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Fractional flow reserve as a standard of reference for ischemia early after ST elevation myocardial infarction
CARREV-01574; No of Pages 6 Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Cardiovascular Revascularization Medicine
Fractional flow reserve as a standard of reference for ischemia early after ST elevation myocardial infarction☆ Ali Ghaemian a,⁎, Jamshid Yazdani b, Ali Asghar Farsavian a, Samad Golshani a, Maryam Nabati a, Mozhdeh Dabirian a, Rozita Jalalian a, Seyed Mohamad Abedi c, Bahareh Mirjani a a b c
Mazandaran Cardiovascular Research Center, Mazandaran University of Medical Sciences, Iran Faculty of Health, Mazandaran University of Medical Sciences, Iran Department of Nuclear Medicine, Mazandaran University of Medical Sciences, Iran
a r t i c l e
i n f o
Article history: Received 6 January 2019 Received in revised form 4 April 2019 Accepted 17 April 2019 Available online xxxx Keywords: STEMI Fractional flow reserve Single vessel disease
a b s t r a c t Background: The purpose of the present study was to assess the value of the fractional flow reserve (FFR) of the infarct-related artery (IRA) early after ST elevation myocardial infarction (STEMI) in detecting reversible ischemia. Methods: Single photon emission computed tomography (SPECT) at rest and after dipyridamole stress, and within 24 hour FFR of the IRA was performed on 69 patients 3 to 7 days after STEMI. FFR was 0.80 or less in 61 (88.4%) of them. In these patients, percutaneous coronary intervention (PCI) was performed, and a second SPECT study was repeated within 14 days. Results: SPECT showed reversible ischemia in 36 (59%) of these 61 patients, and converted to negative in 29 of them. Thus, the SPECT results of these 29 patients were defined as true positive before angioplasty and true negative after angioplasty. Considering the true-positive and true-negative SPECT results as the gold standard, the sensitivity, specificity, and positive and negative predictive values of the FFR of 0.80 or less compared to this gold standard were 96.7%, 100%, 100%, and 96.6%, respectively (ĸ = 0.97, P b 0.001). Conclusions: In the early phase after STEMI, the reliability of FFR to determine residual ischemia in the IRA is very high in those patients with true-positive SPECT before and true-negative SPECT after PCI. © 2019 Elsevier Inc. All rights reserved.
1. Introduction The current recommended treatment in patients presenting with acute ST-segment elevation myocardial infarction (STEMI) is percutaneous coronary intervention (PCI) and recanalization of the culprit lesion of the infarct-related artery (IRA) [1–3]. However, many stable STEMI patients are referred for catheterisation 2 days after their myocardial infarction (MI). Also most of them are treated with thrombolytic agents, there is a group of patients who do not undergo any reperfusion therapy. For these patients, evidence of ischemia or myocardial viability is needed to determine whether PCI is appropriate. However, the evaluation of post-infarction patients using non-invasive testing does not have high accuracy, and the detection of myocardial ischemia in partially infarcted areas is challenging. Currently, the fractional flow reserve (FFR) is the standard invasive technique used to assess the functional severity of coronary lesions [4]. Pijls et al. and Tonino et al. showed that the FFR plays a role in ☆ The authors have no conflicts of interest to declare. ⁎ Corresponding author at: Mazandaran Heart Center, Artesh BLVD, Sari, Iran. E-mail address: [email protected] (A. Ghaemian).
avoiding unnecessary angioplasty in lesions that are not hemodynamically significant [5,6]. Moreover, the Fractional Flow Reserve Versus Angioplasty for Multivessel Evaluation (FAME 2) trial showed that the PCI improves outcomes and is economically attractive compared with medical treatment alone in patients with stable coronary artery disease [7]. A cut-off value for FFR of 0.80 has been accepted as the criterion for considering the hemodynamically significant stenosis of an epicardial coronary artery. In patients who have acute MI due to microvascular dysfunction and probable myocardial stunning, the culprit vessel may produce falsenegative FFR values; acute FFR measurements in the IRA have also been considered controversial [4]. Studies have suggested that to measure the FFR accurately after an STEMI, at least 6 days are required for the recovery of the microcirculatory function [8,9]. Non-invasive measurements of myocardial perfusion can also be used to assess the viability of the myocardium after an MI using single photon emission computed tomography (SPECT), positron emission tomography (PET), or cardiovascular magnetic resonance imaging [10], but shortly after STEMI. However, the reliability of these tests is controversial. In many countries including Iran, the primary PCI for treating STEMI patients is not well organised and does not cover all areas of the country
https://doi.org/10.1016/j.carrev.2019.04.019 1553-8389/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: A. Ghaemian, J. Yazdani, A.A. Farsavian, et al., Fractional flow reserve as a standard of reference for ischemia early after ST elevation myocardial ..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.04.019
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equally. For example, primary PCI was performed in fewer than 50% of STEMI patients in southeast Asia, India, China, and Latin America between 2011 and 2012 [11]. Besides, in a large Eastern European registry between 2010 and 2015, only 62.4% of STEMI patients who were eligible for reperfusion were treated by primary PCI, and late elective PCI (N48 h from admission) was performed more often in patients who received fibrinolysis than in those with no reperfusion therapy [12]. But, the incidence of 30-day mortality was higher for patients with no reperfusion. Thus, there is a group of patients who experience STEMI but are treated with thrombolytic agents or do not undergo any reperfusion therapy. The aim of the present study was to assess the usefulness of the FFR value of 0.80 in stable patients presenting 3 to 7 days after an STEMI in whom primary PCI was not performed. SPECT imaging was also performed to evaluate the occurrence of a reversible myocardial ischemia at a dipyridamole MIBI scan, the conversion of a positive SPECT result to a negative SPECT result after PCI, and only in those patients with SPECT-conversion correlation between SPECT and a FFR. 2. Methods 2.1. Study population Between August 2015 and March 2017, a total of 542 patients with an STEMI were admitted to Mazandaran Heart Center, Sari, Iran and underwent primary PCI. During the same period, 217 patients were
admitted with a diagnosis of an STEMI 48 h after their MI symptoms. STEMI was defined as chest pain lasting for N30 min, an ST elevation N 2 mm in at least two contiguous leads, and elevated troponin T levels. Forty-four patients refused to participate in the study, and 173 were included. Of these 173, there were 104 exclusions. Finally, 69 patients remained, and an echocardiogram was performed for all of them. Forty-two out of 69 patients were treated with thrombolytic agents before catheterization. In previous two relatively similar studies on STEMI patients 57 and 48 patients were included in the study, respectively [8,9]. The exclusion criteria of our study were as follows: remaining residual chest pain; previous coronary artery bypass graft surgery or PCI; significant left main, or two- or three-vessel disease; a totally occluded culprit vessel; and cardiogenic shock or decompensated heart failure (Fig. 1). In 27 of the 69 patients, two angiographies were performed. The first one was diagnostic to establish one-vessel disease. Then, SPECT, FFR, and PCI were performed within 24 h. However, in 42 patients, SPECT was performed before angiography and ad hoc FFR and PCI were performed if there was one-vessel disease. In all the 69 patients, the operator was unaware of the SPECT results and PCI was performed based on FFR of 0.80 or less. In all patients who had FFR measured and underwent PCI, SPECT was repeated within 14 days after PCI. This study was approved by the Review Board of Mazandaran University of Medical sciences and all patients gave written informed consent.
