Prolonged Clinical Follow-up of OPTIMA-5

ST-segment Elevation Myocardial Infarction (STEMI) Clinical Trial

Official title:

A Single Bolus r-SAK Prior to Primary PCI for ST-elevation Myocardial Infarction (OPTIMA-5): 1-Year Follow-up

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05649696
• Other study ID #: 020
• Status: Completed
• Phase: Phase 4
• Start date: October 29, 2021
• Est. completion date: October 1, 2023

Study information

• Verified date: February 2024
• Source: The First Affiliated Hospital with Nanjing Medical University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The OPTIMA-5 trial is a prospective, multi-center, randomized, patient blinded, controlled trial comparing a single bolus of half-dose recombinant staphylokinase (r-SAK) with normal saline (NS) in patients with ST-segment elevation myocardial infarction (STEMI) presenting ≤12 hours of symptom onset and expected to undergo primary percutaneous coronary intervention (PPCI) within 120 minutes. The results of OPTIMA-5 showed that a single bolus r-SAK prior to PPCI for STEMI improves infarct related artery (IRA) patency and reduces infarct size without increasing major bleeding. On this basis, this study was designed to investigate the effect of the novel reperfusion strategy on 1-year outcomes of patients with STEMI.

Description:

Acute myocardial infarction (AMI) is one of the leading causes of death all over the world, and accounted for more than 100 thousand deaths in the US in 2019. Early PPCI reduces mortality in patients with STEMI. If PPCI cannot be performed within 120 minutes of presentation, guidelines recommend the use of thrombolytic therapy. However, it remains uncertain whether adjunctive thrombolytic therapy administered immediately prior to PPCI improves outcomes in patients undergoing the procedure within 120 minutes.

SAK is a fibrin specific fibrinolytic agent produced by Staphylococcus aureus that was first discovered in 1948. A recombinant form of SAK was approved by China Food and Drug Administration (CFDA) for treatment of patients with STEMI. It has been demonstrated that r-SAK is more potent than urokinase and recombinant streptokinase in rabbit models.

The OPTIMA-5 trial is an investigator-initiated, prospective, multi-center, randomized, patient blinded, controlled trial comparing a single bolus of half-dose r-SAK with NS in patients with STEMI presenting ≤12 hours of symptom onset and expected to undergo PPCI within 120 minutes. Between October 29, 2021 and August 14, 2022, 283 STEMI patients were screened in 8 centers in China and 200 were randomized to r-SAK group or control in a 1:1 ratio using a computer-generated randomization sequence.

On this basis, this study was aimed to conduct a 1-year follow-up study to further confirm the efficacy and safety of this novel reperfusion strategy for patients with STEMI.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 210
• Est. completion date: October 1, 2023
• Est. primary completion date: September 14, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Arm 1 and 2 inclusion and exclusion criteria

Inclusion Criteria:

1. Age 18-75 years, weight =45 kg;

2. Diagnosed as STEMI (meeting the following two criteria simultaneously):

i. Ischemic chest pain lasts =30 minutes; ii. Electrocardiogram indicates that ST-segment elevation =2 mm in 2 or more contiguous precordial leads or =1 mm in 2 or more peripheral leads;

3. Time from onset of persistent chest pain to randomization <12 hours;

4. Primary PCI expected to be performed within 120 minutes.

Exclusion Criteria:

1. Cardiogenic shock;

2. Active bleeding or at high risk of bleeding (including grade ? or ? retinopathy or retinal gastrointestinal or urinary tract hemorrhage within the past 1 month);

