Fractional flow reserve in non-culprit coronary arteries of patients with acute ST elevation myocardial infarction

In the presence of non-culprit coronary stensosis, the optimal therapy for that is still a matter of debate. While guidelines discourage a concomitant treatment of infarct- and non-infarct-related arteries, recent studies document advantages of a complete (preventive) revascularization during primary PCI, which may result in overtreatment, as angiography alone does not provide robust information about the functional severity of MVD.

JOURNAL OF MEDICAL RESEARCH FRACTIONAL FLOW RESERVE IN NON-CULPRIT CORONARY ARTERIES OF PATIENTS WITH ACUTE ST ELEVATION MYOCARDIAL INFARCTION Vu Quang Ngoc1, Ken Kozuma2, Nguyen Quoc Thai1, Pham Manh Hung3 Vietnam National Heart Institude, Bach Mai Hospital, Hanoi, Vietnam Department of Cardiology, Teikyo University, Tokyo, Japan Department of Cardiology, Hanoi Medical University, Hanoi, Vietnam Multi-vessel disease (MVD) with stenotic lesions other than the culprit artery (the so-called nonculprit artery) - is present in 40-60% of acute ST elevation myocardial infarction (STEMI) patients, which is a determintant of higher risk of death and re-intervention compared to single vessel dissease [1] In the presence of non-culprit coronary stensosis, the optimal therapy for that is still a matter of debate While guidelines discourage a concomitant treatment of infarct- and non-infarct-related arteries, recent studies document advantages of a complete (preventive) revascularization during primary PCI, which may result in overtreatment, as angiography alone does not provide robust information about the functional severity of MVD Fractional flow reserve (FFR) measurements have been established in this acute setting as a possibly valuable guide for non-culprit lesions after uncomplicated primary PCI accordingly FFR value ≤ 0.80 has been determined to be predictive of functional significance and, in addition, is the threshold at which revascularisation should be considered The clinical implications of an FFR-guided treatment strategy in STEMI patients with MVD have been proved in a variety of randomized clinical trials CVLPRIT [2], DANAMI3-PRIMULTI [3] In Vietnam, FFR has been validated in a large number of studies but limited to data of patients with stable ischemic heart disease [4] We undertook the study to assess the FFR of non-culprit arteries in patients with acute STEMI and MVD after uncomplicated primary PCI 81 acute STEMI patients at institutions (Vietnam National Heart Institute - Hanoi - Vietnam and Teikyo University Hospital - Tokyo - Japan), who met the inclusion criteria, were enrolled in the prospective, non-randomized study from Nov 2017 to Sept 2018 The mean age was 60.9 ± 12.2 (yrs) 63% of patients were male The most common culprit artery was LAD (57.6%) 60.5% involved vessels, and 39.5% involved vessels Mean percentage diameter stenosis (PDS) was 55.17 ± 9.85% FFR of 135 non-culprit lesions contained of 23.8% lesions with FFR ≤ 0.80, 76.2% lesions with FFR > 0.80 The mean FFR value was 0,82 ± 0,16 The study showed 100% of technical success rate, and 99.3% procedural success rate FFR revealed correlation with minimum lumen diameter (MLD), inverse correlation with lesion length (LL), but no correlation with PDS Measuring FFR of non-culprit artery after uncomplicated primary PCI setting is safe and provides helpful information on functionally ischemic impact, and further, on revascularization strategy in STEMI patients with MVD Keywords: acute myocardial infarction, STEMI, primary coronary intervention, fractional flow reserve I INTRODUCTION Acute ST segment elevation myocardial infarction (STEMI) most commonly occurs Corresponding author: Vu Quang Ngoc, Vietnam National Heart Institude, Bachmai Hospital Email: dr.vuquangngoc.cardio@gmail.com Received: 27/11/2018 Accepted: 12/03/2019 JMR 118 E4 (2) - 2019 when thrombus formation results in complete occlusion of a major epicardial coronary vessel The most serious form of acute coronary syndromes, STEMI is a life-threatening, timesensitive emergency that must be diagnosed and treated promptly via primary percutaneous coronary intervention (PCI) to restore blood 105 JOURNAL OF MEDICAL RESEARCH flow as soon as possible in the occluded vessel Multi-vessel disease (MVD) is present in about 40-60% of patients with STEMI referred for PCI, which is a determinant of higher risk of death and revascularization compared to single vessel disease [1] Although the presence of MVD has been associated with a worse prognosis, not all studies have shown improved outcomes when these so called "non-culprit lesions" are treated with PCI In theory, one might argue that this is because the lesion in the non-infarct artery is an "innocent bystander" and therefore should be approached in much