- Email: [email protected]
Are high doses of intracoronary adenosine an alternative to standard intravenous adenosine for the assessment of fractional flow reserve?
Are high doses of intracoronary adenosine an alternative to standard intravenous adenosine for the assessment of fractional flow reserve? Gianni Casella, MD,a,b Marcus Leibig, MD,a Thomas M. Schiele, MD,a Reiner Schrepf, MD,a Victoria Seelig, MD,a Hans-Ulrich Stempfle, MD, PD,a Petra Erdin, MD,a Johannes Rieber, MD,a Andreas Ko ¨ nig, MD,a Uwe Siebert, MD, MPH, MSc,a,c and Volker Klauss, MD, PDa Munich, Germany, Bologna, Italy, and Boston, Mass
Background
Achievement of maximal hyperemia of the coronary microcirculation is a prerequisite for the measurement of fractional flow reserve (FFR). Intravenous adenosine is considered the standard method, but its use in the catheterization laboratory is time consuming and expensive compared with intracoronary adenosine. Therefore, this study compared different high, intracoronary doses of adenosine for the potential to achieve a maximal hyperemia equivalent to the standard intravenous route.
Methods FFR was assessed in 50 patients with 50 intermediate lesions during cardiac catheterization. FFR was calculated as the ratio of the distal coronary pressure to the aortic pressure at hyperemia. Different incremental doses of intracoronary adenosine (60, 90, 120, and 150 g as boli) and a standard intravenous infusion of 140 g/kg/min were administered in a randomized fashion. Results Different incremental doses of intracoronary adenosine were well tolerated, with fewer systemic adverse effects than intravenous adenosine. At baseline, there were no significant differences for mean aortic and distal coronary pressure or heart rate in the different adenosine doses and routes. FFR decreased with increasing adenosine doses, with the lowest values observed with the 150-g intracoronary bolus and 140-g/kg/min dose of intravenous adenosine. All intracoronary doses, except the 150-g bolus, resulted in mean FFR values that were significantly (P ⬍.05) higher than FFR after the administration intravenous adenosine. Furthermore, 5 patients (10%) with a FFR value ⬎0.75 and 3 subjects (6%) with a FFR value ⬎0.80 who received a 60-g intracoronary bolus reached a value below the cutoff point of 0.75 with the intravenous administration. Conclusions
This study suggests a dose-response relationship on hyperemia for intracoronary adenosine doses ⬎60 g. The administration of very high intracoronary adenosine boli is safe and associated with fewer systemic adverse effects than standard intravenous adenosine. However, intravenous adenosine administration with 140 g/kg/min produced a more pronounced hyperemia than intracoronary adenosine in most patients and should be the preferred mode of application for the assessment of FFR. (Am Heart J 2004;148:590 –5.)
The measurement of fractional flow reserve (FFR) is commonly used in clinical practice to determine the hemodynamic significance of epicardial coronary stenoses detected at angiography.1 However, for an accurate calculation of FFR, a key point is to achieve a
From the aDepartment of Cardiology, Medizinische Poliklinik – Klinikum Innenstadt, Ludwig-Maximilians University, Munich, Germany, bDepartment of Cardiology, Ospedale Maggiore, Bologna, Italy, and cInstitute for Technology Assessment and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass. Submitted February 8, 2004; accepted April 14, 2004. Reprint requests: Gianni Casella, MD, Via Milani, 8, Imola (Bo), 40026, Italy. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2004.04.008
maximal vasodilatation to minimize the contribution of microvascular resistance.2 With suboptimal levels of coronary hyperemia, FFR will be artificially high, resulting in a potentially significant underestimation of the functional severity of the coronary stenosis. Adenosine, mainly intravenously, has been validated for FFR measurements in many studies.3 Compared with the intracoronary route, intravenous adenosine administration requires relatively large doses, and it is associated with more systemic adverse effects and costs.4,5 Thus, currently many cardiac catheterization laboratories prefer intracoronary adenosine for routine evaluation. However, several observations cast some doubts about the ability of the former 12- to 18-g boli of adenosine to achieve maximal vasodilatation in all patients,4,6 and higher dosages have been suggested.7,8
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Therefore, this study was designed to test the hypothesis that a dose-response relationship on hyperemia exists for intracoronary adenosine doses ⬎60 g and such very high intracoronary doses may achieve a vasodilatation of the coronary microcirculation comparable with that of the standard intravenous route.
