One-year outcomes of a single bolus r-SAK before primary PCI for STEMI: Follow-up of the OPTIMA-5 study

Abstract

The Optimal Management of Antithrombotic and Thrombolytic Agents-5 (OPTIMA-5) study demonstrated that a single bolus of half the standard dose of recombinant staphylokinase (r-SAK) before primary percutaneous coronary intervention (PCI) significantly improved the patency of the infarct-related artery in patients with ST-segment elevation myocardial infarction (STEMI), who were expected to undergo PCI within 120 min. The present study aimed to investigate the one-year clinical outcomes and the effect of the anti-r-SAK antibodies on a second r-SAK thrombolysis in OPTIMA-5 patients. The clinical outcome measured was major adverse cardiovascular events (MACE) within 360 days. Patients' anti-r-SAK antibody levels were determined on day 90 (± 7 days), day 180 (± 7 days), and day 360 (± 14 days) after thrombolysis, and in vitro r-SAK antibody neutralization experiments were performed to explore an optimal interval for a second r-SAK thrombolysis. Results showed that the MACE incidence was numerically lower in the r-SAK group compared with the normal saline (NS) group (14.0% vs. 20.0%, hazard ratio [HR] = 0.67, 95% confidence interval [CI]: 0.34-1.32; log-rank P = 0.245). The anti-r-SAK antibody levels in the r-SAK group decreased with time, but remained significantly higher than those in the NS group on day 90 (± 7 days) (2.96 ± 0.68 vs. 0.22 ± 0.53, P < 0.001), day 180 (± 7 days) (2.19 ± 0.74 vs. 0.44 ± 0.65, P < 0.001), and day 360 (± 14 days) (1.73 ± 0.97 vs. 0.37 ± 0.71, P < 0.001). The in vitro anti-r-SAK antibody neutralization experiments demonstrated that the thrombolysis rate decreased exponentially as the antibody titer increased from 1.90 to 2.20 (67.80% ± 14.19% vs. 44.32% ± 21.54%, P < 0.0001). Therefore, for STEMI patients who are expected to undergo PCI within 120 min, a single bolus of half-dose r-SAK before primary PCI may reduce the one-year MACE risk. The anti-r-SAK antibody persists over one year, and a second r-SAK thrombolysis may not be indicated until at least one year after the first administration, if necessary.

Keywords

recombinant staphylokinase / myocardial infarction / thrombolysis / percutaneous coronary intervention

Fundings

This work was supported by the National Natural Science Funding of China (Grant No. 82170351), the Special Fund for Key R&D Plans (Social Development) of Jiangsu Province (Grant No. BE2019754), and Kanion Pharmaceutical Group, Lianyungang, Jiangsu, China

Acknowledgments

The authors would like to thank all the staff of Xintrum Pharmaceuticals Co., Ltd. (Nanjing, Jiangsu, China) for their assistance in detecting anti-r-SAK antibody titers and r-SAK concentration.

References

[1] Bhatt DL, Lopes RD, Harrington RA. Diagnosis and treatment of acute coronary syndromes: A review[J]. JAMA, 2022, 327(7): 662-675. doi: 10.1001/jama.2022.0358

[2] Ibánez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[J]. Rev Esp Cardiol (Engl Ed), 2017, 70(12): 1082.

[3] Writing Committee Members, Lawton JS, Tamis-Holland JE, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: executive summary: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice guidelines[J]. J Am Coll Cardiol, 2022, 79(2): 197-215. doi: 10.1016/j.jacc.2021.09.005

[4] Chen P, Eikelboom JW, Tan C, et al. Single bolus r-SAK before primary PCI for ST-segment-elevation myocardial infarction[J]. Circ Cardiovasc Interv, 2024, 17(2): e013455. doi: 10.1161/CIRCINTERVENTIONS.123.013455

