Fibrinolytic Beats Current Standard for Intermediate

NEW ORLEANS — A fibrinolysis-based intervention in acute intermediate-risk pulmonary embolism (PE) was shown to reduce major events, particularly cardiopulmonary decompensation, with an acceptably low rate of bleeding in a multinational phase 3 trial. When compared to anticoagulation alone, the current guideline-recommended standard, a catheter-administered 9-mg dose of the tissue plasminogen activator (tPA) alteplase and concomitant ultrasound reduced events by half at no significant cost in adverse events, according to Stavros V. Konstantinides, MD, professor of medicine and clinical trials at the University Medical Center of Johannes Gutenberg University in Mainz, Germany. The results of this trial, called HI-PEITHO, were presented as a late-breaking session at the 2026 American College of Cardiology (ACC) Meeting. The results were simultaneously published in The New England Journal of Medicine. Study Leads to 'New Era of Change' In past studies of fibrinolysis for intermediate-risk PE, bleeding and other risks were not enough to compensate for PE-related benefit. The new strategy, using an ultrasound-facilitated catheter device, is a breakthrough that “leads the way into an era of change,” according to Joshua Beckman, MD, chief of vascular medicine, University of Texas Southwestern Medical School in Dallas. The clear advantage of fibrinolysis at 7 days confirms clinical utility, but Beckman, who was the ACC-invited discussant on this late breaker, said that if the results continue to be positive with follow-up at 6 and 12 months, they “will be even more important.” In this trial, 544 PE patients meeting eligibility criteria, including cardiopulmonary distress, an elevated troponin level, and a ratio of right to left ventricular diameter of ≥ 1.0, were randomly assigned to fibrinolysis-based therapy plus anticoagulation or anticoagulation alone. The tPA was delivered by the minimally invasive EKOS endovascular system (Boston Scientific), a device that also delivers clot-dissolving ultrasonic waves. The primary efficacy outcome was a composite of PE-related death, cardiopulmonary resuscitation (or collapse), or symptomatic PE recurrence. For those treated with the device, the event rate at 7 days was 4.0% vs 10.3% in the arm receiving anticoagulation alone. The relative risk reduction for the device vs standard therapy exceeded 60% (RR, 0.39; P = .005). The incidence of major bleeding was numerically higher in the experimental arm across several scales but not statistically significant different. For example, major bleeding rates, as defined by the International Society on Thrombosis and Haemostasis (ISTH), were 4.1% and 2.2% (P = .32), respectively. There was no intracranial hemorrhage seen in either arm. There were also no substantial between-group differences in other serious adverse events. At 30 days, the mortality rate remained low in both arms if higher in the experimental arm (1.8% vs 1.1%). There was a numerically lower rate of serious adverse events (14.8% vs 16.2%; P = .62) and symptomatic PE recurrence (0.4% vs 0.7%) in the experimental arm at 30 days. Preserved Cardiorespiratory Function Is Main Benefit The advantage of the device vs anticoagulation alone was driven entirely by the lower rate of cardiorespiratory decompensation or collapse (3.7% vs 10.3%). There was one PE recurrence in both arms. PE-related deaths occurred in 3 vs 1 patient in the experimental and control arms, respectively, which did not approach significance. The protection against cardiorespiratory decompensation or collapse was supported by the lower rate of rescue therapy that was provided to patients in the experimental arm (2.9% vs 9.2%). Fibrinolysis has been pursued as a treatment for intermediate-risk PE in multiple trials, including the 2014 PEITHO trial, which included many of the investigators involved in HI-PEITHO, including Konstantinides. In that trial, the combination of tenecteplase (ranging in dose from 30 to 50 mg) plus heparin was compared to heparin plus placebo. For the primary outcome of death or hemodynamic decompensation or collapse at 7 days, the tPA therapy was more efficacious (2.6% vs 5.6%; RR, 0.42; P = .02), but more patients had stroke in the tPA arm (2.4% vs 0.2%) and there was more major bleeding (11.5% vs 2.4%). This trial, using a tPA at a far lower dose and combining it with ultrasound, has provided the first effective therapy for a group of patients that has remained at considerable risk for adverse events on the standard of anticoagulant therapy alone, Beckman reported. “There really was no understanding before this trial as to how to manage PE patients in the high intermediate-risk zone,” he said, explaining that the gap in knowledge was between higher-risk patients, for which thrombolysis or thrombectomy is indicated, and low-risk patients, where risks of aggressive therapy are not typically warranted. Although HI-PEITHO did not show a mortality benefit from intervention, Beckman noted that short-term death rates from PE are very low, so such as a benefit would be unlikely. But he thinks that the benefit that was seen on preserving cardiorespiratory function is clinically meaningful. However, he thinks the field might move even further forward when the long-term results are made available. Given prior studies showing that “nearly 50% of PE patients still are significantly impaired 1 year after PE,” the impact of the study might be even greater. “The field of pulmonary embolism has moved from out-front reduction in mortality and major events to making patients feel better for the rest of their lives,” he said. “I will be really interested to see the physiologic outcomes as they become available in the next several months.” Konstantinides reported financial relationships with Bayer, Bristol Myers Squibb, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Penumbra, Stryker, and Boston Scientific, which provided funding for the HI-PEITHIO trial. Beckman reported no conflicts of interest.