Inhibition of Late Sodium Current (INa) to Prevent Coronary MICROvascular Dysfunction in Patients Presenting With ST-Elevation Myocardial Infarction and Multivessel Disease: INaMICRON Study

Summary

This is a Phase IIb, multicentric, prospective, randomized (1:1 ratio), open label, and no profit study, with the aim of evaluating the efficacy of late INa current inhibition to improve coronary microcirculation in patients presenting with acute myocardial infarction and multivessel disease. All consecutive patients presenting with acute MI undergoing primary PCI (pPCI) on a major coronary artery, and with at least one remaining angiographically significant (% diameter stenosis \> 50%) non-culprit stenosis will be enrolled. The primary objective of the study is to evaluate the potential effect of Ranolazine in preserving coronary microcirculation subtended to the culprit vessel as compared with control group. Coronary microcirculation will be assessed both at the time of the culprit lesion revascularization and within 6+/-2 weeks by measuring the Index of Microcirculatory Resistance (IMR) either invasively or derived by the angiography (angioIMR). In addition, the following secondary endpoints will be assessed: 1. The prevalence of residual CMD downstream to the culprit vessel in all patients (CMDculprit). CMDculprit will be defined as the finding of an IMR/angioIMR value \> 25, assessed after successful pPCI. 2\. The prevalence of CMD downstream to the non-culprit vessel in the two group of patients (CMDnon-culprit). CMDnon-culprit will be defined as the finding of an IMRnon-culprit or an angioIMRnon-culprit value \> 25. IMRnon-culprit or angioIMRnon-culprit will be assessed at the time of staged PCI of the non-culprit stenosis. 3\. The incidence of peri-procedural CMD after staged PCI of the non-culprit stenoses, defined as a 20% increase of IMR values assessed before and after elective PCI of the non-culprit vessel (CMDprocedural). 4\. The difference between the two groups of patients, in terms of incidence of periprocedural Myocardial Infarction (PMI), eventually occurring during the staged procedure. 5\. The effects of INa current inhibition on endothelial function assessed at follow up as compared with control group. 6\. The extent of the Infarct Size, as assessed by the CMR, as compared with control group. 7\. The incidence of MACE, defined as composite of death, myocardial infarction, periprocedural MI, or any unplanned percutaneous coronary revascularization at short (42+/-7 days) term follow-up. 8\. Angina symptoms and quality of life

