a single “Whoosh,” the maneuver can be repeated without repositioning the device to deliver further suction. If the thrombus is not successfully removed into the syringe and is adherent to the catheter tip despite these maneuvers, the entire FlowTriever device can be removed from the sheath under suction to ensure any tip adherent thrombus does not embolize. After clearing the catheter, the device can be reinserted to continue aspiration thrombectomy. Venography can be performed through the device lumen to evaluate for residual thrombus in caval thrombosis and PE, though caution should be taken to ensure the catheter is clear of clot prior to injection to avoid embolization. The FlowTriever can also be tracked into the main, left, and right pulmonary arteries for pulmonary thrombectomy. After successful aspiration, all devices are removed and the venotomies are closed with purse-string sutures.

FlowTriever Case

A teenage girl with a history of inherited hypercoagulability, middle cerebral artery stroke in childhood, and two lifetime PE events presented with saddle PE and underwent surgical embolectomy and pulmonary thrombendarterectomy followed by IVC filter placement. One month later, despite therapeutic anticoagulation on warfarin with target INR 3-4 and aspirin 81 mg daily, she developed a right heart clot demonstrated on echocardiography as a mobile intracardiac 2.6 × 1.4 cm echogenic mass within the right atrium. Aspiration thrombectomy with FlowTriever T24 was performed under direct fluoroscopic and TEE guidance with successful thrombus removal ( Fig. 2 ).

Fig. 2.

( a ) CTA demonstrating large burden of pulmonary embolus; ( b ) transesophageal echocardiogram demonstrating concurrent right atrial thrombus; ( c ) aspiration thrombectomy of right heart thrombus with FlowTriever T24; ( d ) posttreatment right atrial clot burden is shown.

AlphaVac

The AlphaVac is a first-generation mechanical aspiration thrombectomy device redesigned with the benefits of the AngioVac system, however, allowing for rapid large-volume aspiration without the need for extracorporeal bypass. The cannula again retains nitinol basket reinforced, self-expandable funnel shaped distal tip and a proprietary handle designed to create an off-circuit method of action. The device is available in variable size and tip angulations indluing: 18 French 85 degree tip angulation and 22 French 20 and 180 degree tip angulations. The device encompasses features such as the volume limiting switch, limiting blood loss. during the procedure.

The APEX trial is a current interventional clinical trial investigating the safety and efficacy of the AlphaVac F1885 mechanical aspiration system for the treatment of PE in 122 patients with acute intermediate-risk submassive PE. ³⁶ The primary endpoints are the RV:LV ratio reduction 48 hours postprocedure and the rate of major adverse events. Secondary endpoints include the use of thrombolytics, length of stay in the intensive care unit, and additional safety endpoints. The trial is ongoing and results are not yet available.

AlphaVac Technique

The procedure is performed under moderate sedation or general anesthesia. All patients are anticoagulated with therapeutic heparin (or argatroban in the case of heparin-induced thrombocytopenia). Ultrasound-guided percutaneous access of the right common femoral vein or right internal jugular vein is obtained with standard micropuncture technique. Following vascular access, the venotomy is serially dilated over a stiff 0.035-inch working wire to accommodate placement of a 26-Fr Gore Dry Seal sheath, after which a venogram is performed, followed by AlphaVac insertion. The device selection is made on a case-by-case basis depending on target location and anatomy. The AngioVac F22 cannula technology is AngioDynamics' Proprietary Funnel Tip Design that allows for potentially easier navigation and placement throughout the patient's venous system. Additional features of the F22 cannula technology include radiopaque nitinol tip for visibility, funneled tip to enhance venous drainage flow, and a shaft supported by a flat stainless steel coiled wire within the catheter body to support kink resistance, and column strength. The device is advanced under fluoroscopic and/or TEE guidance depending on clot location. Two aspiration volumes can be used: 10 cc aspiration when hunting for thrombus and 30 cc aspiration when thrombus is engaged. The Y-adapter allows for placement of adjunct devices such as balloons or snares which may be used at the discretion of the operator. After successful aspiration, all devices are removed and the venotomies are closed with purse-string sutures.

AlphaVac Case

A septuagenarian man with left lower extremity DVT, large-volume mobile right atrial thrombus, and acute intermediate-risk PE was emergently transferred for intervention. Echocardiography demonstrated extensive mobile atrial clot and large right pulmonary lobar clot burden. Aspiration thrombectomy of right atrial clot was performed with 22-Fr AlphaVac device with two 30-cc aspirations with volume lock under continuous fluoroscopic and TEE guidance. Estimated blood loss was 200 mL. Pulmonary arterial embolism was subsequently treated with catheter-directed lysis, as the AlphaVac device in its current iteration was not long enough for pulmonary intervention from the common femoral vein access. The patient was later discharged on oral anticoagulation ( Fig. 3 ).

Fig. 3.

( a ) Intraoperative image of the AlphaVac thrombectomy cannula advanced to the cavoatrial junction; ( b ) pulmonary angiography demonstrating large-volume right pulmonary artery embolism; ( c ) transesophageal echocardiogram demonstrating mobile right atrial thrombus; ( d ) posttreatment right atrial clot burden is shown.

Potential Complications

Potential complications include vascular access injuries from large bore access, major hemorrhage or aspiration-related blood loss with potential need for blood transfusion, pulmonary embolization of thrombus fragments, arrhythmia, cardiac perforation, and embolic stroke in the setting of PFO. Major adverse events are overall uncommon, however. In the RAPID registry of AngioVac procedures, there was a 1.3% incidence of death with only one procedure-related death from thrombus embolization resulting in massive PE. There was a 3.8% incidence of vascular access trauma and 2.6% incidence of major hemorrhage. Incidence of distal fragment embolization was 3.0%, incidence of arrhythmia was 1.3%, and incidence of cardiac perforation was 0.4%. ²⁶ The study population included variable thrombus etiologies and patient demographics and the adverse event incidence does not necessarily reflect the overall risk in the general population, though the potential for such complications is evident.

Postprocedural Care

Postprocedural care is variable but includes standard vascular access checks, cardiac monitoring, neurovascular checks, and typically continued therapeutic anticoagulation. In the authors' experience, patients are typically admitted for monitored care, though some may require intensive care unit admission, while others may be discharged after postanesthesia care the same day. Purse-string sutures are removed prior to discharge. Postprocedure imaging CT venography, CT pulmonary angiography, or echocardiogram is not always obtained, but may be necessary if there is a change in the patient's clinical status. Appropriate multidisciplinary care and interventional radiology clinic follow-up is essential for all patients.

Conclusion

Right atrial thrombus most commonly presents as clot-in-transit in the setting of acute PE and is associated with high mortality requiring more than therapeutic anticoagulation treatment. Novel endovascular aspiration thrombectomy devices can rapidly debulk thrombus via large bore aspiration systems without the need for concurrent thrombolytics. Several devices each with their advantages and disadvantages are available to the interventional physician and treatment decisions should depend on patient presentation, operator's experience, and local resources.