Cardiovascular Revascularization Medicine 17 (2016) 441–443
Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
Comparison of fractional flow reserve measurements using intracoronary adenosine versus intracoronary sodium nitroprusside infusions in moderately stenotic coronary artery lesions☆ Morteza Safi a, Mohammad Hasan Namazi a, Esfandiar Fooladi a, Hossein Vakili a, Saeed Alipour Parsa a, Isa Khaheshi a, Mohammad Amin Abbasi b, Mohammad Reza Movahed c,d,⁎ a
Cardiovascular Research Center, Modarres hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Department of Internal Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran c CareMore, Arizona, Tucson, AZ, USA d University of Arizona, Sarver Heart Center, Tucson, AZ, USA b
a r t i c l e
i n f o
Article history: Received 1 February 2016 Received in revised form 7 May 2016 Accepted 13 May 2016 Keywords: Fractional flow reserve Nitroprusside Ischemia evaluation Functional study
a b s t r a c t Introduction: The aim of this study was to investigate the efficacy and safety of intracoronary (IC) sodium nitroprusside infusion in comparison to IC adenosine for fractional flow reserve (FFR) measurement in moderately diseased coronary artery lesions for functional assessment. Methods: During a nine month period, a consecutive of 98 patients with suspected or known coronary artery disease with moderate stenosis found during angiography (40% to 70% stenosis), were enrolled in this study. Hyperemia was induced by bolus doses of IC adenosine followed by sodium nitroprusside for FFR measurement. Results: Both IC adenosine and IC sodium nitroprusside induced similar and significant reduction in FFR. There was no statistically difference in FFR values between adenosine vs sodium nitroprusside infusions (mean FFR 84.3 ± 6.3 vs 85.7 ± 6.2, p = 0.1) respectively. Furthermore, comparing different FFR cut-off points between the groups (FFR b 0.75, 0.75–0.8 and N 0.8) showed no significant differences (p value = 0.7). Conclusion: An IC bolus of sodium nitroprusside (0.6 μg/kg) infusion induces a similar degree of hyperemia to IC bolus of 100–300 μg of adenosine. Therefore, IC sodium nitroprusside could be considered as an alternative drug to adenosine for FFR measurement with lower side effect profile. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Fractional flow reserve (FFR) measurement is used to assess the hemodynamic significance of an intermediate coronary artery lesion [1,2]. It represents the ratio of mean arterial pressure after a stenotic lesion to the pressure before the lesion after inducing maximal blood flow [3]. Studies have shown that lesions with an FFR measurement of less than 0.75 or 0.8 are frequently associated with myocardial ischemia [4]. In patients with coronary stenosis based on coronary angiography and an FFR of ≥0.8, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) showed no significant benefit in clinical outcome [5]. For FFR measurement, pharmacologic stimuli are needed to induce coronary hyperemia. Intravenous (IV) adenosine infusion is currently considered the gold standard for FFR evaluation. However, the intracoronary (IC) or IV administration of adenosine may lead to undesirable side effects such as severe bradycardia, flushing, hypotension, gastrointestinal symptoms and bronchospasm. Sodium ☆ Author have no conflict of interest. ⁎ Corresponding author at: Arizona CareMore Regional Cardiology, 7091 E. Speedway Blvd., Tucson, AZ 85710. Tel.: +1 949 400 009. E-mail address:
[email protected] (M.R. Movahed). http://dx.doi.org/10.1016/j.carrev.2016.05.011 1553-8389/© 2016 Elsevier Inc. All rights reserved.
nitroprusside (NTP) represents a valuable alternative to the adenosine with lower side effect profile. Small studies have been promising. The purpose of this study was to compare the efficacy and safety of IC NTP with IC adenosine for fractional flow reserve (FFR) measurement in order to confirm previous small investigations and also to evaluate side effect profile of NTP in comparison to adenosine. 2. Patients and methods During a nine month period, a consecutive of 98 patients with chronic stable angina who were found to have moderate coronary stenotic lesions during angiography (40% to 70% stenosis) were enrolled. Angiogram was performed for clinical indications. Patients with hemodynamic instability (SBP b 100) were excluded. Written informed consent was obtained from each patient before the procedure. The study was approved by institutional review board. 2.1. Catheterization procedure After diagnostic angiography via femoral artery, patients with moderate coronary lesions were enrolled for FFR evaluation. Those patients
442
M. Safi et al. / Cardiovascular Revascularization Medicine 17 (2016) 441–443
Table 1 Baseline characteristics of patients.