Fig. 1. Flow chart of the study.
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2.2. Myocardial SPECT SPECT scans, taken on two separate days, were based on a 2-day protocol: after dipyridamole stress (0.56 mg dipyridamole/kg over 4 min) and at rest with gating. Following an intravenous injection of 740 to 900 MBq of technetium (99mTc) sestamibi, imaging was performed. For acquiring tracer uptake data, 64 projections were acquired over a 180 arch from the 45-degree right anterior oblique to the 45-degree left posterior position using a variable angle dual-head gamma camera (Siemens, eCam, Signature). Data were reconstructed with filtered back projection (Butterworth filter order 10, frequency cut-off 0.4, using commercially available Siemens workstation). Imaging of the uptake of the tracer after stress and at rest was scored on a 5-point scale (0 = normal, 1 = 50%–69%, 2 = 30%–49%, 3 = 10%–29%, and 4 = absent) based on the European Society of Nuclear Medicine guidelines [13]. When the stress images showed larger or more severe defects than the resting images, the SPECT was considered to be positive for a reversible flow maldistribution. SPECT results that converted from positive before angioplasty to negative after angioplasty were considered to be truly positive. 2.3. Catheterisation and coronary angiography Coronary angiography was performed using the radial or femoral arterial approach by introducing a 6F catheter. After intracoronary administration of 200 μg of isosorbidedinitrate, coronary angiography was performed in multiple projections. Quantitative coronary angiography analysis was performed using Siemens Healthcare Axiom Artis VB35D110803 (Siemens Medical Solutions, Siemens AG, Forchheim, Germany). All patients received at least 300 mg of aspirin and 600 mg of clopidogrel, and were anticoagulated with 70 to 100 U/kg of heparin. Following the coronary angiography, a 0.014-in Certus pressure wire (St. Jude Medical Uppsala, Sweden) was advanced to the tip of the guiding catheter without side holes, and the central aortic (Pa) pressure and the wire pressure were equalised. The pressure wire was then advanced to the distal part of the lesion of the IRA and placed in the distal part of the vessel. The baseline distal coronary pressure (Pd) was recorded. Coronary vasodilatation was induced through the intracoronary administration of 60 to 300 μg of adenosine in 55 patients or through the intravenous administration of 140 μg/kg/min in 14 patients. The phasic and mean aortic and distal coronary pressures were monitored, and the FFR was measured as the ratio of Pd to Pa at the time of peak hyperemia. In 61 (88.4%) patients, the FFR was 0.80 or less, and PCI was performed; at least one stent was placed. After PCI, the hyperemic pressure calculation was repeated. To confirm that no drift had occurred, the wire was pulled back into the guiding catheter. 2.4. Statistical analysis The variables are reported as mean ± standard deviation (SD). The concordance between categorised FFR and the SPECT results was analysed by kappa statistics, and specificity and sensitivity were calculated. FFR values and left ventricular ejection fraction (LVEF) before and after angioplasty were compared by paired sample t-test. The comparison between LVEF of SPECT positive and negative patients was performed by independent sample t-test. Graph drawings were done by Minitab 17, and a P value b 0.05 was considered significant. 3. Results Of the 69 patients enrolled in the study, 61 patients had a FFR of 0.80 or less; PCI was performed for these patients within 5.2 ± 1.5 days (3– 7 days) after the MI. For these 61 patients, the first SPECT was performed within 24 h before the PCI, whereas the second SPECT was performed within 14 days after the PCI. Table 1 shows the clinical and angiographic data of the patients and Table 2 shows the procedural
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Table 1 Clinical characteristics of the patients (n = 61). Age (year) Sex, M/F Risk factors, n (%) Smoking habits Diabetes mellitus Systemic arterial hypertension Hypercholesterolemia Infarct-related artery, n (%) LAD LCX RCA Diagonal Global LVEF, %
55 ± 10 45/16 29 (47.5) 13 (21.3) 13 (21.3) 11 (18) 38 (62.3) 7 (11.5) 14 (23) 2 (3.3) 41.5 ± 9
LAD, indicates left anterior descending coronary artery; LCX, left circumflex. Artery; RCA, right coronary artery and, LVEF, left ventricular ejection fraction.
characteristics and outcomes. Patients were followed on a regular basis for 213 ± 67 days after the PCI, and an echocardiogram was performed on 51 patients during the follow-up period. In the remaining 8 patients considering FFR N 0.80, PCI was not performed and they were not included in the study.
