Phase 2, randomized, open-label study on catheter-directed thrombolysis with plasmin versus rtPA and placebo in acute peripheral arterial occlusion

Abstract

Background: Patients with acute peripheral arterial occlusion (aPAO) are candidates for operative thrombectomy, bypass, or catheter-directed thrombolysis (CDT) using a plasminogen activator. Human plasma-derived plasmin may offer another CDT option.

Objectives: To evaluate the efficacy, safety, and tolerability of two intrathrombus delivery methods and two doses of plasmin compared with recombinant tissue plasminogen activator (rtPA) and placebo in patients with aPAO.

Patients/methods: This was a phase 2, randomized, open-label study of intra-arterial CDT of plasmin in patients with aPAO. The study used infusion catheters with or without balloon occlusion (BOC) to evaluate 150 mg plasmin (2 and 5 h post-infusion) and 250 mg plasmin (5 h post-infusion). The efficacy of plasmin, rtPA and placebo was assessed.

Results: One hundred and seventy-four subjects were enrolled. Overall, the thrombolytic efficacy (>50% thrombolysis) was 59% (58/99) for 150 mg plasmin without BOC, which is comparable to 89% (8/9) for rtPA without BOC (p = 0.149) and 40% (2/5) for placebo control (p = 0.648). The thrombolytic efficacy was 33% of the 250 mg plasmin group. There was no difference (p > 0.999) in thrombolytic efficacy with BOC (59%, 58/99) or without BOC (59%, 17/29). Plasmin-treated groups experienced treatment-emergent adverse events (TEAEs) at 71% (76/107) without BOC and 63% (24/38) with BOC; 78% (7/9) of the rtPA-treated group and 89% (8/9) of the placebo group had TEAEs. Serious AEs (SAEs) occurred in 29% (31/107) of the 150 mg plasmin group without BOC and 24% (9/38) with BOC. No SAEs occurred in the 250 mg plasmin group.

Conclusions: Plasmin demonstrated less bleeding during catheter-directed administration at 150 mg and 250 mg doses compared to rtPA. BOC utilization did not improve efficacy. CDT with plasmin has a potential thrombolytic benefit in patients presenting with aPAO.

ClinicalTrials.gov Identifier: NCT01222117

Trial registration: ClinicalTrials.gov identifier: NCT01222117.

Keywords:

• Arterial occlusive disease
• plasmin
• ischemia
• peripheral arterial disease
• thrombolytic therapy

Transparency

Declaration of funding

This study was funded by Grifols, the sponsor of this clinical trial. The sponsor (Grifols) participated in study design, data collection, analysis, interpretation, and manuscript preparation.

Declaration of financial/other interests

Anthony J. Comerota has been paid a consulting fee for responsibility as the principal investigator and has received funding as a study site (Jobst Vascular Institute). Lazar Davidovic has received funding as a study site (University of Belgrade, Clinic for Vascular and Endovascular Surgery, Serbian Clinical Center). Richard Shlansky-Goldberg has been paid a consulting fee for responsibility as a steering committee member. Kim Hanna and Kecia L. Courtney are employees of Grifols, which is a manufacturer of plasmin. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors thank Tam M. Nguyen-Cao, PhD, CMPP of Grifols for her expert manuscript review and medical writing services under the direction of the authors. We acknowledge Dr Victor Marder (deceased) of University of California, Los Angeles for his contributions to the design of this study protocol; he was a steering committee member. We acknowledge Junliang Chen, PhD of Grifols for his assistance with the post hoc statistical analyses in this study. We also thank the following investigators for their participation in this trial: Juan F. Bautista of Hospital Nacional Guillermo Almenara Irigoyen-EsSalud, Peru; Sumit Bhatla of Remington Davis, Inc., USA; Miroslav Bulvas of University Hospital Kralovske Vinohrady, Czech Republic; John Hoch of University of Wisconsin, USA; Adrian Iancu of Institutul Inimii de Urgenta Pentru Boli Cardiovasculare, Romania; Dusan Kucera of Vaskularni centrum Vitkovicka nemocnice, Czech Republic; Patrick Lauwers of Universitair Ziekenhuis Antwerpen, Belgium; Lubomir Spak of East Slovakian Institute of Cardiovascular Diseases, Slovakia; Geert Maleux of Universitair Ziekenhuis Leuven, Belgium; Dragoslav Nenezic of Institut za kardiovaskularne bolesti Dedinje, Serbia; Przemyslaw Nowakowski of KS American Heart of Poland Sp. z o.o w Chrzanowie; Rajiv Parakha of Medanta – The Medicity, India; Vladan Popovic of Klinički Centar Vojvodine, Serbia; Dierk Scheinert of University Hospital Leipzig, Germany; Ivan Vulev of The National Institute of Cardiovascular Diseases, Slovakia; Jean-Claude Wautrecht of Hopital Erasme, Belgium; Fred Weaver of University of Southern California, USA; Norbert Weiss of Universitätsklinikum Carl Gustav Carus Dresden, Germany. The authors would like to acknowledge the participation of the following institutions: Amrita Institute of Medical Science & Research, India; Boston Medical Center, USA; Fakultná nemocnica Trenčín, Slovakia; Greenville Memorial Hospital- Vascular Health Alliance, USA, Hospital Nacional Edgardo Rebagliati Martins, Peru; Institute of General and Emergency Surgery NAMS of Ukraine, Ukraine; Institutul de Boli Cardiovasculare “Prof. Dr. George I. M. Georgescu,” Romania; Institutul de Urgenta pentru Boli Cardiovasculare “Prof. Dr. C.C. Iliescu,” Romania; Klinički Centar Niš - Klinika za vaskularnu hirurgiju, Serbia; Life Care Institute of Medical Sciences and Research, India; Samodzielny Publiczny Szpital Kliniczny Nr 2 PUM, Poland; МБаи National Cardiology Hospital, Bulgaria; Sterling Hospital, India; Wojewodzki Szpital Specjalistyczny nr 4 SUM, Poland.