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Table I. Demographic data of the study population Study cohort (50 patients, 50 lesions) 66 ⫾ 8 40/10
A total of 50 patients were prospectively enrolled. The study population consisted of 40 men and 10 women with a mean age of 66 years (SD ⫾ 8 years; range, 52–76 years). Most patients had normal left ventricular function, and only intermediate coronary lesions were assessed. Exclusion criteria included acute coronary syndromes, prior myocardial infarction in the territory supplied by the target vessel, diffuse coronary stenoses, and atrioventricular conduction abnormalities in the electrocardiogram. All patients gave informed consent to participate in the study.
Age (y) Male/female Risk factors Hypertension Diabetes Smoking Hyperlipidemia Family history of CAD Angiographic parameters 3-Vessel disease Ejection fraction (%) Percent stenosis (%) Target vessel LAD LCx RCA
Study protocol
CAD, Coronary artery disease; LAD, left anterior descending artery; LCx, left circumflex artery; RCA, right coronary artery.
Methods Study population
Coronary angiography was performed with the standard femoral approach. Heparin was administered at the beginning of the procedure (5000 units). Non-ionic contrast material was used for all patients. The heart rate and arterial pressure were continuously monitored throughout the procedure. After coronary angiography, a 0.014-inch highfidelity pressure-recording guidewire (PressureWire, Radi Medical Systems, Uppsala, Sweden) was introduced through a 6F guiding catheter into the coronary artery. Special attention was given to avoid arterial pressure wave damping or variation of the measured coronary guide pressure. The guidewire was externally calibrated and then advanced to the distal tip of the catheter, as previously described.9 Afterward, it was verified that both the catheter and the pressure wire recorded equal pressures. The pressure wire was subsequently advanced into the coronary artery with the pressure sensor placed beyond the lesion site. Distal coronary and aortic pressures were measured at baseline and at maximal hyperemia. Pressure signals were continuously recorded at a paper speed of 25 mm/s, and a beat-to-beat analysis of mean pressure was performed automatically (Radi Analyzer, Radi Medical Systems, Uppsala, Sweden). Once a stable pressure signal was obtained, baseline measurements were recorded. In all patients, intracoronary nitroglycerin (0.25 mg) was administered before coronary angiography and was repeated before FFR measurements afterward.
Pharmacological protocol All patients received multiple boli of intracoronary adenosine. Incremental doses of intracoronary adenosine (60, 90, 120, and 150 g for both coronary arteries) were administered in a randomized fashion. Subsequent doses were given after pressure curves returned to baseline values. Each bolus was followed by a flush with saline. Thereafter, adenosine via a brachial or femoral vein at a dose of 140 g/kg/min was administered as an intravenous infusion until a steady-state hyperemia was achieved for a minimal duration of 1 minute. The electrocardiogram was simultaneously recorded.
44 (88%) 17 (34%) 10 (20%) 44 (88%) 22 (44%) 22 (44%) 61.2 ⫾ 12 64.6 ⫾ 12.5 27 (54%) 10 (20%) 13 (26%)
Calculations of pressure-derived FFR FFR is defined as the ratio of the hyperemic flow in a stenotic artery to the hyperemic flow in the same artery in the hypothetical case in which there is no stenosis present.10 FFR expresses maximum hyperemic blood flow in a stenotic vessel as a fraction of normal maximal blood flow in that vessel. FFR is calculated from intracoronary and aortic pressure measurements obtained during maximal hyperemia with this equation: FFR ⫽ Pd ⫺ Pv/Pa ⫺ Pv, or FFR ⫽ Pd/Pa (when Pv is negligible), in which Pa is the mean proximal coronary pressure (mean arterial pressure), Pd is the mean distal coronary pressure, and Pv is the mean central venous pressure. In this study, the simplified formula (in which Pv is considered negligible) was applied.