3.1. Correlation between FFR and SPECT In all 69 patients, SPECT, coronary angiography, and the FFR were obtained. Whereas the FFR 0.80 or less (0.61 ± 0.01) in 61 (88.4%) patients, the SPECT was positive in only 37 (53.6%) patients. In the 61 patients with the FFR of 0.80 or less, the SPECT was positive in 36 (59%) patients and negative in 25 (41%) patients before angioplasty. However, the SPECT became negative in 52 (85.2%) patients after angioplasty (Fig. 2). After angioplasty, the FFR increased from 0.61 ± 0.01 to 0.88 ± 0.07 (P b 0.001). In seven (11.5%) patients, the SPECT was positive before the PCI and remained positive after the PCI. The FFR in these patients increased from 0.63 ± 0.02 to 0.94 ± 0.05 (P b 0.01). In two patients, the SPECT was negative before the PCI and converted to positive after the PCI. The FFR increased from 0.61 to 0.68 in one patient and from 0.62 to 0.81 in the other. In 23 (37.7%) patients, the SPECT was negative both before and after the PCI. In these patients, the FFR increased from 0.65 ± 0.01 to 0.93 ± 0.05 (P b 0.001). In 29 (47.5%) patients, the SPECT was positive before the PCI, although it became negative after the PCI. The FFR increased from 0.58 ± 0.01 to 0.94 ± 0.06 (P b 0.001). Considering the conversion from positive to negative after the PCI, the results of these patients can be classified a posteriori as being true positive and true negative. As shown in Fig. 3, the sensitivity, specificity, and positive and negative predictive values of the FFR of 0.80 or less were 56.3%, 84.5%, 80%, and 63.5%, respectively, for all 61 patients before and after angioplasty. The concordance between the FFR and the results of the SPECT was 69.7% (ĸ = 0.4, P b 0.001; Fig. 3). When only the 29 patients with the true-positive SPECT before PCI and true-negative SPECT after PCI were compared with the FFR value of 0.80, the sensitivity, specificity, and positive and negative predictive values were 96.7%, 100%, 100%, and 96.6%, respectively. The Table 2 Procedural characteristics and outcomes (n = 61). Procedural characteristics, mean ± SD Diameter stenosis (%) at base line (mm) Stent diameter (mm) Stent length (mm) Clinical outcomes at follow-up, n (%) Death Myocardial infarction Target vessel revascularisation
92.6 ± 5.8 3 ± 0.4 25 ± 7.6
0 (0) 0 (0) 2 (3)
Please cite this article as: A. Ghaemian, J. Yazdani, A.A. Farsavian, et al., Fractional flow reserve as a standard of reference for ischemia early after ST elevation myocardial ..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.04.019
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Fig. 2. Values of FFR before and after angioplasty and the results of scintigraphy in patient population as a whole (top) and in patient with true positive SPECT results (bottom).
concordance for the corresponding values was 98.2%, as shown in Fig. 3 (ĸ = 0.97, P b 0.001). 3.2. Relation between FFR and ejection fraction The ejection fraction (EF) of patients with a positive SPECT before the PCI was 0.45 ± 0.08, whereas the EF for patients with a negative SPECT was 0.36 ± 0.07 (P b 0.001). Before PCI, the FFR of the patients with a positive SPECT was 0.59 ± 0.14, whereas the FFR for those with a negative SPECT was 0.64 ± 0.13 (P = 0.18). Before the PCI, FFR had a non-significant reverse correlation with the EF. The LVEF of the patients, which was 0.42 ± 0.1 before the PCI, increased to 0.47 ± 0.13 during follow-up (P = 0.001). The increase in the EF was significant in both the SPECT-positive patients (0.46 ± 0.08 to 0.51 ± 0.12; P = 0.01) and the SPECT-negative patients (0.35 ± 0.07 to 0.40 ± 0.13; P = 0.026), as shown in Fig. 4. 4. Discussion The present study demonstrates that in the sub-acute phase, which is 3 to 7 days after an STEMI, the FFR is 0.80 or less in most clinically and hemodynamically stable patients (88.4%) with a patent IRA. An FFR of 0.80 or less has limited sensitivity, high specificity, and nearly
70% diagnostic accuracy for detecting reversibility on SPECT imaging in general. However, in those patients in whom SPECT was positive before PCI and switched to negative after the intervention, the corresponding values increased to 96.7%, 100%, and 98.2%, respectively. Another interesting observation was that in nearly 38% of patients SPECT was negative both pre and post PCI suggesting scar/non-viable myocardium, however FFR went from positive to negative in those patients. Our data also show that irrespective of the SPECT results, the revascularisation of patients with a FFR of 0.80 or less will improve them clinically and increase the LVEF. In this study, we included only single-vessel disease STEMI patients to prevent any confounding effect of the disease of other vessels on the SPECT images. Hence, some patients had two invasive procedures. First, they received diagnostic coronary angiography; and after confirming one-vessel disease, SPECT and within 24 hour FFR were performed. In all patients, first SPECT, FFR, and PCI were performed within 3 to 7 days after STEMI, and FFR was performed within 24 h after first SPECT. In addition, in all patients a second SPECT was performed within 14 days after the first one. It is well known that SPECT in itself has a limited accuracy for detecting ischemia shortly after STEMI, and the practice of SPECT prior to revascularisation is not a standard clinical practice in STEMI patients when the infarct related coronary artery is not occluded. But if such test is positive before an intervention and
Fig. 3. Concordance between FFR and SPECT in patient population as a whole (left) and patients in whom SPECT was truly positive and truly negative (right).
Please cite this article as: A. Ghaemian, J. Yazdani, A.A. Farsavian, et al., Fractional flow reserve as a standard of reference for ischemia early after ST elevation myocardial ..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.04.019
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Fig. 4. Values of LVEF before and after PCI in all patients and in patients with SPECT positive and negative after PCI during follow up.