Timeline

Start

2026-02

Primary completion

2026-06

Completion

2026-06

Publications

• Background Topal DG, Aleksov Ahtarovski K, Lonborg J, Hofsten D, Nepper-Christensen L, Kyhl K, Schoos M, Ghotbi AA, Goransson C, Bertelsen L, Holmvang L, Helqvist S, Pedersen F, Schnabel R, Kober L, Kelbaek H, Vejlstrup N, Engstrom T, Clemmensen P. Impact of age on reperfusion success and long-term prognosis in ST-segment elevation myocardial infarction - A cardiac magnetic resonance imaging study. Int J Cardiol Heart Vasc. 2021 Mar 2;33:100731. doi: 10.1016/j.ijcha.2021.100731. eCollection 2021 Apr.
• Background Zeymer U, Ludman P, Danchin N, Kala P, Laroche C, Sadeghi M, Caporale R, Shaheen SM, Legutko J, Iakobsishvili Z, Alhabib KF, Motovska Z, Studencan M, Mimoso J, Becker D, Alexopoulos D, Kereseselidze Z, Stojkovic S, Zelveian P, Goda A, Mirrakhimov E, Bajraktari G, Al-Farhan H, Serpytis P, Raungaard B, Marandi T, Moore AM, Quinn M, Karjalainen PP, Tatu-Chitolu G, Gale CP, Maggioni AP, Weidinger F; ACVC EAPCI EORP ACS STEMI investigators group of the ESC. Reperfusion therapies and in-hospital outcomes for ST-elevation myocardial infarction in Europe: the ACVC-EAPCI EORP STEMI Registry of the European Society of Cardiology. Eur Heart J. 2021 Nov 21;42(44):4536-4549. doi: 10.1093/eurheartj/ehab342.
• Background El Farissi M, Zimmermann FM, De Maria GL, van Royen N, van Leeuwen MAH, Carrick D, Carberry J, Wijnbergen IF, Konijnenberg LSF, Hoole SP, Marin F, Fineschi M, Pijls NHJ, Oldroyd KG, Banning AP, Berry C, Fearon WF. The Index of Microcirculatory Resistance After Primary PCI: A Pooled Analysis of Individual Patient Data. JACC Cardiovasc Interv. 2023 Oct 9;16(19):2383-2392. doi: 10.1016/j.jcin.2023.08.030.
• Background 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). Circulation. 2018 Nov 13;138(20):e618-e651. doi: 10.1161/CIR.0000000000000617. No abstract available.
• Background Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, Mitchell GF, Sheffy J, Vita JA, Benjamin EJ. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008 May 13;117(19):2467-74. doi: 10.1161/CIRCULATIONAHA.107.748574. Epub 2008 May 5.
• Background Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004 Dec 7;44(11):2137-41. doi: 10.1016/j.jacc.2004.08.062.
• Background Mangiacapra F, Pellicano M, Di Serafino L, Bressi E, Peace AJ, Di Gioia G, Morisco C, Bartunek J, Wijns W, Bruyne B, Barbato E. Platelet reactivity and coronary microvascular impairment after percutaneous revascularization in stable patients receiving clopidogrel or prasugrel. Atherosclerosis. 2018 Nov;278:23-28. doi: 10.1016/j.atherosclerosis.2018.08.044. Epub 2018 Aug 30.
• Background Mejia-Renteria H, Lee JM, Choi KH, Lee SH, Wang L, Kakuta T, Koo BK, Escaned J. Coronary microcirculation assessment using functional angiography: Development of a wire-free method applicable to conventional coronary angiograms. Catheter Cardiovasc Interv. 2021 Nov 15;98(6):1027-1037. doi: 10.1002/ccd.29863. Epub 2021 Jul 9.
• Background Westra J, Andersen BK, Campo G, Matsuo H, Koltowski L, Eftekhari A, Liu T, Di Serafino L, Di Girolamo D, Escaned J, Nef H, Naber C, Barbierato M, Tu S, Neghabat O, Madsen M, Tebaldi M, Tanigaki T, Kochman J, Somi S, Esposito G, Mercone G, Mejia-Renteria H, Ronco F, Botker HE, Wijns W, Christiansen EH, Holm NR. Diagnostic Performance of In-Procedure Angiography-Derived Quantitative Flow Reserve Compared to Pressure-Derived Fractional Flow Reserve: The FAVOR II Europe-Japan Study. J Am Heart Assoc. 2018 Jul 6;7(14):e009603. doi: 10.1161/JAHA.118.009603.
• Background De Bruyne B, Adjedj J, Xaplanteris P, Ferrara A, Mo Y, Penicka M, Flore V, Pellicano M, Toth G, Barbato E, Duncker DJ, Pijls NH. Saline-Induced Coronary Hyperemia: Mechanisms and Effects on Left Ventricular Function. Circ Cardiovasc Interv. 2017 Apr;10(4):e004719. doi: 10.1161/CIRCINTERVENTIONS.116.004719.
• Background Gutierrez-Barrios A, Izaga-Torralba E, Rivero Crespo F, Gheorghe L, Canadas-Pruano D, Gomez-Lara J, Silva E, Noval-Morillas I, Zayas Rueda R, Calle-Perez G, Vazquez-Garcia R, Alfonso F. Continuous Thermodilution Method to Assess Coronary Flow Reserve. Am J Cardiol. 2021 Feb 15;141:31-37. doi: 10.1016/j.amjcard.2020.11.011. Epub 2020 Nov 19.
• Background Gallinoro E, Candreva A, Colaiori I, Kodeboina M, Fournier S, Nelis O, Di Gioia G, Sonck J, van 't Veer M, Pijls NHJ, Collet C, De Bruyne B. Thermodilution-derived volumetric resting coronary blood flow measurement in humans. EuroIntervention. 2021 Oct 1;17(8):e672-e679. doi: 10.4244/EIJ-D-20-01092.
• Background Keulards DCJ, Van 't Veer M, Zelis JM, El Farissi M, Zimmermann FM, de Vos A, Teeuwen K, Brueren GRG, Wijnbergen IF, Vlaar PJ, Tonino PAL, Pijls NHJ. Safety of absolute coronary flow and microvascular resistance measurements by thermodilution. EuroIntervention. 2021 Jun 25;17(3):229-232. doi: 10.4244/EIJ-D-20-00074. No abstract available.
• Background Wijnbergen I, van 't Veer M, Lammers J, Ubachs J, Pijls NH. Absolute coronary blood flow measurement and microvascular resistance in ST-elevation myocardial infarction in the acute and subacute phase. Cardiovasc Revasc Med. 2016 Mar;17(2):81-7. doi: 10.1016/j.carrev.2015.12.013. Epub 2016 Jan 7.
• Background Xaplanteris P, Fournier S, Keulards DCJ, Adjedj J, Ciccarelli G, Milkas A, Pellicano M, Van't Veer M, Barbato E, Pijls NHJ, De Bruyne B. Catheter-Based Measurements of Absolute Coronary Blood Flow and Microvascular Resistance: Feasibility, Safety, and Reproducibility in Humans. Circ Cardiovasc Interv. 2018 Mar;11(3):e006194. doi: 10.1161/CIRCINTERVENTIONS.117.006194.
• Background Fearon WF, Balsam LB, Farouque HM, Caffarelli AD, Robbins RC, Fitzgerald PJ, Yock PG, Yeung AC. Novel index for invasively assessing the coronary microcirculation. Circulation. 2003 Jul 1;107(25):3129-32. doi: 10.1161/01.CIR.0000080700.98607.D1. Epub 2003 Jun 23.
• Background Aarnoudse W, van den Berg P, van de Vosse F, Geven M, Rutten M, Van Turnhout M, Fearon W, de Bruyne B, Pijls N. Myocardial resistance assessed by guidewire-based pressure-temperature measurement: in vitro validation. Catheter Cardiovasc Interv. 2004 May;62(1):56-63. doi: 10.1002/ccd.10793.
• Background Ng MK, Yeung AC, Fearon WF. Invasive assessment of the coronary microcirculation: superior reproducibility and less hemodynamic dependence of index of microcirculatory resistance compared with coronary flow reserve. Circulation. 2006 May 2;113(17):2054-61. doi: 10.1161/CIRCULATIONAHA.105.603522. Epub 2006 Apr 24.
• Background Keulards DCJ, El Farissi M, Tonino PAL, Teeuwen K, Vlaar PJ, van Hagen E, Wijnbergen IF, de Vos A, Brueren GRG, Van't Veer M, Pijls NHJ. Thermodilution-Based Invasive Assessment of Absolute Coronary Blood Flow and Microvascular Resistance: Quantification of Microvascular (Dys)Function? J Interv Cardiol. 2020 Nov 17;2020:5024971. doi: 10.1155/2020/5024971. eCollection 2020.
• Background Byrne RA, Rossello X, Coughlan JJ, Barbato E, Berry C, Chieffo A, Claeys MJ, Dan GA, Dweck MR, Galbraith M, Gilard M, Hinterbuchner L, Jankowska EA, Juni P, Kimura T, Kunadian V, Leosdottir M, Lorusso R, Pedretti RFE, Rigopoulos AG, Rubini Gimenez M, Thiele H, Vranckx P, Wassmann S, Wenger NK, Ibanez B; ESC Scientific Document Group. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023 Oct 12;44(38):3720-3826. doi: 10.1093/eurheartj/ehad191. No abstract available.
• Background Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, Wolff AA; Combination Assessment of Ranolazine In Stable Angina (CARISA) Investigators. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004 Jan 21;291(3):309-16. doi: 10.1001/jama.291.3.309.
• Background Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, Pepine CJ, Wang W, Nelson JJ, Hebert DA, Wolff AA; MARISA Investigators. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004 Apr 21;43(8):1375-82. doi: 10.1016/j.jacc.2003.11.045.
• Background Orn S, Manhenke C, Greve OJ, Larsen AI, Bonarjee VV, Edvardsen T, Dickstein K. Microvascular obstruction is a major determinant of infarct healing and subsequent left ventricular remodelling following primary percutaneous coronary intervention. Eur Heart J. 2009 Aug;30(16):1978-85. doi: 10.1093/eurheartj/ehp219. Epub 2009 Jun 6.
• Background Mangiacapra F, Peace AJ, Di Serafino L, Pyxaras SA, Bartunek J, Wyffels E, Heyndrickx GR, Wijns W, De Bruyne B, Barbato E. Intracoronary EnalaPrilat to Reduce MICROvascular Damage During Percutaneous Coronary Intervention (ProMicro) study. J Am Coll Cardiol. 2013 Feb 12;61(6):615-21. doi: 10.1016/j.jacc.2012.11.025. Epub 2013 Jan 2.
• Background Fanaroff AC, Kaltenbach LA, Peterson ED, Hess CN, Cohen DJ, Fonarow GC, Wang TY. Management of Persistent Angina After Myocardial Infarction Treated With Percutaneous Coronary Intervention: Insights From the TRANSLATE-ACS Study. J Am Heart Assoc. 2017 Oct 19;6(10):e007007. doi: 10.1161/JAHA.117.007007.
• Background Ling H, Fu S, Xu M, Wang B, Li B, Li Y, Liu X, Zhang X, Wang Q, Li A, Liu M. Ranolazine for improving coronary microvascular function in patients with nonobstructive coronary artery disease: a systematic review and meta-analysis with a trial sequential analysis of randomized controlled trials. Quant Imaging Med Surg. 2024 Feb 1;14(2):1451-1465. doi: 10.21037/qims-23-1029. Epub 2024 Jan 9.
• Background Ahmed B, Mondragon J, Sheldon M, Clegg S. Impact of ranolazine on coronary microvascular dysfunction (MICRO) study. Cardiovasc Revasc Med. 2017 Sep;18(6):431-435. doi: 10.1016/j.carrev.2017.04.012. Epub 2017 Apr 22.
• Background Gutierrez JA, Karwatowska-Prokopczuk E, Murphy SA, Belardinelli L, Farzaneh-Far R, Walker G, Morrow DA, Scirica BM. Effects of Ranolazine in Patients With Chronic Angina in Patients With and Without Percutaneous Coronary Intervention for Acute Coronary Syndrome: Observations From the MERLIN-TIMI 36 Trial. Clin Cardiol. 2015 Aug;38(8):469-75. doi: 10.1002/clc.22425. Epub 2015 Jun 8.
• Background Wilson SR, Scirica BM, Braunwald E, Murphy SA, Karwatowska-Prokopczuk E, Buros JL, Chaitman BR, Morrow DA. Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial. J Am Coll Cardiol. 2009 Apr 28;53(17):1510-6. doi: 10.1016/j.jacc.2009.01.037.
• Background Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, Wolff AA, Skene A, McCabe CH, Braunwald E; MERLIN-TIMI 36 Trial Investigators. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007 Apr 25;297(16):1775-83. doi: 10.1001/jama.297.16.1775.
• Background Sossalla S, Wagner S, Rasenack EC, Ruff H, Weber SL, Schondube FA, Tirilomis T, Tenderich G, Hasenfuss G, Belardinelli L, Maier LS. Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts--role of late sodium current and intracellular ion accumulation. J Mol Cell Cardiol. 2008 Jul;45(1):32-43. doi: 10.1016/j.yjmcc.2008.03.006. Epub 2008 Mar 14.
• Background Hayashida W, van Eyll C, Rousseau MF, Pouleur H. Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease. Cardiovasc Drugs Ther. 1994 Oct;8(5):741-7. doi: 10.1007/BF00877121.
• Background Fraser H, Belardinelli L, Wang L, Light PE, McVeigh JJ, Clanachan AS. Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts. J Mol Cell Cardiol. 2006 Dec;41(6):1031-8. doi: 10.1016/j.yjmcc.2006.08.012. Epub 2006 Oct 5.
• Background Hasenfuss G, Maier LS. Mechanism of action of the new anti-ischemia drug ranolazine. Clin Res Cardiol. 2008 Apr;97(4):222-6. doi: 10.1007/s00392-007-0612-y. Epub 2007 Nov 28.
• Background Pelliccia F, Pasceri V, Marazzi G, Rosano G, Greco C, Gaudio C. A pilot randomized study of ranolazine for reduction of myocardial damage during elective percutaneous coronary intervention. Am Heart J. 2012 Jun;163(6):1019-23. doi: 10.1016/j.ahj.2012.03.018. Epub 2012 May 21.
