Abstract: The purpose of this study was to compare the efficacy and safety of intracoronary (IC) sodium nitroprusside (SNP) and IC adenosine (AD) for fractional flow reserve (FFR) measurement. We compared the FFR response and side effect profiles of IC AD and IC SNP in 40 patients with a combined total of 53 moderate coronary stenoses. Boluses of AD at doses of 40 µg (A1) and 60 µg (A2), and SNP at doses of 0.3 µg/kg (S1), 0.6 µg/kg (S2), and 0.9 µg/kg (S3) were used to achieve coronary hyperemia. The mean FFR value decreased significantly by 7.96% (A1), 10.51% (A2), 8.74% (S1), 10.58% (S2), and 10.73% (S3) compared with the baseline distal coronary pressure/aortic pressure. IC SNP delayed the mean time to peak value of FFR by 87.5%, 79.0%, and 88.6% in S1, S2, and S3, respectively, compared with A2 (P<.001). The mean duration of the plateau phase was longer in S1 (50.47 ± 14.25 s), S2 (51.33 ± 16.41 s) and S3 (57.60 ± 18.07 s) compared with A2 (27.93 ± 11.90 s; P<.01). IC AD caused shortness of breath in 11 patients (27.5%), flushing in 4 patients (10%), headache in 8 patients (20%), and transient second-degree atrioventricular block (AVB) in 6 patients (15%). IC SNP may be used as a hyperemic agent in FFR measurements. It may be preferable to IC AD as a routine clinical stimulus and has the additional advantage of showing a longer plateau phase.
J INVASIVE CARDIOL 2014;26(3):119-122
Key words: fractional flow reserve, coronary artery disease, coronary angiography
Fractional flow reserve (FFR) measurement is used to assess the hemodynamic significance of coronary arterial stenosis.1,2 Studies have shown that patients with an FFR measurement of <0.75 almost always present with myocardial ischemia.3 In patients with coronary stenosis based on coronary angiography (CAG) and an FFR of ≥0.75, deferral of percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) is safe in daily clinical practice and reduces costs.4 In multivessel coronary artery disease, FFR-guided PCI shows improved clinical outcomes compared to CAG-guided strategies.5
When FFR is measured, 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) administration of vasodilator agents, such as adenosine (AD) or sodium nitroprusside (SNP), represents a valuable alternative in everyday practice, theoretically allowing delivery of a higher drug concentration into coronary circulation and reducing the occurrence of systemic symptoms. Parham et al found that IC SNP produces similar, but longer, periods of hyperemia than IC adenosine. They also found that when induced with IC SNP, the measured FFR values correlate well with the FFR values measured with IC adenosine. However, this study was limited to 21 patients with normal coronary arteries and 9 patients with single-vessel coronary artery disease.6
The aim of this study was to compare the FFR response and side effect profiles of IC adenosine and IC SNP in patients with single-vessel and multivessel coronary artery stenoses identified by coronary angiography.
Study population. A total of 40 patients between the ages of 34 to 75 years were enrolled in this study, which compared the FFR values induced by IC SNP and IC AD by two experienced interventional cardiologists. Major exclusion criteria included cardiomyopathy, congestive heart failure with a left ventricular ejection fraction <40%, myocardial infarction, significant valvular or congestive heart disease, and renal failure. This study was approved by the Institutional Review Board of the Shenyang Northern Hospital.
Practicalities in measuring FFR. CAG was performed according to the standard procedure, as previously described.7 Based on quantitative coronary angiography assessment, the severity of each stenosis was defined as not significant (<50%), moderate (50%-70%) and severe (>70%).
After administration of heparin 100 IU/kg IV, a 0.014˝ pressure monitoring guidewire (PressureWire Certus; St Jude Medical) was calibrated and introduced into the guiding catheter. The pressure transducer was advanced just outside the tip of the guiding catheter, and the pressure measured by the sensor was then equalized to that of the guiding catheter. Subsequently, the pressure wire was advanced in the coronary artery with the pressure sensor placed distal to the target lesion site. Distal coronary and aortic pressures were measured at baseline. FFR was calculated as the distal coronary/aortic pressure during maximal hyperemia.
IC AD was administered in 2 serial doses (A1 = 40 µg; A2 = 60 µg) in the standard bolus to calculate FFR, followed by a repeated FFR measurement with IC SNP in 3 serial doses (S1 = 0.3 µg/kg; S2 = 0.6 µg/kg; S3 = 0.9 µg/kg). Each bolus was followed by a saline flush. Subsequent doses or drugs were given at least 60 s after returning to baseline hemodynamic conditions. These measurements were performed in duplicate after the FFR and blood pressure returned to baseline simultaneously.
At baseline and after the IC AD and IC SNP treatments, detailed medical data were recorded, including the FFR value, time to peak value of FFR, duration of the plateau phase, time to the maximal change of systolic and diastolic blood pressure, duration of hypotension, and change in heart rate. Patients’ symptoms (namely, an angina-like sensation, dyspnea, or flushing), the development of complete atrioventricular block (AVB), and any other complications were carefully recorded.
Statistical analysis. Continuous data are expressed as mean ± standard deviation. Differences in the means of the FFR values, time to peak value of FFR, duration of the plateau phase, change of systolic and diastolic blood pressure, and change in heart rate were compared using analysis of variance (ANOVA). A Z-test was used to test for significant linear trends in the association of the FFR values with the stimuli. The Cohen’s kappa coefficient was calculated to measure intraobserver (comparison of FFR between two times by the same doctor) and interobserver (comparison of FFR by different doctors) variability. All statistics were two-tailed, and a P-value of <.05 was considered statistically significant. All statistical analyses were performed with the Statistical Package for the Social Sciences version 16.0 (SPSS, Inc).
Characteristics of target arteries. The characteristics of target arteries are shown in Table 1. The study was performed with a total of 53 coronary arteries in 40 patients with moderate stenosis. Target lesions were located in the left anterior descending (n = 24), left circumflex (n = 13), and right coronary arteries (n = 16). The mean percentage of stenosis measured was 62.8 ± 8.6%. Lesion lengths of less than 10 mm, 10-20 mm of lesion length, and diffuse (>20 mm) or multiple sequential stenosis accounted for 56.6% (n = 30), 20.7% (n = 11), and 22.6% (n = 12) of the cases, respectively.
Dose-effect relationship of intracoronary adenosine and intracoronary sodium nitroprusside on fractional flow reserve. As shown in Figure 1, the FFR values decreased significantly after administering stimuli (IC AD and IC SNP) compared with the baseline distal coronary pressure/aortic pressure values (P<.01). At baseline, the mean value of the FFR was 0.91 ± 0.05, and increasing IC AD and IC SNP doses resulted in progressively lower values of FFR (0.84 ± 0.06 with A1; 0.82 ± 0.07 with A2; 0.83 ± 0.07 with S1; 0.81 ± 0.07 with S2; and 0.81 ± 0.07 with S3). Notably, A2 showed an FFR value that was not significantly different from S1 (P=.19), S2 (P=.33), and S3 (P=.39); however, compared to S1, S2 and S3 showed significantly lower FFR values (P=.02 and P=.03, respectively). The mean kappa values in the evaluation of interobserver variability and intraobserver variability were 0.95 and 0.96 for FFR, respectively.
Increasing IC AD and SNP doses resulted in the lowest FFR values (18.8% with A1; 20.7% with A2; 18.8% with S1; 28.3% with S2; and 28.3% with S3) in the tested lesions. After introducing the IC A2 bolus, 7.6% of lesion arteries with FFR ≥0.75 were <0.75 after IC S2 and S3. All patients with FFR <0.75 after the A2 dosage also showed an FFR <0.75 after administration with the IC S2 and S3 dosages. As shown in Figure 2, there was a significant correlation between the FFR values of IC A2 and IC S2 (R=0.95; P<.01).
Systemic effects of intracoronary adenosine and intracoronary sodium nitroprusside. No significant differences in the systolic blood pressures were found among A1, A2, and S1 compared to the baseline (decreases of 3.99%, 6.64%, and 6.87%, respectively; P=.31) (Figure 3). A continuous decrease occurred when IC SNP was increased from 0.6 µg/kg to 0.9 µg/kg. S2 and S3 lowered systolic blood pressure by 10.56% and 15.55%, respectively (S2 vs A2 [P=.02]; S2 vs S1 [P=.04]; S3 vs A2 [P<.01]; and S3 vs S1 [P<.01]). Compared with S2, S3 decreased systolic blood pressure further (P=.01). Compared with A2 and S1 (decreases of 10.08% and 11.32%), the diastolic blood pressure decreased by 16.50% and 21.10% in S2 and S3, respectively (A2 vs S2 [P=.01]; A2 vs S3 [P<.01]; S1 vs S2 [P=.05]; and S1 vs S3 [P<.01]). No significant differences were found between S2 and S3 (P=.13) or among A1, A2, and S1 (P=.17). The mean time to the maximal change in the systolic and diastolic blood pressures was longer by 86.0%, 79.8%, and 72.9% in S1, S2, and S3, respectively, compared with A2 (P<.01) (Figure 4). No significant differences were found among S1, S2, and S3 (P=.32). The mean duration of hypotension was longer by 60.3%, 77.4%, and 89.3% in S1, S2, and S3, respectively, than A2 (P<.01). There were no significant differences between S1 and S2, but S3 was longer than S2 (P=.02).