converts to negative afterward, this conversion indicates that the positive test was true positive before PCI and that the negative test was true negative thereafter. In other words, only in such patients a gold standard is available. Further, the accuracy of FFR compared with that gold standard was almost 100%. Thus, the FFR can be used to distinguish patients with and without reversibility in partially infarcted myocardium early after MI. However, non occluded infarct related arteries in STEMI do not require physiologic assessment and patients even with FFR N 0.80 may have clinical improvement with revascularisation. Particularly, patients presenting between 12 and 48 h after the onset of symptoms, even if pain free and with stable hemodynamics may still benefit from early PCI. The physiological significance of an epicardial coronary artery obstruction is better assessed using a pressure wire-based FFR than using coronary angiography alone [6,14]. Coronary microcirculation changes after an STEMI have been shown using PET [15], Doppler echocardiography [16], and invasive pressure wires [17]. Because of microvascular dysfunction, an inability to induce maximal hyperemia, and the probability of underestimating a given stenosis, the FFR accuracy in the early post-MI period has been debated. Studies have shown that after an STEMI, patients with anatomically equivalent stenoses have higher FFR values than those with stable angina [18]. However, it is pointed out that the recovery of the microcirculatory function takes 4 to 6 days before the FFR can be measured in the IRA [8,9]. Hoole et al. showed that a subgroup of patients with an STEMI have preserved microcirculatory function even during the acute phase [19]. The researchers also showed that in 37 of 41 patients (90%), the FFR was 0.80 or less during the primary PCI in the IRA [19]. Although we performed the FFR 3 to 7 days after the STEMI, 88.4% of our patients had a FFR of 0.80 or less. Thus, it seems that even in the acute and sub-acute phases after an STEMI, the majority of patients have a FFR of 0.80 or less in the IRA. Tamita et al. reported that during the first 12 h after an acute MI in patients with TIMI 3 flow, a low FFR may indicate a significant residual stenosis in the IRA, which may be helpful for assessing the results of a coronary intervention in acute MI cases [18]. However, determining the physiological significance of a lesion detected by coronary angiography is important in stable patients who do not undergo a primary PCI and are admitted after 48 h of their MI. During this period, the accuracy of noninvasive testing, such as SPECT, is relatively limited. Samady et al. reported that in patients early after the MI, the FFR had a better correlation with dipyridamole myocardial contrast echocardiography than with the baseline SPECT [9]. The reason may be related to an underestimation of the reversibility by SPECT early after
the MI [9,20–22]. The limited spatial resolution of the SPECT scan (about 15 mm) may explain this underestimation [23]. Also in our study a portion of the participants have had negative SPECT pre and post PCI, with FFR that was positive at baseline and became negative after PCI. This is a good demonstration that the SPECT was false negative in this group of patients. In addition, these patients clinically improved with revascularisation with an increase in their EF. Thus, in sub-acute STEMI phase, perhaps SPECT by itself cannot be used as a gold standard. The chance for false-positive and false-negative SPECT results is considerable. But, if a patient has a positive SPECT, a low FFR, and has PCI thereafter, in which following the SPECT reverts from positive to negative, it is justified a posteriori to state that the first SPECT was true positive and the second was true negative. Based on the Bayesian consideration, by focusing on positive SPECT results before the PCI that converted to negative after the PCI, highly probable true-positive and true-negative SPECT results could be provided [24–26]; and, it can be considered as a gold standard, and then FFR can be compared to this gold standard. In our study the sensitivity and specificity of the FFR of 0.80 or less for detecting reversibility using SPECT increased from 56.3% to 96.7% and from 84.5% to 100%, respectively, when only true-positive and true-negative SPECT results were considered. Thus, the primary message of our study is that in those patients in whom such gold standard is available, the sensitivity and specificity of FFR to this gold standard is very high, close to 100%. Thus, although the myocardial flow reserve is reduced and improves over time [15,27], and the limited flow reserve affects the vasodilator-dependent physiological assessment of the coronary obstruction early after an MI, FFR might be as good and can be used from 3 days after STEMI on to indicate residual ischemia related to the IRA. De Bruyne et al. showed that 6 or more days after an MI, the FFR of the IRA had an inverse relationship with the LVEF; the LVEF of SPECTpositive patients was significantly higher than that of SPECT-negative patients before the PCI [8]. In the present study, although the LVEF had an inverse relationship with the FFR, it was not significant. After an MI, because of the loss of myocardial mass, the FFR will be larger for a given degree of diameter stenosis and does not underestimate the stenosis severity. However, we measured the FFR 3 to 7 days after the MI, but the recovery of microvascular function can take as long as 6 weeks to occur [28]. Thus, the FFR correlation to myocardial mass would take more time to be evident accurately. After the PCI, the LVEF of both the SPECT-positive and SPECT-negative patients increased compared with the pre-PCI values. This finding supports the use of the FFR in the sub-acute STEMI phase for determining the necessity of revascularisation of the IRA.
Please cite this article as: A. Ghaemian, J. Yazdani, A.A. Farsavian, et al., Fractional flow reserve as a standard of reference for ischemia early after ST elevation myocardial ..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.04.019
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4.1. Limitations There were some limitations in this study. Not all patients underwent follow-up echocardiography; only 51 patients received follow-up echocardiograms. However, the baseline characteristics of the 51 patients did not differ from the study population. Another limitation was that the second SPECT was performed within 14 days after PCI, although the conversion of a positive SPECT to a negative takes up to 3 months to occur in the partially infarcted myocardium. Because we wanted to prevent the effect of any probable restenosis on the results of the study, the timeline was accelerated. Finally, the number of patients in this study is small. But, considering the fact that we included only single-vessel disease patients with meticulous sequential testing in a limited timeline for selecting them, it took approximately 20 months to recruit 69 patients in our tertiary referral heart hospital. 5. Conclusions The FFR of the IRA is useful for determining residual ischemia and making decisions about revascularisation in stable patients 3 to 7 days after an MI and its reliability in patients with true-positive SPECT before and true-negative SPECT after PCI is very high. Acknowledgments The text has been reviewed by a native reviewer from the Elsevier Language Editing Services, and we have the Certificate. We thank Mojtaba Shokri for his full time cooperation for performing the study and preparing the manuscript. Funding sources Sixty pressure wires were provided by the Eastern Europe and Middle East branch of the St. Jude Medical Coordination Center. The study was supported financially by the Vice Chancellor for Research Technology, Mazandaran University of Medical Sciences. Disclosures None. References [1] Cardiology TFotMoS-SEAMIotESo. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with STsegment elevation. Eur Heart J 2012;33:2569–619. [2] O'Gara PT, Kushner FG, Ascheim DD, et al. ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013 2013;61:485–510. [3] Windecker S, Kolh P, Alfonso F, et al. Authors/Task Force members. 2014 ESC/EACTS Guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014; 35:2541–619. [4] Pijls NH, J-WE Sels. Functional measurement of coronary stenosis. J Am Coll Cardiol 2012;59:1045–57.
