Randomized trials have shown that in patients with acute intermediate-high risk pulmonary embolism (PE), administration of systemic thrombolytics leads to less clinical deterioration, at the expense of increased major bleeding.¹ To maintain the efficacy of thrombolytics while minimizing risks, percutaneous transcatheter treatment has gained popularity over the last decade, initially as catheter-directed thrombolysis (CDT), with the later adoption of percutaneous mechanical thrombectomy (MT).

The safety and efficacy of these catheters were studied mostly in single-arm registries and nonrandomized studies.^2-4 However, as their use has now become widespread, so has the pressing need for high-level evidence to answer these important questions:

1. Does catheter-based therapy improve clinical outcomes compared to standard of care (defined as systemic anticoagulation only and escalation of therapy in unstable patients)?
2. Is there any specific advantage of one device-based approach vs. another (i.e., CDT vs. MT)?

To answer these questions, efforts led to the design and eventual initiation of several multicenter, randomized trials (industry, investigator-initiated and publicly funded). Although the first question is in principle the more important one to answer, it happened that the first trial to conclude and publish its primary results belonged to the latter question: PEERLESS (Large-bore Mechanical Thrombectomy vs. Catheter-directed Thrombolysis for Treatment of Intermediate-risk Pulmonary Embolism) was the first prospective, randomized clinical trial to evaluate interventional treatment options for managing acute PE.⁵

PEERLESS Design and Results

Sponsored by the manufacturer of the FlowTriever MT device (Inari Medical, Irvine, CA), PEERLESS randomized 550 patients with acute intermediate-risk PE and additional risk factors, including biomarker elevation, tachycardia and tachypnea, to either MT using the FlowTriever device or CDT using any commercially available catheter (most commonly the EKOS device, Boston Scientific, Marlborough, MA), all in accordance to local standard of care.

The outcome was a win-ratio of all-cause mortality, intracranial hemorrhage, major bleeding, clinical deterioration and/or escalation to a bailout therapy, and intensive care unit (ICU) admission and ICU length of stay during the index hospitalization or up to seven days. The win-ratio is a helpful statistical method to place a higher emphasis on the more important outcome (in this case mortality followed by intracranial hemorrhage) and to utilize both dichotomous and continuous variables as part of the primary outcome.⁶

PEERLESS was recently presented as a late-breaking clinical trial at TCT 2024. The trial found that the primary endpoint was significantly different between the two treatment arms, with a win-ratio of 5:1 in favor of MT. This primary outcome finding suggests that a patient is five-times more likely to avoid one of the primary endpoints with MT compared to CDT.

This outcome from the PEERLESS trial, however, was expected as the need for an ICU stay favored MT given that almost all centers universally observe patients in the ICU during CDT infusion. What was unexpected, however, was that the deterioration/escalation of care was significantly different in favor of MT (odds ratio 3.1; 95% CI, 1.1-8.6). A closer look revealed that all deterioration in the MT arm happened during the device treatment, and resolved within the same day, while those with CDT happened mostly after the treatment and appeared more severe in nature, like cardiac arrest and need for intubation.

In the MT arm, the functional status of patients and the right ventricular function were better at 24 hours post treatment compared to the CDT arm. This may help explain the lesser deterioration and need for bailout in the former group, perhaps related to a faster resolution of the mechanical obstruction produced by the pulmonary arterial clot with MT compared to CDT.

Two other important differences were almost a day shorter total hospital length of stay and a significantly less 30-day readmission rate in the MT arm compared to the CDT arm. Despite these early differences, total mortality and functional status were similar at 30 days between treatment arms. Also, the intracranial bleed and total bleeding rates were similar between devices.

PEERLESS Limitations

There are important limitations to the PEERLESS trial that need to be addressed before one can fully interpret the results. Although the initial intent was to recruit patients at representative bleeding risk as observed in clinical practice, the population ended up being lower bleeding risk overall. This was exemplified by a relative contraindication to thrombolytics in only 4% of patients, which is well below the published rates of around 30% in a typical acute PE patient population.⁴ It is possible that MT may have appeared safer than CDT in terms of bleeding had the trial been successful at recruiting a higher bleeding-risk population.

Another important limitation is the lack of standardization in the CDT arm, resulting in a wide distribution in catheters and thrombolytic doses used. However, this limitation was necessary to reflect as closely as possible contemporary CDT practice across enrolling institutions.

Lastly, the decision to escalate care, such as crossing over from CDT to MT, was left to the operator. While this results in subjective indications, there was numerically more deteriorations in CDT arm and a slower resolution of symptoms, which aligned with the higher need for bailout MT.

Perhaps the biggest criticism that the PEERLESS trial has faced was the inclusion of the ICU stay in the outcome, which automatically biases the results in favor of the MT arm. To address this issue, the hierarchical win-ratio was adopted, with the ICU stay being in the bottom of the list. Of note, the win-ratio was no longer significant when analyzed without the ICU outcome included, speaking to the weight this endpoint had on the primary outcome of the trial. Nonetheless, it is important to understand the difference between the groups in hospital resource utilization in a well-conducted trial setting, since this has traditionally been one of the favoring positions for using MT over CDT. This was particularly relevant following the COVID-19 pandemic and lack of available ICU-level beds.

Practice Implications?

With these findings and limitations in mind, what should the medical community conclude from the PEERLESS trial? Should MT be used more often to treat acute PE? Are more trials needed to compare the two?