The heart rate (70.02 ± 13.5 bpm, 74.60 ± 20.1 bpm, 74.06 ± 16.5 bpm, 74.42 ± 18.7 bpm, and 75.79 ± 21.5 bpm before the agents were administered) increased by 2.01%, 0.84%, 1.23%, 1.34%, and 3.11% in A1, A2, S1, S2, and S3, respectively (P=.52).
Time to peak value of fractional flow reserve and duration of the plateau phase. There were significant differences in the mean time to peak value of FFR and the mean duration of the plateau phase among the stimuli (P<.01) (Figure 4). The mean time to peak value of FFR was longer by 87.5%, 79.0%, and 88.6% in S1, S2, and S3, respectively, compared with A2 (P<.001). No significant differences were found among S1, S2, and S3 (P=.23). The mean duration of the plateau phase was longer in S1 (50.47 ± 14.25 s), S2 (51.33 ± 16.41 s), and S3 (57.60 ± 18.07 s) compared with A2 (27.93 ± 11.90 s; P<.01), and no significant differences were found among S1, S2, and S3 (P=.25).
Side effect profile. During IC AD infusion, a total of 16 patients (40%) reported at least one side effect. Eleven patients (27.5%) reported shortness of breath, 4 patients (10%) developed flushing, 8 patients (20%) reported headache, and 6 patients (15%) developed transient second-degree AVB. All symptoms promptly disappeared after the treatments were discontinued. No patients reported unpleasant symptoms after SNP injection.
FFR is an easily obtainable lesion-specific parameter for the functional assessment of coronary stenosis. Maximal hyperemia is extremely important for FFR measurements, because suboptimal microcirculatory vasodilation might result in underestimation of the functional severity of coronary stenoses. Adenosine is the most widely administered agent due to its rapid onset, short duration of action, high safety profile, and simplicity of use.8 Two methods, either intracoronary or intravenous continuous AD routes, are equivalent in achieving coronary hyperemia for FFR measurements.9 However, recent studies have shown that the standard doses used for the adenosine bolus do not always obtain maximal hyperemia.10 In this study, we used two serial of doses of IC AD (40 µg and 60 µg) and three serial of doses of IC SNP (0.3 µg/kg, 0.6 µg/kg, and 0.9 µg/kg) to compare the efficacy and safety of IC AD and IC SNP for FFR measurement.
Our results suggest that a 40 µg bolus of IC AD sufficiently induces hyperemia in distal lesion coronaries for CAD patients. We also found that a 60 µg bolus of IC AD was also safe. The 60 µg bolus of IC AD may be a suitable dose for FFR measurement in clinical practice. The 60 µg dose of IC AD was able to achieve hyperemia, while >60 µg doses of IC AD did not further decrease the FFR.11,12
SNP works by producing nitric oxide, which subsequently induces smooth muscle vasodilatation. It can directly relax arterial and venous smooth muscles without affecting other types of smooth muscles or producing myocardial contractility. It dilates the coronary microcirculation and induces the hyperemic response when administered to the artery. Based on a small sample size (n = 9), the maximal coronary hyperemia, equivalent to that induced by IC AD, could be achieved by IC SNP.6 Our study showed that a bolus of IC SNP can achieve lower FFR values than IC AD. In addition, the rate of FFR values that are <0.75 are higher with IC SNP than with 40 µg and 60 µg of IC AD. The correlation between 60 µg of IC AD and 0.6 µg/kg of IC SNP for FFR measurement was excellent. These data suggest that IC SNP is superior to IC AD in achieving coronary hyperemia for FFR measurements. Because the frequencies of stenosed arteries with FFR values <0.75 showed no significant differences between IC S2 and IC S3, 0.6 µg/kg of IC SNP achieves maximal hyperemia and is a suitable dose for FFR measurements. Doses higher than 0.6 µg/kg of IC SNP do not increase coronary hyperemia for FFR measurements and increase the propensity for hypotension.
IC AD and SNP reduced the systemic pressure, and this reduction was accompanied by a slightly increased heart rate. IC AD caused less hypotension than IC SNP. However, the systolic blood pressure decreased significantly less with the 0.6 µg/kg dose of IC SNP compared to the 0.9 µg/kg dose of IC SNP. Taken together, 0.6 µg/kg of IC SNP was superior to 0.9 µg/kg for FFR measurement because increasing the dose of SNP did not induce a further decline in the FFR value, but induced a marked decline in the blood pressure and showed a longer period of hypotension. The FFR values were obtained in the same artery with identical pressure wire positions, so the difference was caused by the hyperemia induced by different doses of AD and SNP. The duration of the plateau phase when IC SNP was administered was twice that with IC AD; therefore, it is feasible to obtain accurate values of FFR using IC SNP. In addition, this may be suitable for utilizing the pressure pullback maneuver to assess serial lesions or diffuse disease.
Study limitations. First, in all cases, FFR measurements were made using IC AD, and the doses of AD used were ≤60 µg. Studies have shown that IC AD achieves a lower level of hyperemia than intravenous AD.13 Therefore, it is likely that the FFR values were underestimated in our study. However, considering the objectives of our study, this underestimation is unlikely to affect our conclusion. Second, the current gold standard for measuring FFR is the intravenous continuous AD route. In this study, we did not compare our method with intravenous continuous AD. Third, the order of IC AD/SNP administration was not randomized. Thus, the possibility of drug interactions from a preceding bolus exists. Fourth, we only tested 3 doses of SNP. A high dose may produce maximal hyperemia without affecting the hemodynamic responses. Finally, this study is limited by its small sample size.
This study shows that IC SNP, compared with IC AD administration, is effective to induce maximal arteriolar vasodilation and is better tolerated by the patient. IC SNP could be considered a potential alternative in patients with contraindications to AD administration.
- Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med. 1996;334(26):1703-1708.
- 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(3):213-224.
- de Bruyne B, Bartunek J, Sys SU, Pijls NH, Heyndrickx GR, Wijns W. Simultaneous coronary pressure and flow velocity measurements in humans. Feasibility, reproducibility, and hemodynamic dependence of coronary flow velocity reserve, hyperemic flow versus pressure slope index, and fractional flow reserve. Circulation. 1996;94(8):1842-1849.
- Oud N, Marques KM, Bronzwaer JG, et al. Patients with coronary stenosis and a fractional flow reserve of >/=0.75 measured in daily practice at the VU University Medical Center. Neth Heart J. 2010;18(9):402-407.
- Fearon WF, Bornschein B, Tonino PA, et al. Economic evaluation of fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. Circulation. 2010;122(24):2545-2550.
- Parham WA, Bouhasin A, Ciaramita JP, Khoukaz S, Herrmann SC, Kern MJ. Coronary hyperemic dose responses of intracoronary sodium nitroprusside. Circulation. 2004;109(10):1236-1243.
- Lopez-Palop R, Carrillo P, Frutos A, et al. Usefulness of the fractional flow reserve derived by intracoronary pressure wire for evaluating angiographically intermediate lesions in acute coronary syndrome. Rev Esp Cardiol. 2010;63(6):686-694.
- De Luca G, Venegoni L, Iorio S, Giuliani L, Marino P. Effects of increasing doses of intracoronary adenosine on the assessment of fractional flow reserve. JACC Cardiovasc Interv. 2011;4(10):1079-1084.
- Rudzinski W, Waller AH, Rusovici 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):540-544.
- Nitenberg A, Durand E, Delatour B, Sdiri W, Raha S, Lafont A. Postocclusion hyperemia provides a better estimate of coronary reserve than intracoronary adenosine in patients with coronary artery stenosis. J Invasive Cardiol. 2007;19(9):390-394.
- Casella G, Leibig M, Schiele TM, et al. Are high doses of intracoronary adenosine an alternative to standard intravenous adenosine for the assessment of fractional flow reserve? Am Heart J. 2004;148(4):590-595.
- Rzeczuch K, Jankowska E, Kaczmarek A, et al. Measurement of coronary fractional flow reserve. Standard doses of intracoronary adenosine are insufficient to induce maximal hyperaemia. Kardiol Pol. 2003;58(4):269-274.
- Jeremias A, Filardo SD, Whitbourn RJ, et al. Effects of intravenous and intracoronary adenosine 5´-triphosphate as compared with adenosine on coronary flow and pressure dynamics. Circulation. 2000;101(3):318-323.
From the 1Department of Cardiology, Cardiovascular Research Institute of People’s Liberation Army, Shenyang Northern Hospital, Shenyang and 2Department of Cardiology, The 230th Hospital of People’s Liberation Army, Dandong, Liaoning, China.
Funding: This work was supported by grants from Sunshine Cardiovascular Research Foundation of Chinese Medical Doctor Association (SCRFCMDA201219).
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted October 30, 2012, provisional acceptance given November 26, 2012, final version accepted September 25, 2013.
Address for correspondence: Dr Yaling Han, Department of Cardiology, Cardiovascular Research Institute of People’s Liberation Army, Shenyang Northern Hospital, Shenyang, Liaoning 110016, China. Email: Hanyl@medmail.com.cn