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Please cite this article as: A. Ghaemian, J. Yazdani, A.A. Farsavian, et al., Fractional flow reserve as a standard of reference for ischemia early after ST elevation myocardial ..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.04.019
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Cardiovascular Revascularization Medicine
Fractional flow reserve as a standard of reference for ischemia early after ST elevation myocardial infarction☆ Ali Ghaemian a,⁎, Jamshid Yazdani b, Ali Asghar Farsavian a, Samad Golshani a, Maryam Nabati a, Mozhdeh Dabirian a, Rozita Jalalian a, Seyed Mohamad Abedi c, Bahareh Mirjani a a b c
Mazandaran Cardiovascular Research Center, Mazandaran University of Medical Sciences, Iran Faculty of Health, Mazandaran University of Medical Sciences, Iran Department of Nuclear Medicine, Mazandaran University of Medical Sciences, Iran
a r t i c l e
i n f o
Article history: Received 6 January 2019 Received in revised form 4 April 2019 Accepted 17 April 2019 Available online xxxx Keywords: STEMI Fractional flow reserve Single vessel disease
a b s t r a c t Background: The purpose of the present study was to assess the value of the fractional flow reserve (FFR) of the infarct-related artery (IRA) early after ST elevation myocardial infarction (STEMI) in detecting reversible ischemia. Methods: Single photon emission computed tomography (SPECT) at rest and after dipyridamole stress, and within 24 hour FFR of the IRA was performed on 69 patients 3 to 7 days after STEMI. FFR was 0.80 or less in 61 (88.4%) of them. In these patients, percutaneous coronary intervention (PCI) was performed, and a second SPECT study was repeated within 14 days. Results: SPECT showed reversible ischemia in 36 (59%) of these 61 patients, and converted to negative in 29 of them. Thus, the SPECT results of these 29 patients were defined as true positive before angioplasty and true negative after angioplasty. Considering the true-positive and true-negative SPECT results as the gold standard, the sensitivity, specificity, and positive and negative predictive values of the FFR of 0.80 or less compared to this gold standard were 96.7%, 100%, 100%, and 96.6%, respectively (ĸ = 0.97, P b 0.001). Conclusions: In the early phase after STEMI, the reliability of FFR to determine residual ischemia in the IRA is very high in those patients with true-positive SPECT before and true-negative SPECT after PCI. © 2019 Elsevier Inc. All rights reserved.
1. Introduction The current recommended treatment in patients presenting with acute ST-segment elevation myocardial infarction (STEMI) is percutaneous coronary intervention (PCI) and recanalization of the culprit lesion of the infarct-related artery (IRA) [1–3]. However, many stable STEMI patients are referred for catheterisation 2 days after their myocardial infarction (MI). Also most of them are treated with thrombolytic agents, there is a group of patients who do not undergo any reperfusion therapy. For these patients, evidence of ischemia or myocardial viability is needed to determine whether PCI is appropriate. However, the evaluation of post-infarction patients using non-invasive testing does not have high accuracy, and the detection of myocardial ischemia in partially infarcted areas is challenging. Currently, the fractional flow reserve (FFR) is the standard invasive technique used to assess the functional severity of coronary lesions [4]. Pijls et al. and Tonino et al. showed that the FFR plays a role in ☆ The authors have no conflicts of interest to declare. ⁎ Corresponding author at: Mazandaran Heart Center, Artesh BLVD, Sari, Iran. E-mail address: [email protected] (A. Ghaemian).
avoiding unnecessary angioplasty in lesions that are not hemodynamically significant [5,6]. Moreover, the Fractional Flow Reserve Versus Angioplasty for Multivessel Evaluation (FAME 2) trial showed that the PCI improves outcomes and is economically attractive compared with medical treatment alone in patients with stable coronary artery disease [7]. A cut-off value for FFR of 0.80 has been accepted as the criterion for considering the hemodynamically significant stenosis of an epicardial coronary artery. In patients who have acute MI due to microvascular dysfunction and probable myocardial stunning, the culprit vessel may produce falsenegative FFR values; acute FFR measurements in the IRA have also been considered controversial [4]. Studies have suggested that to measure the FFR accurately after an STEMI, at least 6 days are required for the recovery of the microcirculatory function [8,9]. Non-invasive measurements of myocardial perfusion can also be used to assess the viability of the myocardium after an MI using single photon emission computed tomography (SPECT), positron emission tomography (PET), or cardiovascular magnetic resonance imaging [10], but shortly after STEMI. However, the reliability of these tests is controversial. In many countries including Iran, the primary PCI for treating STEMI patients is not well organised and does not cover all areas of the country
https://doi.org/10.1016/j.carrev.2019.04.019 1553-8389/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: A. Ghaemian, J. Yazdani, A.A. Farsavian, et al., Fractional flow reserve as a standard of reference for ischemia early after ST elevation myocardial ..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.04.019
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equally. For example, primary PCI was performed in fewer than 50% of STEMI patients in southeast Asia, India, China, and Latin America between 2011 and 2012 [11]. Besides, in a large Eastern European registry between 2010 and 2015, only 62.4% of STEMI patients who were eligible for reperfusion were treated by primary PCI, and late elective PCI (N48 h from admission) was performed more often in patients who received fibrinolysis than in those with no reperfusion therapy [12]. But, the incidence of 30-day mortality was higher for patients with no reperfusion. Thus, there is a group of patients who experience STEMI but are treated with thrombolytic agents or do not undergo any reperfusion therapy. The aim of the present study was to assess the usefulness of the FFR value of 0.80 in stable patients presenting 3 to 7 days after an STEMI in whom primary PCI was not performed. SPECT imaging was also performed to evaluate the occurrence of a reversible myocardial ischemia at a dipyridamole MIBI scan, the conversion of a positive SPECT result to a negative SPECT result after PCI, and only in those patients with SPECT-conversion correlation between SPECT and a FFR. 2. Methods 2.1. Study population Between August 2015 and March 2017, a total of 542 patients with an STEMI were admitted to Mazandaran Heart Center, Sari, Iran and underwent primary PCI. During the same period, 217 patients were
admitted with a diagnosis of an STEMI 48 h after their MI symptoms. STEMI was defined as chest pain lasting for N30 min, an ST elevation N 2 mm in at least two contiguous leads, and elevated troponin T levels. Forty-four patients refused to participate in the study, and 173 were included. Of these 173, there were 104 exclusions. Finally, 69 patients remained, and an echocardiogram was performed for all of them. Forty-two out of 69 patients were treated with thrombolytic agents before catheterization. In previous two relatively similar studies on STEMI patients 57 and 48 patients were included in the study, respectively [8,9]. The exclusion criteria of our study were as follows: remaining residual chest pain; previous coronary artery bypass graft surgery or PCI; significant left main, or two- or three-vessel disease; a totally occluded culprit vessel; and cardiogenic shock or decompensated heart failure (Fig. 1). In 27 of the 69 patients, two angiographies were performed. The first one was diagnostic to establish one-vessel disease. Then, SPECT, FFR, and PCI were performed within 24 h. However, in 42 patients, SPECT was performed before angiography and ad hoc FFR and PCI were performed if there was one-vessel disease. In all the 69 patients, the operator was unaware of the SPECT results and PCI was performed based on FFR of 0.80 or less. In all patients who had FFR measured and underwent PCI, SPECT was repeated within 14 days after PCI. This study was approved by the Review Board of Mazandaran University of Medical sciences and all patients gave written informed consent.