Coronary angiography The coronary angiogram was reviewed before coronary pressure was measured. Percent diameter stenosis was calculated with the guiding catheter as a scaling device.11
Statistical analysis Data are presented as the mean plus or minus SD. The Student paired t test was used to compare FFR values after different intracoronary adenosine doses and routes. Because this was an exploratory study, no correction for the performance of multiple statistical tests was applied. Results were considered statistically significant when the P value was ⬍.05.
Results Patient characteristics All 50 patients were included in the analysis. Demographic data are presented in Table I. Procedural suc-
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Figure 1
FFR values for different doses and routes (intracoronary and intravenous) of adenosine.
Figure 2
Figure 3
Percentage of patients having a FFR less than the cutoff value of 0.75 with increasing doses of adenosine.
Table II. Major side effects of different dosages and routes of administration of adenosine
Angina Dyspnoe Nausea A-V block
60 g
90 g
120 g
150 g
Ado IV
0 0 0 4 (8%)
0 0 0 3 (6%)
0 0 0 5 (10%)
0 0 0 8 (16%)
13 (26%) 8 (16%) 1 (2%) 3 (6%)
Ado IV, Intravenous adenosine.
Difference in mean FFR for different intracoronary doses compared with standard intravenous administration. The differences decrease with increasing intracoronary doses, and get non-significant for an intracoronary dose of 150 g.
cess was 100% for advancing the pressure wire distal to the stenosis. There were no procedure-related complications. Several systemic adverse effects (Table II) were observed during intravenous adenosine administration, whereas intracoronary boli elicited an asymptomatic transient atrioventricular block in as much as 16% of patients. Thirty-two patients (64%) underwent percutaneous coronary intervention (PCI) after FFR measurements.
FFR measurements At rest, the mean aortic and distal coronary blood pressure and the heart rate were not significantly different with the separate injections. The dose-response relationship in different adenosine doses and routes of administration and FFR are shown in Figure 1. The
mean FFR decreased with all doses, but the lowest values were achieved with the 150 g dose and with intravenous adenosine. For absolute values, in 25 patients (50%), the FFR values decreased when intracoronary doses ⬎60 g were administered. Thus, there was a clear dose-response relationship between intracoronary adenosine and FFR values. In addition, in 38 patients (76%), intravenous adenosine further decreased FFR. This decrease ranged from 0.01 to 0.23. This clearly demonstrates the potential overestimation of FFR values when calculated with intracoronary adenosine alone. The absolute mean difference between FFRic and FFRiv decreased with increasing intracoronary doses and was non-significant only for the 150-g dose (Figure 2). With the 60-g intracoronary adenosine dose, 32% of FFR values were less than the cutoff point of 0.75. Higher doses increased this percentage to 40%, 41%, 41%, and 46% for 90 g, 120 g, 150 g, and the intravenous administration, respectively (Figure 3). Five patients (10%) with a FFR value ⬎0.75 and 3 subjects (6%) with a FFR value ⬎0.80 with the 60-g intracoronary bolus reached a value below the cutoff point of 0.75 with the intravenous administration. This further reduction of FFR determined a change of strategy in
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Table III. Incremental effects of intravenous adenosine in patients with borderline values after intracoronary 60 g adenosine Patient 1 2 3 4 5 6 7 8
FFRic 60 g
FFRiv
Side effects with FFRiv
Strategy after FFRiv
0.75 0.78 0.75 0.75 0.75 0.80 0.81 0.82
0.74 0.55 0.74 0.71 0.68 0.76 0.78 0.79
Angina Angina Angina Angina
PCI PCI PCI PCI PCI PCI PCI deferred PCI deferred
ic, Intracoronary; iv, intravenous; FFR, fractional flow reserve; PCI, percutaneous coronary intervention.
most patients. All 5 subjects with FFRic values ⬎0.75 underwent coronary interventions after FFRiv measurement. Likewise, 1 of the 3 patients with FFRic values ⬎0.80 was treated with coronary angioplasty after FFRiv measurement. (Table III). Presence or absence of cardiovascular risk factors did not affect the results in any of the 5 dose-categories studied.