3. Ischemic stroke or TIA in the past 6 months;

4. History of hemorrhagic stroke;

5. Platelet count <100×109/L or hemoglobin <100 g/L;

6. Known intracranial aneurysm;

7. Severe trauma, surgery or head injury within 1 month;

8. Suspected aortic dissection or infective endocarditis;

9. Recent puncture with difficult hemostasis by compression (eg, visceral biopsy, compartment puncture);

10. Currently taking anticoagulants;

11. Poorly controlled hypertension ( =180/110 mmHg);

12. Hepatic or renal impairment (glutamic-pyruvic transaminase, glutamic oxalacetic transaminase, or ? -glutamyl transferase >2.5 times upper limit of normal value; creatinine >1.5 times upper limit of normal value);

13. Known allergy to r-SAK;

14. Pregnancy, lactation, or planning for pregnancy;

15. History of myocardial infarction or CABG;

16. Having taken antiplatelet drugs other than aspirin and ticagrelor, such as clopidogrel, prasugrel or cilostazol after the symptom onset;

17. Patients with other conditions that made them unsuitable to be recruited at the discretion of the investigators.

Arm 3 inclusion and exclusion criteria Inclusion criteria

1. Age =18, =75 years old, weight =45kg, gender is not limited;

2. Taking maintenance dose of aspirin and ticagrelor for more than 3 days, or taking loading dose of aspirin (300mg) and ticagrelor (180mg);

3. Inpatients with suspected coronary atherosclerotic heart disease scheduled for coronary angiography or interventional therapy.

Exclusion criteria

1. Patients who had received r-SAK thrombolytic therapy before;

2. Previous diagnosis of Staphylococcus aureus infection;

3. Patients who were participating in other clinical trials;

4. Other patients considered unsuitable for inclusion by the investigators.

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction
• ST Elevation Myocardial Infarction
• ST-segment Elevation Myocardial Infarction (STEMI)

Intervention

Drug:
• Recombinant Staphylokinase
Intravenous injection of r-SAK is administered within 10 minutes after diagnosis of acute ST-segment elevation myocardial infarction
• Normal Saline
Intravenous injection of normal saline is administered within 10 minutes after diagnosis of acute ST-segment elevation myocardial infarction

Locations

Country	Name	City	State
China	Changzhou Second People's Hospital	Changzhou
China	The second Affiliated Hospital of Dalian Medical University	Dalian
China	Huai 'an Second People's Hospital affiliated to Nanjing Medical University	Huai'an
China	Lianyungang First People's Hospital	Lianyungang
China	The First Affiliated Hospital of Nanjing Medical University	Nanjing	Jiangsu
China	Taizhou People's Hospital	Taizhou
China	Affiliated Hospital of Jiangnan University	Wuxi
China	The Second Affiliated Hospital of Zhejiang University Medical College	Zhejiang

Sponsors (1)

Lead Sponsor	Collaborator
The First Affiliated Hospital with Nanjing Medical University

Country where clinical trial is conducted

China, 

References & Publications (15)

Agnoletti G, Cargnoni A, Agnoletti L, Di Marcello M, Balzarini P, Pasini E, Gitti G, Martina P, Ardesi R, Ferrari R. Experimental ischemic cardiomyopathy: insights into remodeling, physiological adaptation, and humoral response. Ann Clin Lab Sci. 2006 Summer;36(3):333-40. — View Citation

Collen D, Lijnen HR. Thrombolytic agents. Thromb Haemost. 2005 Apr;93(4):627-30. doi: 10.1160/TH04-11-0724. — View Citation

Correction to: Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018 Mar 20;137(12):e493. doi: 10.1161/CIR.0000000000000573. No abstract available. — View Citation

Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007 May 1;115(17):2344-51. doi: 10.1161/CIRCULATIONAHA.106.685313. — View Citation

Halvorsen S, Storey RF, Rocca B, Sibbing D, Ten Berg J, Grove EL, Weiss TW, Collet JP, Andreotti F, Gulba DC, Lip GYH, Husted S, Vilahur G, Morais J, Verheugt FWA, Lanas A, Al-Shahi Salman R, Steg PG, Huber K; ESC Working Group on Thrombosis. Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J. 2017 May 14;38(19):1455-1462. doi: 10.1093/eurheartj/ehw454. No abstract available. — View Citation