Fig. 1. Flow chart of the study.
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2.2. Myocardial SPECT SPECT scans, taken on two separate days, were based on a 2-day protocol: after dipyridamole stress (0.56 mg dipyridamole/kg over 4 min) and at rest with gating. Following an intravenous injection of 740 to 900 MBq of technetium (99mTc) sestamibi, imaging was performed. For acquiring tracer uptake data, 64 projections were acquired over a 180 arch from the 45-degree right anterior oblique to the 45-degree left posterior position using a variable angle dual-head gamma camera (Siemens, eCam, Signature). Data were reconstructed with filtered back projection (Butterworth filter order 10, frequency cut-off 0.4, using commercially available Siemens workstation). Imaging of the uptake of the tracer after stress and at rest was scored on a 5-point scale (0 = normal, 1 = 50%–69%, 2 = 30%–49%, 3 = 10%–29%, and 4 = absent) based on the European Society of Nuclear Medicine guidelines [13]. When the stress images showed larger or more severe defects than the resting images, the SPECT was considered to be positive for a reversible flow maldistribution. SPECT results that converted from positive before angioplasty to negative after angioplasty were considered to be truly positive. 2.3. Catheterisation and coronary angiography Coronary angiography was performed using the radial or femoral arterial approach by introducing a 6F catheter. After intracoronary administration of 200 μg of isosorbidedinitrate, coronary angiography was performed in multiple projections. Quantitative coronary angiography analysis was performed using Siemens Healthcare Axiom Artis VB35D110803 (Siemens Medical Solutions, Siemens AG, Forchheim, Germany). All patients received at least 300 mg of aspirin and 600 mg of clopidogrel, and were anticoagulated with 70 to 100 U/kg of heparin. Following the coronary angiography, a 0.014-in Certus pressure wire (St. Jude Medical Uppsala, Sweden) was advanced to the tip of the guiding catheter without side holes, and the central aortic (Pa) pressure and the wire pressure were equalised. The pressure wire was then advanced to the distal part of the lesion of the IRA and placed in the distal part of the vessel. The baseline distal coronary pressure (Pd) was recorded. Coronary vasodilatation was induced through the intracoronary administration of 60 to 300 μg of adenosine in 55 patients or through the intravenous administration of 140 μg/kg/min in 14 patients. The phasic and mean aortic and distal coronary pressures were monitored, and the FFR was measured as the ratio of Pd to Pa at the time of peak hyperemia. In 61 (88.4%) patients, the FFR was 0.80 or less, and PCI was performed; at least one stent was placed. After PCI, the hyperemic pressure calculation was repeated. To confirm that no drift had occurred, the wire was pulled back into the guiding catheter. 2.4. Statistical analysis The variables are reported as mean ± standard deviation (SD). The concordance between categorised FFR and the SPECT results was analysed by kappa statistics, and specificity and sensitivity were calculated. FFR values and left ventricular ejection fraction (LVEF) before and after angioplasty were compared by paired sample t-test. The comparison between LVEF of SPECT positive and negative patients was performed by independent sample t-test. Graph drawings were done by Minitab 17, and a P value b 0.05 was considered significant. 3. Results Of the 69 patients enrolled in the study, 61 patients had a FFR of 0.80 or less; PCI was performed for these patients within 5.2 ± 1.5 days (3– 7 days) after the MI. For these 61 patients, the first SPECT was performed within 24 h before the PCI, whereas the second SPECT was performed within 14 days after the PCI. Table 1 shows the clinical and angiographic data of the patients and Table 2 shows the procedural
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Table 1 Clinical characteristics of the patients (n = 61). Age (year) Sex, M/F Risk factors, n (%) Smoking habits Diabetes mellitus Systemic arterial hypertension Hypercholesterolemia Infarct-related artery, n (%) LAD LCX RCA Diagonal Global LVEF, %
55 ± 10 45/16 29 (47.5) 13 (21.3) 13 (21.3) 11 (18) 38 (62.3) 7 (11.5) 14 (23) 2 (3.3) 41.5 ± 9
LAD, indicates left anterior descending coronary artery; LCX, left circumflex. Artery; RCA, right coronary artery and, LVEF, left ventricular ejection fraction.
characteristics and outcomes. Patients were followed on a regular basis for 213 ± 67 days after the PCI, and an echocardiogram was performed on 51 patients during the follow-up period. In the remaining 8 patients considering FFR N 0.80, PCI was not performed and they were not included in the study.
3.1. Correlation between FFR and SPECT In all 69 patients, SPECT, coronary angiography, and the FFR were obtained. Whereas the FFR 0.80 or less (0.61 ± 0.01) in 61 (88.4%) patients, the SPECT was positive in only 37 (53.6%) patients. In the 61 patients with the FFR of 0.80 or less, the SPECT was positive in 36 (59%) patients and negative in 25 (41%) patients before angioplasty. However, the SPECT became negative in 52 (85.2%) patients after angioplasty (Fig. 2). After angioplasty, the FFR increased from 0.61 ± 0.01 to 0.88 ± 0.07 (P b 0.001). In seven (11.5%) patients, the SPECT was positive before the PCI and remained positive after the PCI. The FFR in these patients increased from 0.63 ± 0.02 to 0.94 ± 0.05 (P b 0.01). In two patients, the SPECT was negative before the PCI and converted to positive after the PCI. The FFR increased from 0.61 to 0.68 in one patient and from 0.62 to 0.81 in the other. In 23 (37.7%) patients, the SPECT was negative both before and after the PCI. In these patients, the FFR increased from 0.65 ± 0.01 to 0.93 ± 0.05 (P b 0.001). In 29 (47.5%) patients, the SPECT was positive before the PCI, although it became negative after the PCI. The FFR increased from 0.58 ± 0.01 to 0.94 ± 0.06 (P b 0.001). Considering the conversion from positive to negative after the PCI, the results of these patients can be classified a posteriori as being true positive and true negative. As shown in Fig. 3, the sensitivity, specificity, and positive and negative predictive values of the FFR of 0.80 or less were 56.3%, 84.5%, 80%, and 63.5%, respectively, for all 61 patients before and after angioplasty. The concordance between the FFR and the results of the SPECT was 69.7% (ĸ = 0.4, P b 0.001; Fig. 3). When only the 29 patients with the true-positive SPECT before PCI and true-negative SPECT after PCI were compared with the FFR value of 0.80, the sensitivity, specificity, and positive and negative predictive values were 96.7%, 100%, 100%, and 96.6%, respectively. The Table 2 Procedural characteristics and outcomes (n = 61). Procedural characteristics, mean ± SD Diameter stenosis (%) at base line (mm) Stent diameter (mm) Stent length (mm) Clinical outcomes at follow-up, n (%) Death Myocardial infarction Target vessel revascularisation
92.6 ± 5.8 3 ± 0.4 25 ± 7.6
0 (0) 0 (0) 2 (3)
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Fig. 2. Values of FFR before and after angioplasty and the results of scintigraphy in patient population as a whole (top) and in patient with true positive SPECT results (bottom).
concordance for the corresponding values was 98.2%, as shown in Fig. 3 (ĸ = 0.97, P b 0.001). 3.2. Relation between FFR and ejection fraction The ejection fraction (EF) of patients with a positive SPECT before the PCI was 0.45 ± 0.08, whereas the EF for patients with a negative SPECT was 0.36 ± 0.07 (P b 0.001). Before PCI, the FFR of the patients with a positive SPECT was 0.59 ± 0.14, whereas the FFR for those with a negative SPECT was 0.64 ± 0.13 (P = 0.18). Before the PCI, FFR had a non-significant reverse correlation with the EF. The LVEF of the patients, which was 0.42 ± 0.1 before the PCI, increased to 0.47 ± 0.13 during follow-up (P = 0.001). The increase in the EF was significant in both the SPECT-positive patients (0.46 ± 0.08 to 0.51 ± 0.12; P = 0.01) and the SPECT-negative patients (0.35 ± 0.07 to 0.40 ± 0.13; P = 0.026), as shown in Fig. 4. 4. Discussion The present study demonstrates that in the sub-acute phase, which is 3 to 7 days after an STEMI, the FFR is 0.80 or less in most clinically and hemodynamically stable patients (88.4%) with a patent IRA. An FFR of 0.80 or less has limited sensitivity, high specificity, and nearly
70% diagnostic accuracy for detecting reversibility on SPECT imaging in general. However, in those patients in whom SPECT was positive before PCI and switched to negative after the intervention, the corresponding values increased to 96.7%, 100%, and 98.2%, respectively. Another interesting observation was that in nearly 38% of patients SPECT was negative both pre and post PCI suggesting scar/non-viable myocardium, however FFR went from positive to negative in those patients. Our data also show that irrespective of the SPECT results, the revascularisation of patients with a FFR of 0.80 or less will improve them clinically and increase the LVEF. In this study, we included only single-vessel disease STEMI patients to prevent any confounding effect of the disease of other vessels on the SPECT images. Hence, some patients had two invasive procedures. First, they received diagnostic coronary angiography; and after confirming one-vessel disease, SPECT and within 24 hour FFR were performed. In all patients, first SPECT, FFR, and PCI were performed within 3 to 7 days after STEMI, and FFR was performed within 24 h after first SPECT. In addition, in all patients a second SPECT was performed within 14 days after the first one. It is well known that SPECT in itself has a limited accuracy for detecting ischemia shortly after STEMI, and the practice of SPECT prior to revascularisation is not a standard clinical practice in STEMI patients when the infarct related coronary artery is not occluded. But if such test is positive before an intervention and
Fig. 3. Concordance between FFR and SPECT in patient population as a whole (left) and patients in whom SPECT was truly positive and truly negative (right).
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Fig. 4. Values of LVEF before and after PCI in all patients and in patients with SPECT positive and negative after PCI during follow up.