the same way one approaches stable ischemic heart disease Opponents to this argument might propose that these non-culprit lesions may also be biologically active as there are often multiple complex plaques in patients with acute myocardial infarction shown in various studies, and therefore these arteries warrant treatment in much the same way one would approach any unstable lesion There have been a number of studies including CVLPRIT [2], DANAMI3-PRIMULTI [3] which showed benefits of total revascularization (culprit + nonculprit artery PCI), but PRAGUE-13 study brought reverse outcomes Measuring Fractional flow reserve - FFR in non-culprit coronary lesions would provide interventional cardiologists with appropriate information of hemodynamic significance of the lesions FFR value > 0.80 has been determined to be predictive of functional significance and, in addition, is the threshold at which revascularization should be considered, while FFR value > 0.80 is safe for conservatively medical treatment In Vietnam, FFR has been validated in a variety of studies but limited to data of patients with stable ischemic heart disease [4] We undertook the study to assess the Fractional Flow Reserve in non-culprit coronary arteries of patients with 106 acute ST elevation myocardial infarction II STUDY POPULATION AND STUDY METHOD Study population The study was conducted from Nov - 2017 to Sep - 2018 with 81 consecutive acute STEMI patients who received primary PCI in Vietnam National Heart Institute (n = 31) and Cardiovascular Division - Teikyo University Tokyo - Japan (n = 50) Inclusion criteria • Patient ≥ 18 years old • Acute STEMI indicated for primary PCI within 12h (from symptoms onset) or > 12h if persistent ischemic demonstration • At least one non-culprit coronary artery lesion with diameter stenosis of 40% to < 70% on QCA [5], [6] • Coronary vessel diameter ≥ 2.0 mm Exclusion criteria • Severe heart failure, cardiac shock, Killip III/IV on admission or after culprit coronary revascularization • STEMI related to in-stent thrombosis • Unsuccessful primary PCI or complicated primary PCI (inability of stent deployment to culprit vessel, or TIMI flow post PCI, residual stenosis > 20%, coronary dissection or rupture) • Non-culprit lesions of < 40% or > 70% of diameter stenosis (on QCA) • Stenosis of left main stem > 50% • Non-culprit artery with TIMI flow II • Chronic total occlusion of non-culprit • Bypass graft lesions • Syntax score > 22 • Inappropriate anatomical features for pressure wire passage • Medical history of allergy to any of the following medication: Aspirin, Clopidogrel, JMR 118 E4 (2) - 2019 JOURNAL OF MEDICAL RESEARCH Ticagrelor, Heparin, contrast agents, or papaverine • Prolonged bradycardia, AV block, long QT syndrome • Anticoagulation disorders or recent history of bleeding (cerebral, gastrointestinal or genitourinary) within months • End-stage renal disease, severe sepsis, end-stage cancer, or other medical conditions with estimated life expectancy of less than year • Pregnancy • Refuse to enroll in the study Study method Study design: prospective observational cohort Sampling method: non-randomized, consecutive sampling All acute STEMI patients with MVD admitted to the National Heart Institute – Bach Mai Hospital and Cardiovascular Division - Teikyo University - Tokyo - Japan, for primary PCI, who are eligible for study inclusion criteria Non-culprit coronary lesions were assessed anatomically by Quantitative Coronary Angiography (QCA) and functionally by Fractional flow reserve per protocol [5] FFR measuring requires the use of a specific PressureWire (solid-state sensor mounted on a floppy-tipped 0.014- inch guidewire) (St Jude Medical Inc., Minneapolis, Minnesota and Uppsala, Sweden) Before introducing the sensor into the vessel to be studied, the pressures recorded by the sensor and by the guiding catheter should be equalized A 200 mcg bolus of intracoronary nitrate, followed by papaverine (10mg in the right coronary artery, 20 mg in the left coronary artery LCA), allows the abolition of any form of epicardial vasoconstriction and hyperemia All procedures were performed during index hospitalization Statistical Analysis: Continuous variables are presented as mean ± SD or median and inter-quartile range from the 25th to the 75th percentile; categorical data are presented as numbers and percentages, as appropriate P values smaller than 0.05 were considered as statistically significant Analyses were performed with SPSS 20.0 (IBM, Inc, New York) Ethical approval provided by Bach Mai University hospital and Teikyo University hospital III RESULTS Baseline parameters From Nov 2017 to Sep 2018 at Vietnam National Heart Institute and Cardiovascular Division - Teikyo University - Tokyo - Japan, FFR measurements were done on 81 STEMI patients, who received primary