Heusch G, Libby P, Gersh B, Yellon D, Bohm M, Lopaschuk G, Opie L. Cardiovascular remodelling in coronary artery disease and heart failure. Lancet. 2014 May 31;383(9932):1933-43. doi: 10.1016/S0140-6736(14)60107-0. Epub 2014 May 13. — View Citation

Li CJ, Huang J, Yang ZJ, Cao KJ. Thrombolytic efficacy of native recombinant staphylokinase on femoral artery thrombus of rabbits. Acta Pharmacol Sin. 2007 Jan;28(1):58-65. doi: 10.1111/j.1745-7254.2007.00455.x. — View Citation

Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449. No abstract available. — View Citation

Pulicherla KK, Kumar A, Gadupudi GS, Kotra SR, Rao KR. In vitro characterization of a multifunctional staphylokinase variant with reduced reocclusion, produced from salt inducible E. coli GJ1158. Biomed Res Int. 2013;2013:297305. doi: 10.1155/2013/297305. Epub 2013 Aug 13. — View Citation

Szemraj J, Stankiewicz A, Rozmyslowicz-Szerminska W, Mogielnicki A, Gromotowicz A, Buczko W, Oszajca K, Bartkowiak J, Chabielska E. A new recombinant thrombolytic and antithrombotic agent with higher fibrin affinity - a staphylokinase variant. An in-vivo study. Thromb Haemost. 2007 Jun;97(6):1037-45. doi: 10.1160/th06-10-0562. — View Citation

Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018). Glob Heart. 2018 Dec;13(4):305-338. doi: 10.1016/j.gheart.2018.08.004. Epub 2018 Aug 25. No abstract available. — View Citation

Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, Nichols M. Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J. 2016 Nov 7;37(42):3232-3245. doi: 10.1093/eurheartj/ehw334. Epub 2016 Aug 14. No abstract available. Erratum In: Eur Heart J. 2019 Jan 7;40(2):189. — View Citation

Ueshima S, Matsuo O. Development of new fibrinolytic agents. Curr Pharm Des. 2006;12(7):849-57. doi: 10.2174/138161206776056065. — View Citation

Vakili B, Nezafat N, Negahdaripour M, Yari M, Zare B, Ghasemi Y. Staphylokinase Enzyme: An Overview of Structure, Function and Engineered Forms. Curr Pharm Biotechnol. 2017;18(13):1026-1037. doi: 10.2174/1389201019666180209121323. — View Citation

Yamamoto J, Kawano M, Hashimoto M, Sasaki Y, Yamashita T, Taka T, Watanabe S, Giddings JC. Adjuvant effect of antibodies against von Willebrand Factor, fibrinogen, and fibronectin on staphylokinase-induced thrombolysis as measured using mural thrombi formed in rat mesenteric venules. Thromb Res. 2000 Mar 1;97(5):327-33. doi: 10.1016/s0049-3848(99)00184-x. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	r-SAK antibody level in human serum	Recombinant staphylokinase (r-SAK) antibody level in human serum	Day 90 ± 7, Day 180 ± 7, Day 360 ± 14
Other	In-vitro thrombolysis rate	In-vitro thrombolysis rate	60 minutes after In-vitro thrombolysis
Other	r-SAK activity before and after in-vitro thrombolysis	r-SAK activity before and after in-vitro thrombolysis	Immediately before in-vitro thrombolysis and 60 minutes after In-vitro thrombolysis
Primary	MACE	A composite of all-cause death, reinfarction, unplanned target vessel revascularization, heart failure or cardiogenic shock, major ventricular arrhythmia	Within 360 days
Secondary	Adverse cardiac and cerebrovascular events	Each of the above independent MACE events, cardiovascular death, cardiac mechanical complications and stroke.	Within 360 days

External Links

•   OPTIMA-5