[5] O'Neill WW, Weintraub R, Grines CL, et al. A prospective, placebo-controlled, randomized trial of intravenous streptokinase and angioplasty versus lone angioplasty therapy of acute myocardial infarction[J]. Circulation, 1992, 86(6): 1710-1717. doi: 10.1161/01.CIR.86.6.1710

[6] Vermeer F, Oude Ophuis AJM, vd Berg EJ, et al. Prospective randomised comparison between thrombolysis, rescue PTCA, and primary PTCA in patients with extensive myocardial infarction admitted to a hospital without PTCA facilities: A safety and feasibility study[J]. Heart, 1999, 82(4): 426-431. doi: 10.1136/hrt.82.4.426

[7] Ross AM, Coyne KS, Reiner JS, et al. A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: The PACT trial[J]. J Am Coll Cardiol, 1999, 34(7): 1954-1962. doi: 10.1016/S0735-1097(99)00444-1

[8] Widimský P, Groch L, Zelízko M, et al. Multicentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The PRAGUE study[J]. Eur Heart J, 2000, 21(10): 823-831. doi: 10.1053/euhj.1999.1993

[9] Wong A, Mak KH, Chan C, et al. Combined fibrinolysis using reduced-dose alteplase plus abciximab with immediate rescue angioplasty versus primary angioplasty with adjunct use of abciximab for the treatment of acute myocardial infarction: Asia-Pacific Acute Myocardial Infarction Trial (APAMIT) pilot study[J]. Catheter Cardiovasc Interv, 2004, 62(4): 445-452. doi: 10.1002/ccd.20101

[10] Le May MR, Wells GA, Labinaz M, et al. Combined angioplasty and pharmacological intervention versus thrombolysis alone in acute myocardial infarction (CAPITAL AMI study)[J]. J Am Coll Cardiol, 2005, 46(3): 417-424. doi: 10.1016/j.jacc.2005.04.042

[11] Thiele H, Engelmann L, Elsner K, et al. Comparison of pre-hospital combination-fibrinolysis plus conventional care with pre-hospital combination-fibrinolysis plus facilitated percutaneous coronary intervention in acute myocardial infarction[J]. Eur Heart J, 2005, 26(19): 1956-1963. doi: 10.1093/eurheartj/ehi432

[12] The ADVANCE MI Investigators. Facilitated percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: Results from the prematurely terminated ADdressing the Value of facilitated ANgioplasty after Combination therapy or Eptifibatide monotherapy in acute Myocardial Infarction (ADVANCE MI) trial[J]. Am Heart J, 2005, 150(1): 116-122. doi: 10.1016/j.ahj.2005.04.005

[13] Assessment of the Safety and Efficacy of A New Treatment Strategy with Percutaneous Coronary Intervention ( ASSENT-4 PCI) Investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): Randomised trial[J]. Lancet, 2006, 367(9510): 569-578. doi: 10.1016/S0140-6736(06)68147-6

[14] Peters S, Truemmel M, Koehler B. Facilitated PCI by combination fibrinolysis or upstream tirofiban in acute ST-segment elevation myocardial infarction: Results of the Alteplase and Tirofiban in Acute Myocardial Infarction (ATAMI) trial[J]. Int J Cardiol, 2008, 130(2): 235-240. doi: 10.1016/j.ijcard.2007.08.048

[15] Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in patients with ST-elevation myocardial infarction[J]. N Engl J Med, 2008, 358(21): 2205-2217. doi: 10.1056/NEJMoa0706816

[16] Thiele H, Eitel I, Meinberg C, et al. Randomized comparison of pre-hospital-initiated facilitated percutaneous coronary intervention versus primary percutaneous coronary intervention in acute myocardial infarction very early after symptom onset: the LIPSIA-STEMI trial (Leipzig immediate prehospital facilitated angioplasty in ST-segment myocardial infarction)[J]. JACC Cardiovasc Interv, 2011, 4(6): 605-614. doi: 10.1016/j.jcin.2011.01.013