PCI, with 135 non-culprit coronary arteries of moderate stenosis (40 - 70% by QCA) Male/female ratio was 1.7/1 The major risk factors included hypertension (67.9%) and smoking (55.6%) Table Baseline parameters Parameter Male (%) Mean age (yrs) JMR 118 E4 (2) - 2019 N 51 (63%) 65.7 ± 12.4 107 JOURNAL OF MEDICAL RESEARCH Parameter N Hypertension (%) 55 (67.9%) Smoking (%) 45 (55.6%) Dislipidemia (%) 41(50.6%) Diabetes mellitus (%) 27 (33.3%) Duration of symptom onset (hrs) 9.24 ± 2.9 Left ventricular ejection fraction (%) 42.2 ± 6.7 Creatinin (μmol/l) 92.9 ± 18.7 Table Non-culprit coronary artery characteristics Parameter N Number of diseased vessel n (%) 2-vessel disease 49 (60.5%) 3-vessel disease 32 (39.5%) Syntax score (points) 17.45 ± 2.69 Lesion type n (%) Type A 11 (8.1%) Type B1 39 (28.9%) Type B2 66 (48.9%) Type C 19 (14.1%) QCA parameters of non-culprit coronary lesions Reference vessel diameter - RVD (mm) 2.88 ± 0.51 Minimal lumen diameter - MLD (mm) 1.43 ± 0.27 Percentage of diameter stenosis - PDS (%) 55.17 ± 9.85 Lesion length - LL (mm) 22.45 ± 7.62 Fractional flow reserve of non-culprit coronary arteries 2.1 FFR measurement FFR evaluation were performed via radial access with 6F guiding catheter in a large proportion of patients (96.3%) Femoral access was chosen among cases (3.7%) The time from primary PCI 108 JMR 118 E4 (2) - 2019 JOURNAL OF MEDICAL RESEARCH to FFR measurement ranged on an average of 2.65 ± 1.09 days Among 135 non-culprit lesions, the percentage of significantly functional stenosis that required revascularization was 23.8%, while the rest 76.2% of lesions not contributed to physiological impact The mean FFR value was 0.82 ± 0.09 Lesion distribution was as followed: 22.9% in proximal left descending artery (LAD), 31.3% in the mid LAD, 4.2% in distal LAD, 4.2% in proximal circumflex (LCx), 14.6% in mid LCx, 8.4% in proximal right coronary artery (RCA), 12.5% in mid RCA, and 1.9% in distal RCA; There was coronary dissection complication related to pressure wire manipulation 2.2 Correlation between FFR and QCA parameters of non-culprit coronary lesions Figure Correlation between FFR and PDS No significant correlation was found between FFR and PDS Figure Correlation between FFR and MLD JMR 118 E4 (2) - 2019 109 JOURNAL OF MEDICAL RESEARCH MLD was weakly correlated with FFR (r = 0,81, p = 0,04) In other words, the less the MLD, the lower the FFR Figure Correlation between FFR and lesion length Lesion length was moderately inversely correlated with FFR (r = - 0.38, p = 0.045) III DISCUSSION Baseline parameters: patients' mean age was 65.7 ± 12.4 (years) A larger proportion of patients were male (63%) The major risk factors include hypertension 67.9%, smoking 55.6% and diabetes mellitus 50.6% Similar findings were also reported in various studies [1-3] The percentage of - vessel disease was 60.5% The complexity of coronary disease was graded by Syntax score (based on segment involved, chronic total ccclusion, tortuosity, angulation, calcification severity, lesion length, bifurcation ) Syntax score > 22 is known to be not only an independent predictor of MACEs in ACS patients with multivessel disease, but also an indication for early referral to coronary artery bypass grafting The mean syntax score in our study was 17.45 ± 2.69 points as only patients whose Syntax score ≤ 22 were enrolled The 110 mean RVD was 2.7 ± 0.5 mm and the mean LL was 22.1 ± 7.0 mm Angiographical characteristics of nonculprit coronary lesions: The complexity of non-culprit coronary lesions was evaluated angiographically based on AHA/ACC 1988 classification, which ranges from type A, type B1, type B2, to type C (the most complex) A 100% success rate was achieved with pressurewire passage distal to stenotic nonculprit lesions, as most of them were classified of type A, B1, and B2 The pressurewire was also passed through all 19 complex lesions (type C) thank to unique handling characteristic and flexible tip that in not so much different from regular workhorse wires We reported case of left main coronary dissection complication related to pressure wire manipulation, which required immediate stent implantation and JMR 118 E4 (2) - 2019 JOURNAL OF MEDICAL RESEARCH lead to uncomplicated discharge days after the procedure In brief, our technical success rate approached 99.3% The time from primary PCI to FFR assessment was on the average of 3.14 ± 1.05 days Correlation between QCA parameters and FFR of non-culprit artery: In acute STEMI patients required emergent coronary angiography, after the culprit artery is determined with certainty (often based on the presence of thrombus, no flow or slow flow at stenotic site ), revascularization and stent implantation is immediately performed to restore blood flow to the infarcted myocardial territory The severity of non-culprit artery