Table 3 Comparison of FFR between groups (p-value by ANOVA test = 0.7). (n = 98)
Age Sex (male/female) Smoking Diabetes Hypertension Dyslipidemia Prevalence of involved coronary arteries Left anterior descending (LAD) Right coronary artery (RCA) Left circumflex artery (LCX) Optus marginalis (OM) Average lesion stenosis Average reference diameter of lesion Average lesion length
FFR
62.3 ± 4.7 (66/32) 43 48 36 29
Group Adenosine (%) Nitroprusside (%)
b0.75 5 (5.1%) 3 (3.1%)
0.75–0.8 17 (17.3%) 15 (15.6%)
N0.8 76 (77.6%) 78 (81.2%)
lesion in different coronary territories (p N 0.05). Furthermore, comparing different FFR cut-off points (FFR b 0.75, 0.75–0.8 and N0.8) showed no significant difference between the drugs (Table 3). Fig. 1 demonstrates the Bland–Altman plot showing the difference of FFR results of adenosine versus sodium nitroprusside intracoronary injections. Hemodynamic status was closely monitored in all patients during the procedure. As shown in Table 2, IC adenosine had a modest effect on blood pressure. In contrast, NTP was associated with a larger reduction in the systolic and diastolic blood pressures. NTP slightly increased heart rate, while IC adenosine was associated with a significant reduction in the heart rate.
43 (43.9%) 26 (22.5%) 22 (26.5%) 7 (7.1%) 61 ± 6% 2.9 mm (2.5–3.8) 16.2 mm (8–28)
who had history of previous acute coronary syndromes including myocardial infarction, congestive heart failure, previous percutaneous coronary intervention, and previous coronary artery bypass grafting, or who had sequential (more than one lesion in the target vessel) were excluded from the study. Intra-coronary (IC) bolus of adenosine (100 μg) was administered through a guide catheter and maximal hyperemia was measured via FFR. The lowest level of FFR was recorded as maximal hyperemic response. After 5 min, hyperemia was induced again by a 0.6 μg/kg bolus of IC NTP with repeat FFR measurement. Patient's symptoms (including angina-like sensation, dyspnea, or flushing), development of AV block or any other complications were carefully recorded. Mean FFR values as well as the number of patients with the cutoff point of different FFR values were compared between the adenosine and NTP treated obtained values.
4. Discussion Our study showed that FFR induced by IC adenosine was equivalent to IC NTP. Intracoronary adenosine had a modest effect on blood pressure. In contrast, NTP was associated with a larger reduction of systolic and diastolic blood pressures. NTP slightly increased heart rate while IC adenosine was associated with a significant reduction of heart rate. Our results were consisted and confirmative of previous small studies [6,7]. Although the angiographic assessment of coronary stenosis is the gold standard for assessing coronary disease severity, it has many limitations in regard to assessing ischemia in the intermediate lesions. In such cases, documentation of myocardial ischemia related to the culprit lesion that can be obtained by functional test is very important [7]. Fractional flow reserve is derived from intracoronary pressure measurements during maximal hyperemia, induced pharmacologically by vasodilator agents such as adenosine, sodium nitroprusside or papaverine, which reflects the ratio of maximal blood flow after the stenosis to before the stenosis [8,9]. FFR values of b 0.75 or b 0.8 have been validated as a cut-off value for ischemia [10]. Adenosine has been validated for FFR measurements in many studies, mostly those comparing it with papaverine [10]. However, despite its common use and its documented safety and efficacy, a clear recommended dosage for IC adenosine is still lacking [11,12]. Our study showed that conventional doses of IC adenosine were efficient to induce maximal hyperemia and caused significant reduction in FFR values, while some studies found that only very high doses can achieve the maximally desired hyperemic response [13,14]. According to our knowledge only few studies investigated sodium nitroprusside in the induction of maximal hyperemia during FFR assessment [15]. In one study intracoronary sodium nitroprusside was considered to be preferable to intracoronary adenosine and has the further advantage of showing a longer plateau phase [16]. Moreover, another studies demonstrated that intracoronary sodium nitroprusside is a safe and efficient agent and simple to use for the FFR measurement. Maximal hyperemia by intracoronary sodium nitroprusside is comparable with that by intracoronary adenosine. Intracoronary sodium nitroprusside could be considered as an alternative drug in patients with
2.2. Statistical analyses Data are shown as means ± SD. Chi-square test was used for categorical variables and independent Student's t-tests or ANOVA tests for continuous variables. Paired t test was used to compare changes in FFR values before and after IC infusion. Statistical analyses were performed with SPSS software for Windows (Statistical Product and Service Solutions, version 16.0, SSPS Inc., Chicago, IL, USA). A p value of less than 0.05 was considered significant. 3. Results Ninety-eight patients (66 men and 32 women) with moderate stenotic coronary lesions found during angiography were studied. The mean age was 62.3 ± 4.7 years. The demographic characteristics of patients can be seen in Table 1. Vessels involved were as follows: left anterior descending in 43 patients (43.9%), left circumflex in 22 (22.5%), right coronary artery in 26 (26.5%) and obtuse marginal artery in 7 patients (7.1%) respectively. The average stenosis seen on angiography was 61% ± 6% which was measured by quantitative coronary angiography (QCA). Both IC adenosine and IC NTP induced a significant reduction in FFR compared with baseline (p b 0.001). But, there were no statistically differences in FFR values between the two drugs (84.3 ± 6.3 vs 85.7 ± 6.2, p = 0.1, Table 2) respectively. FFR was not influenced by location of the Table 2 FFR values before and after drug administration.
FFR Systolic BP Diastolic BP HR
Before drug
After adenosine
After nitroprusside
p Value in the group
p Value between groups
91.5 132 84 76
84.3 121 76 46
85.7 117 70 64
b0.001 0.08 0.09 0.02
0.10 0.20 0.12 0.03
± ± ± ±
4.7 2.6 2.4 9
± ± ± ±
6.3 1.8 1.2 6
± ± ± ±
6.2 1.3 1.4 12
M. Safi et al. / Cardiovascular Revascularization Medicine 17 (2016) 441–443
443
Fig. 1. Bland–Altman plot which shows the difference of FFR results of adenosine versus sodium nitroprusside intracoronary injections.
contraindications to adenosine administration. Since intracoronary sodium nitroprusside is inexpensive, readily accessible and well tolerated, it may be a better alternative for FFR assessment [17,18]. In our study, we confirmed the results of other investigators that sodium nitroprusside-induced hyperemia was equivalent to that induced by adenosine with more sustained duration of the hyperemic response without significant bradycardia. However, a notable drop in the blood pressure remains a drawback of this agent. This study could serve as a pilot study and novel window for future large and multicenter trials which will disclose more detailed results. Moreover, precious clinical and systematic reviews could be published from results of diverse centers. 5. Conclusion An intracoronary bolus of sodium nitroprusside (0.6 μg/kg) induces a similar degree of hyperemia to intracoronary bolus of 100–300 μg adenosine. Therefore, IC sodium nitroprusside could be considered as a potential alternative agent to adenosine in patients with intermediate lesions requiring functional assessment. Acknowledgements We would like to thank Dr. Serati for his help in the preparation and editing of this manuscript. References [1] De Bruyne B, Sarma J. Fractional flow reserve: a review: invasive imaging. Heart 2008;94:949–59. [2] Abe M, Tomiyama H, Yoshida H, Doba N. Diastolic fractional flow reserve to assess the functional severity of moderate coronary artery stenoses: comparison with fractional flow reserve and coronary flow velocity reserve. Circulation 2000;102: 2365–70. [3] Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, Bartunek J, et al. Measurement of fractional flow reserve to assess the functional severity of coronaryartery stenoses. N Engl J Med 1996;334:1703–8.