• Background De Bruyne B, Pijls NHJ, Gallinoro E, Candreva A, Fournier S, Keulards DCJ, Sonck J, Van't Veer M, Barbato E, Bartunek J, Vanderheyden M, Wyffels E, De Vos A, El Farissi M, Tonino PAL, Muller O, Collet C, Fearon WF. Microvascular Resistance Reserve for Assessment of Coronary Microvascular Function: JACC Technology Corner. J Am Coll Cardiol. 2021 Oct 12;78(15):1541-1549. doi: 10.1016/j.jacc.2021.08.017.
• Background Mejia-Renteria H, Wang L, Chipayo-Gonzales D, van de Hoef TP, Travieso A, Espejo C, Nunez-Gil IJ, Macaya F, Gonzalo N, Escaned J. Angiography-derived assessment of coronary microcirculatory resistance in patients with suspected myocardial ischaemia and non-obstructive coronary arteries. EuroIntervention. 2023 Apr 3;18(16):e1348-e1356. doi: 10.4244/EIJ-D-22-00579.
• Background Fearon WF, Shah M, Ng M, Brinton T, Wilson A, Tremmel JA, Schnittger I, Lee DP, Vagelos RH, Fitzgerald PJ, Yock PG, Yeung AC. Predictive value of the index of microcirculatory resistance in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2008 Feb 5;51(5):560-5. doi: 10.1016/j.jacc.2007.08.062.
• Background Fearon WF, Low AF, Yong AS, McGeoch R, Berry C, Shah MG, Ho MY, Kim HS, Loh JP, Oldroyd KG. Prognostic value of the Index of Microcirculatory Resistance measured after primary percutaneous coronary intervention. Circulation. 2013 Jun 18;127(24):2436-41. doi: 10.1161/CIRCULATIONAHA.112.000298. Epub 2013 May 16.
• Background Galiuto L, Gabrielli FA, Lombardo A, La Torre G, Scara A, Rebuzzi AG, Crea F. Reversible microvascular dysfunction coupled with persistent myocardial dysfunction: implications for post-infarct left ventricular remodelling. Heart. 2007 May;93(5):565-71. doi: 10.1136/hrt.2006.091538. Epub 2006 Sep 15.
• Background Niccoli G, Cosentino N, Spaziani C, Fracassi F, Tarantini G, Crea F. No-reflow: incidence and detection in the cath-lab. Curr Pharm Des. 2013;19(25):4564-75. doi: 10.2174/1381612811319250005.
• Background Iwakura K, Ito H, Kawano S, Okamura A, Tanaka K, Nishida Y, Maekawa Y, Masuyama T, Hori M, Fujii K. Prediction of the no-reflow phenomenon with ultrasonic tissue characterization in patients with anterior wall acute myocardial infarction. Am J Cardiol. 2004 Jun 1;93(11):1357-61, A5. doi: 10.1016/j.amjcard.2004.02.030.
• Background Bekkers SC, Yazdani SK, Virmani R, Waltenberger J. Microvascular obstruction: underlying pathophysiology and clinical diagnosis. J Am Coll Cardiol. 2010 Apr 20;55(16):1649-60. doi: 10.1016/j.jacc.2009.12.037.
• Background Frohlich GM, Meier P, White SK, Yellon DM, Hausenloy DJ. Myocardial reperfusion injury: looking beyond primary PCI. Eur Heart J. 2013 Jun;34(23):1714-22. doi: 10.1093/eurheartj/eht090. Epub 2013 Mar 27.
• Background Niccoli G, Scalone G, Lerman A, Crea F. Coronary microvascular obstruction in acute myocardial infarction. Eur Heart J. 2016 Apr 1;37(13):1024-33. doi: 10.1093/eurheartj/ehv484. Epub 2015 Sep 12.
• Background Britten MB, Zeiher AM, Schachinger V. Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome. Coron Artery Dis. 2004 Aug;15(5):259-64. doi: 10.1097/01.mca.0000134590.99841.81.
• Background Lerman A, Holmes DR, Herrmann J, Gersh BJ. Microcirculatory dysfunction in ST-elevation myocardial infarction: cause, consequence, or both? Eur Heart J. 2007 Apr;28(7):788-97. doi: 10.1093/eurheartj/ehl501. Epub 2007 Mar 8.
• Background Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P; ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018 Jan 7;39(2):119-177. doi: 10.1093/eurheartj/ehx393. No abstract available.
• Background Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS. Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med. 2010 Jun 10;362(23):2155-65. doi: 10.1056/NEJMoa0908610.

Drugs

Indications