Discussion This study suggests that the administration of very high intracoronary adenosine boli is safe. Although a dose-response relationship is observed with higher intracoronary doses, intravenous adenosine was more potent in achieving maximal hyperemia. This is of particular relevance in subjects with borderline FFR results (0.75– 0.80). In such cases, an overestimation of FFR and an underestimation of lesion severity, because of suboptimal hyperemia, would result in false-negative values, with the consequence of deferring PCI in patients with functionally significant stenosis.
Clinical relevance of FFR and inducible coronary hyperemia Physiologic lesion assessment is a reliable method for assessing stenosis severity and a better indicator for the necessity of interventions than angiography alone.12 Of the different methods, FFR has several advantages in clinical practice. Namely, this measure is independent of hemodynamic variation,13 has an unequivocal normal value of 1.0 for each vessel,9 and has an ischemic threshold value of 0.75 tightly related to non-invasive indexes of inducible ischemia.1,14 However, even for FFR calculation, it is critical to achieve a maximal decrease in myocardial resistance for an accurate estimate of its value. With submaximal hyperemia, FFR will be artificially high, and therefore it underesti-
mates the functional severity of the lesion. However, the standard for induction of maximal pharmacological hyperemia has not yet been established. Equivalent results have been reported with intravenous and intracoronary adenosine, adenosine triphosphate, dipyridamole, and papaverine.2,12,15 Currently, intravenous adenosine or intracoronary papaverine is considered to be the gold standard for the induction of maximal coronary hyperemia.4,5 Unfortunately, in the catheterization laboratory, intravenous adenosine has several potential disadvantages compared with intracoronary boli. The latter is much easier to administer, has an extremely rapid onset of action, and has a short halflife, which makes it ideal for repetitive measurements. Furthermore, intracoronary adenosine is associated with fewer systemic adverse effects. No major adverse events related to the intracoronary drug administration have been reported from multiple large trials measuring FFR.16 However, intravenous adenosine may achieve a more complete and stable vasodilatation and is more convenient for the assessment of tandem lesions or diffuse coronary artery disease.
Insufficient maximal hyperemia with conventional intracoronary doses The ischemic threshold value of 0.75 has been validated with intravenous adenosine,1,9 but in clinical practice intracoronary adenosine is often preferred. According to previous protocols of FFR measurements, intracoronary adenosine is administered in a single bolus of 8 to 12 g in the right coronary artery and 15 to 18 g in the left coronary artery. However, it has been reported17 that intracoronary adenosine fails to produce maximal hyperemia in approximately 10% to 15% of cases. This suboptimal hyperemia may be caused by an atypical response to adenosine in some patients or, more convincingly, by inadequate dosing of the drug. A clear dose-response relationship for intracoronary adenosine doses as high as 100 g has been demonstrated in animals and humans.6,8,18 Di Segni et al18 observed that incremental doses (as high as 54 g for the left coronary artery and as high as 42 g for the right coronary artery) of intracoronary adenosine attained further vasodilatation and more accurate coronary flow velocity reserve (CVR) measurements. Similar findings were observed by Murtagh et al8 when assessing FFR of intermediate lesions with doses as high as 48 g. Therefore, at present, larger dosages (30 – 40 g for the right coronary artery and 40 – 80 g for the left coronary artery) are recommended.15,19 However, even with these higher doses, Jeremias et al17 demonstrated that intracoronary FFR overestimates intravenous FFR in 8.3% of patients. Our study demonstrates that very high intracoronary doses may limit such a difference. Because a former experience from our group demonstrated a clear dose-response relation-
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594 Casella et al
ship of FFR with doses as high as 60 g,7 we used a baseline adenosine dose of 60 g. However, in this study, despite this very high baseline dose, 10% of vessels with an initial FFR value ⬎0.75 had a subsequent value less than the cutoff point when additional higher doses of intracoronary adenosine or intravenous adenosine were administered. Thus, the threshold value of FFR requested for clinical decision-making was achieved in a subgroup of patients with incremental adenosine doses much higher than the recommended standard dose. This finding may be very important when assessing lesions with borderline values or results of interventions.
