Response: Does Fibrinolytic Strategy of Pulmonary Embolism International ThrOmbolysis (PEITHO)-3 Trial Need More Strong Evidence?

We fully agree with Drs. Güner, Kahraman, and Ertürk that full-dose fibrinolytic therapy is a “double-edged sword” in the treatment of acute pulmonary embolism (PE),[ 1 ] mostly due to the risk of bleeding complications reported in the largest randomized controlled trial to date.[ 2 ] As emphasized in our article to which the authors refer,[ 3 ] these safety concerns provide, along with the promising findings of smaller studies using lower doses of systemic fibrinolysis, a strong rationale for the ongoing Pulmonary Embolism International ThrOmbolysis Trial (PEITHO)-3 (ClinicalTrials.gov Identifier: NCT04430569). Several reports of patients treated with reduced-dose fibrinolysis have been published over the past years. As recently pointed out by Güner et al,[ 4 ] the treatment regimens utilized in these studies were heterogeneous with regard to the total fibrinolytic dose and the duration of treatment. When designing PEITHO-3, we particularly considered the existing randomized trials which directly compared a reduced dose of alteplase with the “standard” conventional 100 mg alteplase regimen.[ 5 ] [ 6 ] [ 7 ] In one of these studies, 50 mg of alteplase was infused over 2 hours,[ 7 ] whereas in the other two, a weight-adapted dose of 0.6 mg/kg, up to a total of 50 mg, was given over 15 minutes.[ 5 ] [ 6 ] Based on their results, a meta-analysis suggested that a reduced dosage may be associated with reduction in the risk of major bleeding (odds ratio: 0.33; 95% confidence interval: 0.12–0.91), apparently without compromising efficacy.[ 8 ] The results of a randomized trial, which compared alteplase at the dose of 0.6 mg/kg over only 2 minutes with placebo in acute PE,[ 9 ] further support the efficacy and safety of a “fast” reduced-dose regimen. In view of these data, we chose, also for reasons of simplicity and practicability, the short-duration infusion of alteplase in our ongoing trial.[ 3 ] We do acknowledge that several cohort studies[ 4 ] [ 10 ] [ 11 ] also reported favorable results with other regimens, but these studies do not suggest that a longer duration of fibrinolytic agent might be superior to the one used in PEITHO-3. Today, various reduced-dose regimens are being used in clinical practice, but international guidelines explicitly warn that the available evidence is not (yet) sufficient to support the efficacy and safety of any of them.[ 12 ] PEITHO-3, a large randomized multicenter multinational controlled trial, will address a large unmet need by testing the hypothesis that reduced-dose systemic thrombolysis may improve the prognosis of patients with acute intermediate-high-risk PE at an acceptably low risk of major bleeding complications. Publication History Received: 11 July 2022 Accepted: 12 July 2022 Article published online: 28 October 2022 © 2022. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany