Is catheter-directed lysis obsolete? STRATIFY revisits low-dose thrombolysis for intermediate-high risk pulmonary embolism

Acute pulmonary embolism (PE) is a prevalent cardiovascular condition associated with high mortality rates. The management of patients with intermediate-high-risk PE—those who are hemodynamically stable but present with impaired right heart function and elevated cardiac biomarkers—remains challenging. The standard care for these patients is anticoagulation therapy and watchful waiting, with full-dose thrombolysis recommended as the first-line therapy if the patient’s condition deteriorates.1 This treatment paradigm has remained largely unchanged for years, and was further supported by the PEITHO Trial in 2014, which demonstrated that the efficacy of full-dose thrombolysis in intermediate-high-risk PE were outweighed by an unacceptable high bleeding rate, including intracranial hemorrhages.2 Experienced clinicians have encountered cases where stable intermediate-high-risk PE patients suddenly deteriorate, progressing to hemodynamic collapse and cardiac arrest with fatal outcomes. This unpredictable deterioration underscores the limitations of the current conservative approach. In contrast to the more proactive treatment strategies employed in other cardiovascular conditions, this ‘watchful waiting’ approach remains suboptimal for managing acute intermediate-high-risk PE. Consequently, there is an urgent need for effective therapeutic interventions that can prevent the potentially fatal progression of these patients’ condition, without increasing risks. Catheter-directed therapies have rapidly emerged as promising alternatives for treating PE.3 These therapies generally follow two main principles: catheter-directed embolectomy and catheter-directed low-dose thrombolysis (6–24 mg of alteplase), with or without ultrasound assistance. Both approaches have shown promise, with several trials indicating that catheter-based treatments more effectively unload the right ventricle compared with anticoagulation alone within 24–48 h.4 Larger clinical trials with clinical endpoints are currently underway to validate if these finding translate into a clinical benefit for the patients [HI-PEITHO NCT04790370, PEERLESS II NCT06055920, PRAGUE-26 (NCT05493163), PE_TRACT NCT04430569]. Another potential strategy involves systemic low-dose thrombolysis. Although previous studies have tested this approach in a heterogeneous population of PE patients, an ongoing trial is investigating whether reduced-dose thrombolysis (15 min intravenous infusion at a dosage of 0.6 mg/kg with a total dose not exceeding 50 mg) may be more effective than anticoagulation alone in intermediate-high-risk PE. As we await results, one important question remains: Are the doses of thrombolytics used in catheter-directed lysis equally effective when administered intravenously? In other words, is catheter-directed thrombolysis necessary or can low-dose thrombolysis be given intravenously with similar results? In this issue of Cardiovascular Research, Kjaergaard et al. present the investigator-initiated STRATIFY trial that addresses this very question.5 The STRATIFY trial included 210 adults with confirmed acute intermediate-high-risk PE. Patients were randomized into one of three treatment groups: anticoagulation alone, low-dose intravenous alteplase (20 mg over 6 h), or low-dose catheter-directed alteplase with ultrasound assistance. The primary outcome was the change in thrombus burden at 48–96 h, assessed using a refined modified Miller score. The trial design mirrors real-world clinical practice: patients randomized to invasive treatment were transferred to a tertiary care centre, while those receiving intravenous therapy were treated locally. The results of the trial suggest that low-dose thrombolysis—whether administered intravenously or via ultrasound-assisted catheter-directed therapy—produced a greater reduction in thrombus burden compared with heparin alone. However, no difference was observed between the intravenous and ultrasound-assisted catheter groups, indicating that the catheter-based ultrasound did not provide additional benefit over intravenous administration. While the primary endpoint—thrombus burden evaluated by the refined modified miller score—is a valid measure of clot resolution, it is a surrogate endpoint that does not always correlate with clinical outcomes. Upon closer examination of the results, no significant difference was found in the reduction of the right-to-left ventricular diameter ratio (RV/LV ratio) between thrombolysis and anticoagulation groups. This suggests that the reduction in thrombus burden did not translate into unloading of the right heart. Furthermore, there were no differences in respiratory rate, blood pressure, heart rate, or quality of life between groups. While a slightly higher dyspnoea index and a numerically higher, but not statistically significant, use of oxygen were observed in the anticoagulation group, the overall reduction in thrombus burden did not appear to result in measurable improvements in other clinical outcomes. A further concern is the safety of low-dose thrombolysis. In the thrombolysis group, there were more bleeding events (20 vs. 3) and more deaths (6 vs. 0) compared with the anticoagulation group. Three of the deaths were due to bleeding—two intracranial and one gastrointestinal—which raises concerns about the safety of low-dose lysis. While the differences in bleeding and mortality did not reach statistical significance, the study was not powered to assess safety outcomes, which should be a consideration for future trials. The STRATIFY trial result indicate that intravenous administration of 20 mg of alteplase over 6 h is as effective as catheter-directed ultrasound-assisted thrombolysis in reducing thrombus burden, as measured by the refined modified Miller score. However, this study also raises critical questions about the broader efficacy and safety of low-dose thrombolysis in this patient population. Is low-dose lysis an effective and safe strategy for treating acute intermediate-high-risk PE, or does it present unnecessary risks without clear benefit? Future trials with clinically meaningful endpoints are needed to answer these questions. As we await these results, it is crucial to include patients with intermediate-high-risk PE in randomized controlled trials, as exemplified by the authors of the STRATIFY trial, to better understand the optimal treatment strategies for this challenging condition. A.A. is funded by a grant from the Elise Jensens Foundation.