Limitations We did not study patients with a decreased sensitivity of the vascular system. Therefore, our results cannot be extrapolated to this patient population. It is speculated that higher doses of vasodilating drugs may be needed to yield a near maximal hyperemic response in patients with microvascular disorders and other conditions possibly accompanied by decreased sensitivity of the vascular system to adenosine. Arterial hypertension, diabetes mellitus, and myocardial infarction impair vasodilatation of the peripheral microvasculature. These pathologies affect a well-represented population in the real world, as suggested from the extremely high prevalence of hypertension and diabetes mellitus in this study. In addition, although very high intracoronary adenosine boli could be an acceptable alternative to intravenous adenosine, intracoronary adenosine produces a plateau hyperemic phase of approximately 4 seconds, which corresponds to 3 to 6 beats, but not to a true steady state. This absence of a prolonged hyperemic state is a strong limitation to FFRic measurement in case of mild to moderate tandem stenoses or in cases of diffuse disease when a pullback maneuver of the pressure wire is necessary to detect the exact location of the critical lesion. Finally, although CVR was not measured in this study, it is reasonable to assume a similar dose-response relationship on hyperemia for CVR assessment as well. This finding has already been demonstrated18 and implies that, at less than maximal vasodilation, CVR would be underestimated and therefore results in an over-assignment of lesions as abnormal.
Conclusions This study suggests a dose-response relationship on hyperemia for intracoronary adenosine doses ⬎60 g. The administration of very high intracoronary adenosine doses is safe and associated with fewer systemic adverse effects than standard intravenous adenosine. However, intravenous adenosine with a dose of 140 g/kg/min produced a more pronounced hyperemia
than intracoronary adenosine in moat patients and should be the preferred mode of application for the assessment of FFR, when available.
References 1. Pijls NHJ, 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;334:1703– 8. 2. Casella G, Klauss V, Stempfle H-U, et al. Beyond morphology: new coronary physiologic approaches to interventions. G Ital Cardiol 1999;29:174 – 81. 3. van der Voort PH, van Hagen E, Heyndrickx 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. 4. Wilson RF, Wyche K, Christensen BV, et al. Effects of adenosine on human coronary circulation. Circulation 1990;82:1595– 606. 5. Kern MJ, Deligonul U, Tatineni S, et al. Intravenous adenosine: continuous infusion and low dose bolus administration for determination of coronary vasodilator reserve in patients with and without coronary artery disease. J Am Coll Cardiol 1991;18:718 –29. 6. Jeremias A, Filardo SD, Whitbourn RJ, et al. Effect of intravenous and intracoronary adenosine 5’-triphosphate as compared with adenosine on coronary flow and pressure dynamics. Circulation 2000;101:318 –23. 7. Casella G, Rieber J, Schiele TM, et al. A randomized comparison of 4 doses of intracoronary adenosine in the assessment of fractional flow reserve. Z Kardiol 2003;92:627–32. 8. Murtagh B, Higano S, Lennon R, et al. Role of incremental doses of intracoronary adenosine for fractional flow reserve assessment. Am Heart J 2003;146:99 –105. 9. Pijls NH, van Gelder B, van der Voort P, et al. Fractional flow reserve: a useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation 1995;92: 3183–93. 10. Pijls NH, van Son JA, Kirkeeide RL, et al. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty. Circulation 1993;87:1354 – 67. 11. Rieber JH, Serruys PW, Kooijman CJ, et al. Assessment of short-, medium-, and long-term variations in the arterial dimensions from computer assisted quantitation of coronary cineangiograms. Circulation 1985;71:280 – 8. 12. Kern MJ, de Bruyne B, Pijls NH. From research to clinical practice: current role of intracoronary physiologically based decision making in the cardiac catheterization laboratory. J Am Coll Cardiol 1997;30:613–20. 13. de Bruyne B, Bartunek J, Sys SU, et al. 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;94:1842–9. 14. de Bruyne B, Bartunek J, Sys SU, et al. Relation between myocardial fractional flow reserve calculated from coronary pressure measurements and exercise-induced myocardial ischaemia. Circulation 1995;92:39 – 46.
