Debate Over Best Treatment for High-Risk PE at ERS 2024

VIENNA — The optimal course of treatment when managing acute, high-risk pulmonary embolism (PE) remains a contentious topic among respiratory specialists.
Systemic thrombolysis, specifically using recombinant tissue plasminogen activator (rtPA), is the current gold standard treatment for high-risk PE. However, the real-world application is less straightforward due to patient complexities. Some clinicians believe that advances in mechanical and surgical techniques have made rtPA a thing of the past. Others think there is still insufficient evidence to support alternatives as the standard of care.
Here at the European Respiratory Society (ERS) 2024 Congress, respiratory specialists presented contrasting viewpoints and the latest evidence on each side of the issue to provide a comprehensive framework for navigating the complex decision-making process required for effective treatment.
“High-risk PE is a mechanical problem and thus needs a mechanical solution,” said Parth M. Rali, MD, an associate professor in thoracic medicine and surgery at the Lewis Katz School of Medicine at Temple University, Philadelphia.
“The marketing on some of the mechanical techniques is very impressive,” said Olivier Sanchez, MD, a pulmonologist in the Department of Pneumology and Intensive Care at the Georges Pompidou European Hospital in France. “But what is the evidence of such treatment in the setting of pulmonary embolism?”
The Case Against rtPA as the Standard of Care
High-risk PE typically involves hemodynamically unstable patients presenting with conditions such as low blood pressure, cardiac arrest, or the need for mechanical circulatory support. There is a spectrum of severity within high-risk PE, making it a complex condition to manage, especially since many patients have comorbidities like anemia or active cancer, complicating treatment. “It’s a very dynamic and fluid condition, and we can’t take for granted that rtPA is a standard of care,” Rali said.
Alternative treatments such as catheter-directed therapies, extracorporeal membrane oxygenation (ECMO), and surgical embolectomy are emerging as promising options, especially for patients who do not respond to or cannot receive rtPA. Mechanical treatments offer benefits in reducing clot burden and stabilizing patients, but they come with their own challenges.
ECMO can stabilize patients who are in shock or cardiac arrest, buying time for the clot to resolve or for further interventions like surgery or catheter-based treatments, said Rali. However, it is an invasive procedure requiring cannulation of large blood vessels, often involving significant resources and expertise.
Catheter-directed thrombolysis is a minimally invasive technique where a catheter is inserted directly into the pulmonary artery to deliver thrombolytic drugs at lower doses. This method allows for more targeted treatment of the clot, reducing the risk for systemic bleeding that comes with higher doses of thrombolytic agents used in systemic therapy, Rali explained. 
Rali reported results from the FLAME study, which investigated the effectiveness of FlowTriever mechanical thrombectomy compared with conventional therapies for high-risk PE. This prospective, multicenter observational study enrolled 53 patients in the FlowTriever arm and 61 in the context arm, which included patients treated with systemic thrombolysis or anticoagulation. The primary endpoint, a composite of adverse in-hospital outcomes, was reached in 17% of FlowTriever patients, significantly lower than the 32% performance goal and the 63.9% rate in the context arm. In-hospital mortality was dramatically lower in the FlowTriever arm (1.9%) compared to the context arm (29.5%). 
When catheter-based treatment fails, surgical pulmonary embolectomy is a last-resort option. “Only a minority of the high-risk PE [patients] would qualify for rtPA without harmful side effects,” Rali concluded. “So think wise before you pull your trigger.” 
rtPA Not a Matter of the Past
In high-risk PE, the therapeutic priority is rapid hemodynamic stabilization and restoration of pulmonary blood flow to prevent cardiovascular collapse. Systemic thrombolysis acts quickly, reducing pulmonary vascular resistance and obstruction within hours, said Sanchez. 
Presenting at the ERS Congress, he reported numerous studies, including 15 randomized controlled trials that demonstrated its effectiveness in high-risk PE. The PEITHO trial, in particular, demonstrated the ability of systemic thrombolysis to reduce all-cause mortality and hemodynamic collapse within 7 days. 
However, this benefit comes at the cost of  increased bleeding risk, including a 10% rate of major bleeding and a 2% risk for intracranial hemorrhage. “These data come from old studies using invasive diagnostic procedures, and with current diagnostic procedures, the rate of bleeding is probably lower,” Sanchez said. The risk of bleeding is also related to the type of thrombolytic agent, with tenecteplase being strongly associated with a higher risk of bleeding, while alteplase shows no increase in the risk of major bleeding, he added. New strategies like reduced-dose thrombolysis offer comparable efficacy and improved safety, as demonstrated in ongoing trials like  PEITHO-3, which aim to optimize the balance between efficacy and bleeding risk. Sanchez is the lead investigator of the PEITHO-3 study.
While rtPA might not be optimal for all patients, Sanchez thinks there is not enough evidence to replace it as a first-line treatment.
Existing studies on catheter-directed therapies often focus on surrogate endpoints, such as right-to-left ventricular ratio changes, rather than clinical outcomes like mortality, he said. Retrospective data suggest that catheter-directed therapies may reduce in-hospital mortality compared with systemic therapies, but they also increase the risk of intracranial bleeding, post-procedure complications, and device-related events.
Sanchez mentioned the same FLAME study described by Rali, which reported a 23% rate of device-related complications and 11% major bleeding in patients treated with catheter-directed therapies. 
“Systemic thrombolysis remains the first treatment of choice,” Sanchez concluded. “The use of catheter-directed treatment should be discussed as an alternative in case of contraindications.”
The Debate Continues
Numerous ongoing clinical studies, such as the  FLARE trial, will address gaps in evidence and refine treatment protocols, potentially reshaping the standard of care in high-risk PE in the near future by providing new data on the efficacy and safety of existing and emerging therapies.
“The coming data will make it clearer what the best option is,” Thamer Al Khouzaie, MD, a pulmonary medicine consultant at Johns Hopkins Aramco Healthcare in Dhahran, Saudi Arabia, told Medscape Medical News. For now, he said, systemic thrombolysis remains the best option for most patients because it is widely available, easily administered with intravenous infusion, and at a limited cost. Catheter-directed treatment and surgical options are only available in specialized centers, require expertise and training, and are also very expensive.
Rali, Sanchez, and Khouzaie report no relevant financial relationships.
Manuela Callari is a freelance science journalist specializing in human and planetary health. Her articles have been published in The Medical Republic, Rare Disease Advisor, The Guardian, MIT Technology Review, and others. 
 
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