Non-immunogenic staphylokinase — a thrombolytic agent in the treatment of massive pulmonary embolism: results of the FORPE clinical trial

Aim . To assess the safety and efficacy of a single intravenous bolus of non-immunogenic staphylokinase compared with alteplase in patients with massive pulmonary embolism and hemodynamic instability. Non-immunogenic staphylokinase is a modified recombinant staphylokinase with low immunogenicity, high thrombolytic activity and fibrin selectivity. Material and methods . This multicenter, open-label, randomized, comparative clinical trial FORPE in two parallel groups was conducted in 23 clinical centers in Russia. A total of 310 patients aged 18 years and older with hemodynamic instability and computed tomography pulmonary angiography verified massive pulmonary embolism and right ventricular dysfunction were included. The patients were randomly assigned in either non-immunogenic staphylokinase (15 mg) or alteplase (100 mg) group. Both medicines were administered intravenously. An independent biostatistician created a randomization sequence using computer-generated random numbers. Randomization was performed using the envelopes. The study was open-label, and emergency unit staff, investigators, and patients were informed about the assigned drug. The primary efficacy endpoint was 7-day all-cause death after randomization. The non-inferiority margin was set at 10% for the difference in 7-day all-cause mortality after randomization between the compared groups. Non-inferiority was tested using the Welch t-test for the primary efficacy endpoint. Secondary efficacy endpoints were analyzed in both the intention-to-treat and per-protocol populations. Results . Of 348 patients screened between December 25, 2020, and July 31, 2023, 310 (89%) were included in the study. Of the total number, 155 (50%) patients were randomized to the non-immunogenic staphylokinase group and 155 (50%) to the alteplase group. In the non-immunogenic staphylokinase group, the primary efficacy endpoint, 7-day all-cause death, was 2% in the intent-to-treat population and 2% in the per-protocol population, whereas in the alteplase group it was 3% (odds ratio (OR) 0,75, 95% confidence interval (CI) 0,11-4,49; p=1,00) and 3% (OR 0,75, 95% CI 0,11-4,52; p=1,00), respectively. The difference in the primary efficacy endpoint was 0,6% (95% CI -2,8 to -4,0) in the intent-to-treat population and 0,6% (95% CI -2,9 to -4,2) in the per-protocol population. Thus, the lower limit of the 95% CI did not cross the non-inferiority margin (p<0,001). There were no cases of hemorrhagic stroke in the non-immunogenic staphylokinase group, whereas there were three cases (2%) of hemorrhagic stroke in the alteplase group (p=0,25). Serious adverse events were experienced by 11 patients (7%) in the non-immunogenic staphylokinase group compared with 12 patients (8%) in the alteplase group (p=1,00). Conclusion . Non-immunogenic staphylokinase is at least as effective as alteplase in the treatment of patients with massive pulmonary embolism with hemodynamic instability and has a higher safety profile. Future observational studies of non-immunogenic staphylokinase are needed to continue assessing its safety and efficacy. Given the high safety and efficacy of non-immunogenic staphylokinase, its use should be studied in patients with moderate-to-high risk pulmonary embolism.

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Publication Details

Journal
Russian Journal of Cardiology
Published
2024-10-23
DOI
https://doi.org/10.15829/1560-4071-2024-6157
Citations
7
Primary Topic
Venous Thromboembolism Diagnosis and Management
Type
article
Field-Weighted Citation Impact
3.85
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article

Non-immunogenic staphylokinase — a thrombolytic agent in the treatment of massive pulmonary embolism: results of the FORPE clinical trial

N. L. Vyazova, К. А. Линев, Zaur Shogenov, Yu. A. Lykov et al.
7 citations
Russian Journal of Cardiology
Venous Thromboembolism Diagnosis and Management
3.85
article

Non-immunogenic staphylokinase — a thrombolytic agent in the treatment of massive pulmonary embolism: results of the FORPE clinical trial

N. L. Vyazova, К. А. Линев, Zaur Shogenov, Yu. A. Lykov, В. В. Кулабухов, E. S. Panina, В. В. Кашталап, Anna G. Soplenkova, С. В. Иванов, Kirienko Ai, Yu. A. Romashova, А. М. Семенов, С. Н. Терещенко, Е. V. Rybin, Dmitry Maximov, Oleg Ivlev, A. G. Koledinsky, Petr S. Vlasov, S. L. Konstantinov, B. B. Orlov, Zh. Yu. Chefranova, I. Meray, Vladimir Aleksandrovich Kutsenko, Екатерина А. Комиссарова, Н. А. Черепанова, Irina Avdeeva, И. С. Муллова, Д. С. Куртасов, С. С. Маркин, Alexander I. Archakov, Dmitry Viktorovich Duplyakov, P. P. Savvinova, Э. А. Пономарев, I. S. Yavelov, G Klein, Н. В. Фурман, N. V. Yasnopolskaya, Leont'ev Sg, Е. B. Yarovaya, В. В. Макухин, В. В. Береговых, А. А. Komarova, E. V. Kulibaba, Р. М. Шахнович, M. P. Semenov, И. А. Либов, V V Bobkov, V. E. Oleynikov, Т. В. Павлова, O. B. Talibov, Sergey A. Pribylov, А. Д. Эрлих, T. B. Pecherina, В. Н. Золкин, A. S. Igoshin, G. I. Stryabkova, Yu. V. Karabach, Natalia V. Solovieva, V. S. Ivanov, R. M. Rabinovich, Elena J. Vasilieva, V. Yu. Tolmacheva, I. Yu. Bogomazov, L. O. Lyudnev
article en
7 citations