converts to negative afterward, this conversion indicates that the positive test was true positive before PCI and that the negative test was true negative thereafter. In other words, only in such patients a gold standard is available. Further, the accuracy of FFR compared with that gold standard was almost 100%. Thus, the FFR can be used to distinguish patients with and without reversibility in partially infarcted myocardium early after MI. However, non occluded infarct related arteries in STEMI do not require physiologic assessment and patients even with FFR N 0.80 may have clinical improvement with revascularisation. Particularly, patients presenting between 12 and 48 h after the onset of symptoms, even if pain free and with stable hemodynamics may still benefit from early PCI. The physiological significance of an epicardial coronary artery obstruction is better assessed using a pressure wire-based FFR than using coronary angiography alone [6,14]. Coronary microcirculation changes after an STEMI have been shown using PET [15], Doppler echocardiography [16], and invasive pressure wires [17]. Because of microvascular dysfunction, an inability to induce maximal hyperemia, and the probability of underestimating a given stenosis, the FFR accuracy in the early post-MI period has been debated. Studies have shown that after an STEMI, patients with anatomically equivalent stenoses have higher FFR values than those with stable angina [18]. However, it is pointed out that the recovery of the microcirculatory function takes 4 to 6 days before the FFR can be measured in the IRA [8,9]. Hoole et al. showed that a subgroup of patients with an STEMI have preserved microcirculatory function even during the acute phase [19]. The researchers also showed that in 37 of 41 patients (90%), the FFR was 0.80 or less during the primary PCI in the IRA [19]. Although we performed the FFR 3 to 7 days after the STEMI, 88.4% of our patients had a FFR of 0.80 or less. Thus, it seems that even in the acute and sub-acute phases after an STEMI, the majority of patients have a FFR of 0.80 or less in the IRA. Tamita et al. reported that during the first 12 h after an acute MI in patients with TIMI 3 flow, a low FFR may indicate a significant residual stenosis in the IRA, which may be helpful for assessing the results of a coronary intervention in acute MI cases [18]. However, determining the physiological significance of a lesion detected by coronary angiography is important in stable patients who do not undergo a primary PCI and are admitted after 48 h of their MI. During this period, the accuracy of noninvasive testing, such as SPECT, is relatively limited. Samady et al. reported that in patients early after the MI, the FFR had a better correlation with dipyridamole myocardial contrast echocardiography than with the baseline SPECT [9]. The reason may be related to an underestimation of the reversibility by SPECT early after
the MI [9,20–22]. The limited spatial resolution of the SPECT scan (about 15 mm) may explain this underestimation [23]. Also in our study a portion of the participants have had negative SPECT pre and post PCI, with FFR that was positive at baseline and became negative after PCI. This is a good demonstration that the SPECT was false negative in this group of patients. In addition, these patients clinically improved with revascularisation with an increase in their EF. Thus, in sub-acute STEMI phase, perhaps SPECT by itself cannot be used as a gold standard. The chance for false-positive and false-negative SPECT results is considerable. But, if a patient has a positive SPECT, a low FFR, and has PCI thereafter, in which following the SPECT reverts from positive to negative, it is justified a posteriori to state that the first SPECT was true positive and the second was true negative. Based on the Bayesian consideration, by focusing on positive SPECT results before the PCI that converted to negative after the PCI, highly probable true-positive and true-negative SPECT results could be provided [24–26]; and, it can be considered as a gold standard, and then FFR can be compared to this gold standard. In our study the sensitivity and specificity of the FFR of 0.80 or less for detecting reversibility using SPECT increased from 56.3% to 96.7% and from 84.5% to 100%, respectively, when only true-positive and true-negative SPECT results were considered. Thus, the primary message of our study is that in those patients in whom such gold standard is available, the sensitivity and specificity of FFR to this gold standard is very high, close to 100%. Thus, although the myocardial flow reserve is reduced and improves over time [15,27], and the limited flow reserve affects the vasodilator-dependent physiological assessment of the coronary obstruction early after an MI, FFR might be as good and can be used from 3 days after STEMI on to indicate residual ischemia related to the IRA. De Bruyne et al. showed that 6 or more days after an MI, the FFR of the IRA had an inverse relationship with the LVEF; the LVEF of SPECTpositive patients was significantly higher than that of SPECT-negative patients before the PCI [8]. In the present study, although the LVEF had an inverse relationship with the FFR, it was not significant. After an MI, because of the loss of myocardial mass, the FFR will be larger for a given degree of diameter stenosis and does not underestimate the stenosis severity. However, we measured the FFR 3 to 7 days after the MI, but the recovery of microvascular function can take as long as 6 weeks to occur [28]. Thus, the FFR correlation to myocardial mass would take more time to be evident accurately. After the PCI, the LVEF of both the SPECT-positive and SPECT-negative patients increased compared with the pre-PCI values. This finding supports the use of the FFR in the sub-acute STEMI phase for determining the necessity of revascularisation of the IRA.
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4.1. Limitations There were some limitations in this study. Not all patients underwent follow-up echocardiography; only 51 patients received follow-up echocardiograms. However, the baseline characteristics of the 51 patients did not differ from the study population. Another limitation was that the second SPECT was performed within 14 days after PCI, although the conversion of a positive SPECT to a negative takes up to 3 months to occur in the partially infarcted myocardium. Because we wanted to prevent the effect of any probable restenosis on the results of the study, the timeline was accelerated. Finally, the number of patients in this study is small. But, considering the fact that we included only single-vessel disease patients with meticulous sequential testing in a limited timeline for selecting them, it took approximately 20 months to recruit 69 patients in our tertiary referral heart hospital. 5. Conclusions The FFR of the IRA is useful for determining residual ischemia and making decisions about revascularisation in stable patients 3 to 7 days after an MI and its reliability in patients with true-positive SPECT before and true-negative SPECT after PCI is very high. Acknowledgments The text has been reviewed by a native reviewer from the Elsevier Language Editing Services, and we have the Certificate. We thank Mojtaba Shokri for his full time cooperation for performing the study and preparing the manuscript. Funding sources Sixty pressure wires were provided by the Eastern Europe and Middle East branch of the St. Jude Medical Coordination Center. The study was supported financially by the Vice Chancellor for Research Technology, Mazandaran University of Medical Sciences. Disclosures None. References [1] Cardiology TFotMoS-SEAMIotESo. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with STsegment elevation. Eur Heart J 2012;33:2569–619. [2] O'Gara PT, Kushner FG, Ascheim DD, et al. ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013 2013;61:485–510. [3] Windecker S, Kolh P, Alfonso F, et al. Authors/Task Force members. 2014 ESC/EACTS Guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014; 35:2541–619. [4] Pijls NH, J-WE Sels. Functional measurement of coronary stenosis. J Am Coll Cardiol 2012;59:1045–57.
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Please cite this article as: A. Ghaemian, J. Yazdani, A.A. Farsavian, et al., Fractional flow reserve as a standard of reference for ischemia early after ST elevation myocardial ..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.04.019