stenosis is then estimated based on visual assessment, which is commonly applied in clinical practice This method enables quick evaluation but subjective and individual-based decision making While QCA was chosen as the method of evaluation in our study, PDS was not shown to be correlated with FFR (r = - 0.057, p = 0.46) A number of studies stated weak correlation between the two, but Park et al [1] found a significantly inversely correlation Our findings demonstrated a non-significant difference of PDS between FFR > 0,80 group and FFR ≤ 0.80 group (p = 0.65) The weak correlation of PDS and FFR was also mentioned by Belle et al [6] Data from meta-analysis [7] suggested that QCA does not help determine the functional significance in coronary lesions Although MLD is not a parameter of choice for interventional cardiologists in their clinical practice to decide whether or not to revascularize, our study found the mean MLD in FFR ≤ 0.80 group was significantly lower than that of FFR > 0.80 group (p = 0.041) There was a mild correlation between FFR and MLD (r = 0.181, p = 0.04), which was also reported in DANAMI-3-PRIMULTI trial [3] The JMR 118 E4 (2) - 2019 smaller the MLD, the lower the FFR value In our study, lesion length in FFR ≤ 0.80 group was significantly greater than that of FFR > 0.80 group, 24.5 ± 12.5 mm and 17.5 ± 8.5 mm respectively (p = 0.016) There was a moderately reverse correlation between FFR and lesion length with r = - 0.38 (p = 0.045), which showed similar findings in CVLPRIT study [2] Ntalianis et al [5] investigated the reliability of FFR of nonculprit coronary stenoses in 101 patients undergoing PCI for an acute myocardial infarction FFR measurements were obtained immediately after PCI of the culprit stenosis and were repeated 35 ± days later The FFR value of the nonculprit stenoses did not change between the acute and followup (0.77 ± 0.13 vs 0.77 ± 0.13, respectively, p > 0.05) During the acute phase of acute coronary syndromes, the severity of nonculprit coronary artery stenoses can reliably be assessed by FFR This allows a decision about the need for additional revascularization and might contribute to a better risk stratification V CONCLUSION In patients with acute STEMI and MVD, FFR measurement after primary PCI appeared to be feasible and revealed hemodynamic significance of non-culprit artery lesions, which resulted in appropriate multi-vessel revascularization strategy in acute setting REFERENCES Park DW, Clare RM, et al (2014) Extent, Location, and Clinical Significance of Non–Infarct-Related Coronary Artery Disease Among Patients With ST-Elevation Myocardial Infarction JAMA 312(19), 2019 - 2027 Gershlick AH, Khan JN, Kelly DJ, et al (2015) Randomized trial of complete 111 JOURNAL OF MEDICAL RESEARCH versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for stemi and multivessel disease: The CvLPRIT trial J Am Coll Cardiol 65(10):,963 - 972 Høfsten DE, Kelbæk H, Helqvist S (2015) The Third DANish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction: Ischemic postconditioning or deferred stent implantation versus conventional primary angioplasty and complete revascularization versus treatment Am Heart J 169(5), 613 - 621 Đinh Huỳnh Linh, Nguyễn Ngọc Quang, Phạm Mạnh Hùng (2010) Đánh giá phân số dự trữ lưu lượng vành tổn thương hẹp vừa động mạch vành Tạp chí y học lâm sàng 59, 58 - 63 Ntalianis A, Sels JW, Davidavicius G, et al (2010) Fractional Flow Reserve for the 112 Assessment of Nonculprit Coronary Artery Stenoses in Patients With Acute Myocardial Infarction JACC Cardiovasc Interv 3(12), 1274 -1281 Van Belle E, Rioufol G, Pouillot C, Cuisset T, Teiger E, Barreau D, et al (2013) Outcome impact of coronary revascularization strategy-reclassification with fractional flow reserve (FFR) at time of diagnostic angiography: Insights from a large french multicenter FFR registry (R3F) Circulation [Internet] 128(24) 2715 Tarantini G, D’Amico G, Brener SJ, Tellaroli P, Basile M, Schiavo A, et al (2016) Survival After Varying Revascularization Strategies in Patients With ST-Segment Elevation Myocardial Infarction and Multivessel Coronary Artery Disease: A Pairwise and Network Meta-Analysis JACC Cardiovasc Interv, 9(17), 1765 – 1776 JMR 118 E4 (2) - 2019 ... Fractional Flow Reserve in non-culprit coronary arteries of patients with 106 acute ST elevation myocardial infarction II STUDY POPULATION AND STUDY METHOD Study population The study was conducted... DANish Study of Optimal Acute Treatment of Patients with ST- segment Elevation Myocardial Infarction: Ischemic postconditioning or deferred stent implantation versus conventional primary angioplasty... recent history of bleeding (cerebral, gastrointestinal or genitourinary) within months • End-stage renal disease, severe sepsis, end-stage cancer, or other medical conditions with estimated life