Abstract

Aim . To assess the safety and efficacy of a single intravenous bolus of non-immunogenic staphylokinase compared with alteplase in patients with massive pulmonary embolism and hemodynamic instability. Non-immunogenic staphylokinase is a modified recombinant staphylokinase with low immunogenicity, high thrombolytic activity and fibrin selectivity. Material and methods . This multicenter, open-label, randomized, comparative clinical trial FORPE in two parallel groups was conducted in 23 clinical centers in Russia. A total of 310 patients aged 18 years and older with hemodynamic instability and computed tomography pulmonary angiography verified massive pulmonary embolism and right ventricular dysfunction were included. The patients were randomly assigned in either non-immunogenic staphylokinase (15 mg) or alteplase (100 mg) group. Both medicines were administered intravenously. An independent biostatistician created a randomization sequence using computer-generated random numbers. Randomization was performed using the envelopes. The study was open-label, and emergency unit staff, investigators, and patients were informed about the assigned drug. The primary efficacy endpoint was 7-day all-cause death after randomization. The non-inferiority margin was set at 10% for the difference in 7-day all-cause mortality after randomization between the compared groups. Non-inferiority was tested using the Welch t-test for the primary efficacy endpoint. Secondary efficacy endpoints were analyzed in both the intention-to-treat and per-protocol populations. Results . Of 348 patients screened between December 25, 2020, and July 31, 2023, 310 (89%) were included in the study. Of the total number, 155 (50%) patients were randomized to the non-immunogenic staphylokinase group and 155 (50%) to the alteplase group. In the non-immunogenic staphylokinase group, the primary efficacy endpoint, 7-day all-cause death, was 2% in the intent-to-treat population and 2% in the per-protocol population, whereas in the alteplase group it was 3% (odds ratio (OR) 0,75, 95% confidence interval (CI) 0,11-4,49; p=1,00) and 3% (OR 0,75, 95% CI 0,11-4,52; p=1,00), respectively. The difference in the primary efficacy endpoint was 0,6% (95% CI -2,8 to -4,0) in the intent-to-treat population and 0,6% (95% CI -2,9 to -4,2) in the per-protocol population. Thus, the lower limit of the 95% CI did not cross the non-inferiority margin (p<0,001). There were no cases of hemorrhagic stroke in the non-immunogenic staphylokinase group, whereas there were three cases (2%) of hemorrhagic stroke in the alteplase group (p=0,25). Serious adverse events were experienced by 11 patients (7%) in the non-immunogenic staphylokinase group compared with 12 patients (8%) in the alteplase group (p=1,00). Conclusion . Non-immunogenic staphylokinase is at least as effective as alteplase in the treatment of patients with massive pulmonary embolism with hemodynamic instability and has a higher safety profile. Future observational studies of non-immunogenic staphylokinase are needed to continue assessing its safety and efficacy. Given the high safety and efficacy of non-immunogenic staphylokinase, its use should be studied in patients with moderate-to-high risk pulmonary embolism.

Russian Journal of CardiologyVol. 29(11)
Penza State University (RU), Belgorod National Research University (RU), Peoples' Friendship University of Russia (RU), Kuban State Medical University (RU), Lomonosov Moscow State University (RU), St. Elizabeth Hospital in Enumclaw (US), Pirogov Russian National Research Medical University (RU), Murmansk Regional Clinical Hospital (RU), Research Institute of Emergency Care (RU), Botkin Hospital (RU), St. Petersburg State Health Care Foundation "Mariinsky City Hospital" (RU), Krasnoyarsk Regional Clinical Hospital (RU), City Clinical Hospital (RU), National Medical Research Center of Cardiology (RU), State Healthcare Institution "Regional Clinical Oncological Dispensary" (RU), Moscow State University (TJ), Institute of Biomedical Chemistry (RU), Amita Health St. Mary's Hospital (US), Samara Regional Clinical Oncology Center (RU), Kursk State Medical University (RU), Kemerovo State University (RU)
Openalex Percentile: Top 6%
Venous Thromboembolism Diagnosis and Management
3.85
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