[17] Vakili B, Nezafat N, Negahdaripour M, et al. Staphylokinase enzyme: An overview of structure, function and engineered forms[J]. Curr Pharm Biotechnol, 2017, 18(13): 1026-1037. doi: 10.2174/1389201019666180209121323

[18] Li C, Huang J, Yang Z, et al. Thrombolytic efficacy of native recombinant staphylokinase on femoral artery thrombus of rabbits[J]. Acta Pharmacol Sin, 2007, 28(1): 58-65. doi: 10.1111/j.1745-7254.2007.00455.x

[19] Collaborative Research Group of Reperfusion Therapy in Acute Myocardial Infarction. A randomized multicenter trial comparing recombinant staphylokinase with recombinant tissue-type plasminogen activator in patients with acute myocardial infarction[J]. Chin J Cardiol, 2007, 35(8): 691-696. doi: 10.3760/j.issn:0253-3758.2007.08.002

[20] Vanderschueren S, Barrios L, Kerdsinchai P, et al. A randomized trial of recombinant staphylokinase versus alteplase for coronary artery patency in acute myocardial infarction[J]. Circulation, 1995, 92(8): 2044-2049. doi: 10.1161/01.CIR.92.8.2044

[21] Dehghani P, Lavoie A, Lavi S, et al. Effects of ticagrelor versus clopidogrel on platelet function in fibrinolytic-treated STEMI patients undergoing early PCI[J]. Am Heart J, 2017, 192: 105-112. doi: 10.1016/j.ahj.2017.07.013

[22] Yang A, Pon Q, Lavoie A, et al. Long-term pharmacodynamic effects of Ticagrelor versus Clopidogrel in fibrinolytic-treated STEMI patients undergoing early PCI[J]. J Thromb Thrombolysis, 2018, 45(2): 225-233. doi: 10.1007/s11239-017-1581-2

[23] Berwanger O, Nicolau JC, Carvalho AC, et al. Ticagrelor vs clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: A randomized clinical trial[J]. JAMA Cardiol, 2018, 3(5): 391-399. doi: 10.1001/jamacardio.2018.0612

[24] Kohli P, Wallentin L, Reyes E, et al. Reduction in first and recurrent cardiovascular events with ticagrelor compared with clopidogrel in the PLATO Study[J]. Circulation, 2013, 127(6): 673-680. doi: 10.1161/CIRCULATIONAHA.112.124248

[25] Hausenloy DJ. Conditioning the heart to prevent myocardial reperfusion injury during PPCI[J]. Eur Heart J Acute Cardiovasc Care, 2012, 1(1): 13-32. doi: 10.1177/2048872612438805

[26] Vanderschueren S, Dens J, Kerdsinchai P, et al. Randomized coronary patency trial of double-bolus recombinant staphylokinase versus front-loaded alteplase in acute myocardial infarction[J]. Am Heart J, 1997, 134(2 Pt 1): 213-219.

[27] Vanderschueren SM, Stassen JM, Collen D. On the immunogenicity of recombinant staphylokinase in patients and in animal models[J]. Thromb Haemost, 1994, 72(2): 297-301. doi: 10.1055/s-0038-1648856

[28] Vanderschueren S, Collen D, Van de Werf F. A pilot study on bolus administration of recombinant staphylokinase for coronary artery thrombolysis[J]. Thromb Haemost, 1996, 76(4): 541-544. doi: 10.1055/s-0038-1650619

[29] Collen D. Staphylokinase: A potent, uniquely fibrin-selective thrombolytic agent[J]. Nat Med, 1998, 4(3): 279-284. doi: 10.1038/nm0398-279

[30] Li C, Eikelboom JW, Zhong Z, et al. Efficacy and safety of a bolus of half-dose r-SAK prior to primary PCI in ST-elevation myocardial infarction: Rationale and design of the OPTIMA-6 trial[J]. Am Heart J, 2023, 265: 31-39. doi: 10.1016/j.ahj.2023.06.012