An early switch from heparin to dabigatran, following standard clinical assessment, was both safe and effective in patients with intermediate-risk pulmonary embolism, according to study results published in Lancet Hematology.
Although research conducted in the past decade has brought advances to anticoagulation treatment, including the development of direct oral anticoagulants (DOACs), it is unclear the extent to which existing data from large trials are relevant to patients with intermediate-risk pulmonary embolism.
Researchers conducted an investigator-initiated, prospective, multinational, multicenter, single-arm, phase 4 trial (PEITHO-2; ClinicalTrials.gov Identifier: NCT02596555) to determine whether acute intermediate-risk pulmonary embolism with parenteral anticoagulation followed by 6 months of DOAC dabigatran was effective and safe for this patient population.
The study was conducted at 42 hospitals in 9 countries and included adults diagnosed with symptomatic acute intermediate-risk pulmonary embolism, confirmed through imaging. Intermediate-risk pulmonary embolism was defined using criteria proposed by the European Society of Cardiology.
The primary efficacy outcome was the occurrence of confirmed recurrent symptomatic venous thromboembolism or pulmonary embolism-related death during a 6-month follow-up period. Secondary efficacy outcomes included pulmonary embolism-related and all-cause death, hemodynamic collapse or decompensation within 30 days, death from any cause within 6 months, and overall duration of unscheduled hospital stay due to pulmonary embolism-related complications or bleeding within 6 months.
Between 2016 and 2019, a total of 1418 patients were diagnosed with acute pulmonary embolism, 402 of whom were included in the intention-to-treat (ITT) population (48% women; median age, 69.5 years). At baseline, signs of right ventricular dysfunction were seen in 338 (84%) patients via echocardiography, in 202 (50%) patients by computed tomography (CT) pulmonary angiography, and in 371 (92%) patients by at least 1 of these 2 imaging methods.
Cardiac troponin concentrations were elevated in 308 (77%) patients at baseline. A total of 283 (70%) patients were classified as having intermediate high-risk pulmonary embolism vs 73 (18%) who were classified as having intermediate low-risk pulmonary embolism.
Overall, 213 (53%) patients had a simplified pulmonary embolism severity index (sPESI) score of 1 or higher; 124 (31%) patients had a sPESI score of 0, despite the presence of signs of both right ventricular dysfunction and elevated cardiac troponin concentrations.
The time interval between pulmonary embolism diagnosis and study enrollment was less than 24 hours and between 24 and 48 hours in 83% and 15% of patients, respectively. Time interval between diagnosis and a switch from heparin to dabigatran was less than 3 days in 1% of patients, 3 days in 92% of patients, 5 days in 3% of patients, and more than 5 days in 2% of patients. Seven patients did not receive dabigatran.
Among 380 patients, dabigatran treatment was initiated at 72 hours in 370 patients (92% of the study population), among whom 96% had intermediate low-risk pulmonary embolism and 92% had intermediate high-risk pulmonary embolism.
In terms of the primary outcome, 7 (2%) of 402 patients experienced recurrent symptomatic venous thromboembolism (VTE) or death from a pulmonary embolism-related cause during the 6-month follow-up period. One patient died of pulmonary embolism 6 days following the index event, 1 died 66 days after, and 5 (1%) experienced nonfatal recurrent VTE.
Among patients with intermediate high-risk pulmonary embolism with a sPESI score of 1 or higher, the primary outcome occurred in 5 (3%) of 159 patients at 6 months.
Pulmonary embolism-related death, hemodynamic collapse, or hemodynamic decompensation occurred within the first 30 days in less than 1% of the ITT population, all of whom had intermediate high-risk pulmonary embolism. None of the patients with intermediate low-risk pulmonary embolism (n=73) had early pulmonary embolism-related death or hemodynamic collapse.
A total of 11 (3%) patients included in the ITT population experienced major bleeding events during the 6-month follow-up period. In total, 16 (4%) of 502 patients were readmitted to the hospital due to recurrence of VTE or bleeding, with a median rehospitalization duration of 8 days.
Study limitations included the lack of a control group, a lack of randomized design to test a low-molecular weight heparin lead-in of 3 days vs traditional drug regimens, and an inability to answer questions on the use of edoxaban or single-oral drug approach.
“Our results help to close existing gap sin the evidence base concerning the initial treatment of patients who have an elevated risk of early complications with anticoagulants,” the researchers wrote. “They also support the clinical relevance of identifying patients with intermediate high-risk pulmonary embolism.”
“The knowledge obtained from the PEITHO-2 study aids in refining future recommendations on the risk-adjusted management of acute pulmonary embolism,” they concluded.
Disclosure: This clinical trial was supported by Boehringer Ingelheim. Please see the original reference for a full list of authors’ disclosures.
Klok FA, Toenges G, Mavromanoli A, et al; for the PEITHO-2 Investigators. Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): A multinational, multicenter, single-arm, phase 4 trial. Lancet Hematol. Published online August 4, 2021. doi:10.1016/S2352-3026(21)00203-9