[4] Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24. [5] Petraco R, Sen S, Nijjer S, et al. Fractional flow reserve-guided revascularization: practical implications of a diagnostic gray zone and measurement variability on clinical decisions. JACC Cardiovasc Interv 2013;6(3):222–5. [6] Leone AM, Porto I, De Caterina AR, et al. Maximal hyperemia in the assessment of fractional flow reserve: intracoronary adenosine versus intracoronary sodium nitroprusside versus intravenous adenosine: the NASCI (Nitroprussiato versus Adenosina nelle Stenosi Coronariche Intermedie) study. JACC Cardiovasc Interv 2012;5(4): 402–8. [7] Hamilos M, Muller O, Cuisset T, et al. Long-term clinical outcome after fractional flow reserve-guided treatment in patients with angiographically equivocal left main coronary artery stenosis. Circulation 2009;120:1505–12. [8] Marcus ML, Skorton DJ, Johnson MR, Collins SM, Harrison DG, Kerber RE. Visual estimates of percent diameter coronary stenosis: “a battered gold standard”. J Am Coll Cardiol 1998;11:882–5. [9] Murtagh B, Higano S, Lennon R, Mathew V, Holmes Jr DR, Lerman A. Role of incremental doses of intracoronary adenosine for fractional flow reserve assessment. Am Heart J 2003;146:99–105. [10] Lopez-Palop R, Saura D, Pinar E, et al. Adequate intracoronary adenosine doses to achieve maximum hyperaemia in coronary functional studies by pressure derived fractional flow reserve: a dose response study. Heart 2004;90:95–6. [11] De Bruyne B, Pijls NHJ, Bartunek J, et al. Fractional flow reserve in patients with prior myocardial infarction. Circulation 2001;104:157–62. [12] van der Voort PH, van Hagen E, Hendrix G, et al. Comparison of intravenous adenosine to intracoronary papaverine for calculation of pressure-derived fractional flow reserve. Cathet Cardiovasc Diagn 1996;39:120–5. [13] Kern MJ. An adenosine-independent index of stenosis severity from coronary waveintensity analysis. JACC 2012;59(15):1012–9. [14] Pijls NHJ, Fearon WF, Tonino PA, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. 2-year follow up of the FAME (fractional flow reserve versus angiography for Multivessel evaluation) study. J Am Coll Cardiol 2010;56:177–84. [15] Parham WA, Bouhasin A, Ciaramita JP, Khoukaz S, Herrmann SC, Kern MJ. Coronary hyperemic dose responses of intracoronary sodium nitroprusside. Circulation 2004; 109:1236–43. [16] Wang X, Li S, Zhao X, Deng J, Han Y. Effects of intracoronary sodium nitroprusside compared with adenosine on fractional flow reserve measurement. J Invasive Cardiol 2014;26(3):119–22. [17] Li S, Deng J, Wang X, Zhao X, Han Y. Efficiencies of intracoronary sodium nitroprusside on fractional flow reserve measurement. Int J Clin Exp Med 2015;8(2):2679–83. [18] Rudzinski W, Waller AH, Rusovici A, Dehnee A, Nasur A, et al. Comparison of efficacy and safety of intracoronary sodium nitroprusside and intravenous adenosine for assessing fractional flow reserve. Catheter Cardiovasc Interv 2013;81(3):540–4.