On the surface, MT came out superior to CDT in the treatment of acute PE. Nonetheless, the mortality rate was similar between the two arms and 30-day outcomes were similar. However, we shouldn't dismiss the importance of avoiding clinical deterioration or bailout therapy, which also allowed avoidance of systemic thrombolysis that can have graver bleeding consequences.

One safe conclusion, for now, is that MT, compared to CDT, leads to a quicker improvement in symptoms, is more likely to avoid ICU stay, and likely leads to less clinical deterioration. Furthermore, this trial continues to support the role of both catheter-based therapies for managing PE, and demonstrates the low adverse event rate, and in particular death rate, among a sick population of patients with PE.

A key question is how generalizable such a conclusion is and will continue to be as new technology comes to market. From a patient population perspective, the results may not apply to those with contraindication to thrombolytics, nor can they be extrapolated to the high-risk population (i.e., those with hypotension or cardiac arrest at presentation).

Although the FLAME trial of the FlowTriever catheter in high-risk acute PE showed very promising results of MT in these patients, there was no comparison to CDT in this specific patient population.⁷ From a catheter perspective, the MT arm was strictly represented by the large-bore FlowTriever catheter, and the performance of smaller catheters with different aspiration mechanisms may not result in similar outcomes, limiting the generalizability of the PEERLESS results to other devices.

Similarly, the CDT arm consisted mostly of the EKOS and other simple infusion catheters. The Bashir catheter (Thrombolex, New Britain, PA), for example, has a different mechanism of action that combines maceration and clot surface exposure to thrombolysis and may thus achieve a faster and larger clot resolution compared to the CDT.⁸

From a wider angle, the PEERLESS results appear to be a win for catheter therapy for acute PE in general, with a very low 30-day all-cause mortality of 0.6%. Was this low mortality attributed to the catheter treatment? It is possible, but we need to wait for more trials randomized to anticoagulation alone to be able to answer this question. Currently, the HI-PEITHO trial, PE-TRACT and PEERLESS-II are all investigating the safety and efficacy of catheter-based intervention on clinical outcomes compared to systemic anticoagulation alone.^9-11

In the meanwhile, it is reasonable to continue treating patients with acute intermediate-high risk PE with catheter-based therapy, especially in those patients where clinical deterioration is feared. MT appears to be the better treatment to reduce deterioration and length of stay compared to CDT, but in centers with no experience in MT and in patient anatomies not suited for large-bore access and thrombectomy, CDT is a reasonable alternative. Most importantly, as PE intervention is still an emerging field, the treating physicians are encouraged to strongly consider recruiting every PE patient in one of the ongoing clinical trials.

References

1. Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347(15):1143-1150.
2. Moriarty JM, Dohad SY, Schiro BJ, et al. Clinical, functional, and quality-of-life outcomes after computer assisted vacuum thrombectomy for pulmonary embolism: Interim analysis of the STRIKE-PE Study. J Vasc Interv Radiol. 2024;35(8):1154-1165 e6.
3. Sterling KM, Goldhaber SZ, Sharp ASP, et al. Prospective multicenter international registry of ultrasound-facilitated catheter-directed thrombolysis in intermediate-high and high-risk pulmonary embolism (KNOCOUT PE). Circ Cardiovasc Interv. 2024;17(3):e013448.
4. Toma C, Jaber WA, Weinberg MD, et al. Acute outcomes for the full US cohort of the FLASH Mechanical Thrombectomy Registry in pulmonary embolism. EuroIntervention. 2023;18(14):1201-1212.
5. Jaber WA, Gonsalves CF, Stortecky S, et al. Large-Bore mechanical thrombectomy versus catheter-directed thrombolysis in the management of intermediate-risk pulmonary embolism: primary results of the PEERLESS randomized controlled trial. Circulation. 2024;Oct 29:doi: 10.1161/CIRCULATIONAHA.124.072364.
6. Pocock SJ, Ariti CA, Collier TJ, Wang D. The Win Ratio: A new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. Eur Heart J. 2012;33(2):176-182.
7. Silver MJ, Gibson CM, Giri J, et al. Outcomes in high-risk pulmonary embolism patients undergoing flowtriever mechanical thrombectomy or other contemporary therapies: Results from the FLAME Study. Circ Cardiovasc Interv. 2023;16(10):e013406.
8. Bashir R, Foster M, Iskander A, et al. Pharmacomechanical catheter-directed thrombolysis with the bashir endovascular catheter for acute pulmonary embolism: The RESCUE study. JACC Cardiovasc Interv. 2022;15(23):2427-2436.
9. Klok FA, Piazza G, Sharp ASP, et al. Ultrasound-facilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediate-high-risk pulmonary embolism: Rationale and design of the HI-PEITHO study. Am Heart J. 2022;251:43-53.
10. Sista AK, Troxel AB, Tarpey T, et al. Rationale and design of the PE-TRACT Trial: A multicenter randomized trial to evaluate catheter-directed therapy for the treatment of intermediate-risk pulmonary embolism. Am Heart J. 2024;281:112-122.
11. Giri J, Mahfoud F, Gebauer B, et al. PEERLESS II: A randomized controlled trial of large-bore thrombectomy versus anticoagulation in intermediate-risk pulmonary embolism. J Soc Cardiovasc Angiogr Interv. 2024;3(6):101982.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Vascular Medicine, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Interventions and Vascular Medicine

Keywords: Cardiology Magazine, ACC Publications, Tachycardia, Thrombectomy, Pulmonary Embolism