Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial

Abstract

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.

Conflict of interest statement

O.S. has received institutional research grants from Bayer, Leo Pharma, Bristol-Myers Squibb, Merck Sharp and Dome, Daiichi-Sankyo, Boehringer Ingelheim, and Sanofi, and personal consultancy/speaker fees from Bayer, Bristol-Myers Squibb, Pfizer, Boston Scientific, Merck Sharp and Dome, Boehringer Ingelheim, Sanofi, and Chiesi. S.B. has received congress and travel payments from Daiichi-Sankyo and Bayer AG, honoraria from BTG Pharmaceuticals, Boston Scientific, Bayer HealthCare, and Leo Pharma, and institutional grants from Sanofi, outside the submitted work. W.A. reports research support from Bayer; activity in advisory boards for Bayer, Boehringer Ingelheim, Daiichi Sankyo, Portola, Janssen, Aspen, and Sanofi. D.D. has received speaker's honoraria from Bayer Vital, Daiichi-Sankyo, and Pfizer/Bristol-Myers Squibb, and consulting fees from Bayer Vital and Daiichi-Sankyo. In addition, D.D. is a member of SFB1425, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation #422681845). K.E. reports lecture fees from AstraZeneca, Bayer Vital, Berlin Chemie, Boehringer Ingelheim, and Novartis, and consulting fees from Bayer Vital, Boehringer Ingelheim, Novartis, and Novo Nordisk. M.F. reports lecture fees and travel grants from Bayer, Bristol-Myers Squibb, and Pfizer, and travel grants from Daiichi-Sankyo and Leo Pharma. M.V.H. reports grants from ZonMW Dutch Healthcare Fund, and grants and personal fees to the hospital from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Bayer Health Care, Aspen, and Daiichi-Sankyo, all outside the submitted work. D.J. has served as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Leo Pharma, Pfizer, ROVI, and Sanofi; served as a speaker or a member of a speakers' bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Leo Pharma, ROVI, and Sanofi; received grants for clinical research from Daiichi-Sankyo, Sanofi, and ROVI. M.K. reports speaker fees from Pfizer, Boehringer Ingelheim, and Bayer AG, outside the submitted work. M.L. reports consultant and speaker fees from Actelion, Bayer, Thermo Fisher Scientific, Daiichi-Sankyo, MSD, and Bristol-Myers Squibb-Pfizer, and project funding from Thermo Fisher Scientific. N.M. reports consulting fees, speaker fees, and project funding from Bayer AG and Bristol-Myers Squibb/Pfizer; speaker fees from AstraZeneca and Boehringer Ingelheim; and consulting fees from Abbott and Terumo. A.P. reports speaker fees from S.C. Pfizer Romania SRL, Servier Pharma SRL, Novartis Pharma Services Romania SRL, Bayer SRL, and SC Sanience SRL.S.R. received honoraria for lectures and/or consultancy from Abbott, Acceleron, Actelion, Arena, Bayer, BMS, Ferrer, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor, and institutional research grants from Actelion, AstraZeneca, Bayer, Janssen, and Novartis. S.S. has received consulting fees and speaker fees from Aspen and Boehringer Ingelheim, speaker fees from Bayer AG and Daiichi-Sankyo, and project funding and speaker fees from Pfizer/Bristol-Myers Squibb. P.V. received honoraria for lectures and/or consultancy from Anthos Therapeutics, Bayer, Boehringer, Daiichi-Sankyo, BMS, and Pfizer, and research support from Bayer, Daiichi-Sankyo, BMS, and Pfizer. S.K. reports institutional research grants and personal consultancy/speaker fees from Actelion/Janssen, Bayer AG, Daiichi-Sankyo, and Boston Scientific; institutional research grants from Boehringer Ingelheim and Servier; and personal consultancy/speaker fees from Bristol-Myers Squibb/Pfizer and Novartis. All other authors report no conflict of interest.

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Figures

Fig. 1

Overview of design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial. AEs, adverse events; PE, pulmonary embolism, RV, right ventricular; i.v., intravenously; V, visit.