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15. de Bruyne B, Pijls NHJ, Barbato E, et al. Intracoronary and intravenous adenosine 5’-triphosphate, adenosine, papaverine, and contrast medium to assess fractional flow reserve in humans. Circulation 2003;107:1877– 83. 16. Pijls NHJ, Klauss V, Siebert U, et al. Coronary pressure measurements after stenting predicts adverse events at follow-up: a multicenter registry. Circulation 2002;105:2950 – 4. 17. Jeremias A, Whitbourn RJ, Filardo SD, et al. Adequacy of intracoronary versus intravenous adenosine-induced maximal coronary
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hyperemia for fractional flow reserve measurements. Am Heart J 2000;140:651–7. 18. Di Segni E, Higano ST, Rihal CS, et al. Incremental doses of intracoronary adenosine for the assessment of coronary velocity reserve for clinical decision making. Cathet Cardiovasc Intervent 2001;54:34 – 40. 19. Pijls NHJ, de Bruyne B. Maximum hyperemic stimuli. In: Coronary pressure. 2nd ed. Dordrecht, The Netherlands; Kluwer Academic Publishers; 2000. p. 97–107.
Background
Achievement of maximal hyperemia of the coronary microcirculation is a prerequisite for the measurement of fractional flow reserve (FFR). Intravenous adenosine is considered the standard method, but its use in the catheterization laboratory is time consuming and expensive compared with intracoronary adenosine. Therefore, this study compared different high, intracoronary doses of adenosine for the potential to achieve a maximal hyperemia equivalent to the standard intravenous route.
Methods FFR was assessed in 50 patients with 50 intermediate lesions during cardiac catheterization. FFR was calculated as the ratio of the distal coronary pressure to the aortic pressure at hyperemia. Different incremental doses of intracoronary adenosine (60, 90, 120, and 150 g as boli) and a standard intravenous infusion of 140 g/kg/min were administered in a randomized fashion. Results Different incremental doses of intracoronary adenosine were well tolerated, with fewer systemic adverse effects than intravenous adenosine. At baseline, there were no significant differences for mean aortic and distal coronary pressure or heart rate in the different adenosine doses and routes. FFR decreased with increasing adenosine doses, with the lowest values observed with the 150-g intracoronary bolus and 140-g/kg/min dose of intravenous adenosine. All intracoronary doses, except the 150-g bolus, resulted in mean FFR values that were significantly (P ⬍.05) higher than FFR after the administration intravenous adenosine. Furthermore, 5 patients (10%) with a FFR value ⬎0.75 and 3 subjects (6%) with a FFR value ⬎0.80 who received a 60-g intracoronary bolus reached a value below the cutoff point of 0.75 with the intravenous administration. Conclusions
This study suggests a dose-response relationship on hyperemia for intracoronary adenosine doses ⬎60 g. The administration of very high intracoronary adenosine boli is safe and associated with fewer systemic adverse effects than standard intravenous adenosine. However, intravenous adenosine administration with 140 g/kg/min produced a more pronounced hyperemia than intracoronary adenosine in most patients and should be the preferred mode of application for the assessment of FFR. (Am Heart J 2004;148:590 –5.)
The measurement of fractional flow reserve (FFR) is commonly used in clinical practice to determine the hemodynamic significance of epicardial coronary stenoses detected at angiography.1 However, for an accurate calculation of FFR, a key point is to achieve a
From the aDepartment of Cardiology, Medizinische Poliklinik – Klinikum Innenstadt, Ludwig-Maximilians University, Munich, Germany, bDepartment of Cardiology, Ospedale Maggiore, Bologna, Italy, and cInstitute for Technology Assessment and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass. Submitted February 8, 2004; accepted April 14, 2004. Reprint requests: Gianni Casella, MD, Via Milani, 8, Imola (Bo), 40026, Italy. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2004.04.008
maximal vasodilatation to minimize the contribution of microvascular resistance.2 With suboptimal levels of coronary hyperemia, FFR will be artificially high, resulting in a potentially significant underestimation of the functional severity of the coronary stenosis. Adenosine, mainly intravenously, has been validated for FFR measurements in many studies.3 Compared with the intracoronary route, intravenous adenosine administration requires relatively large doses, and it is associated with more systemic adverse effects and costs.4,5 Thus, currently many cardiac catheterization laboratories prefer intracoronary adenosine for routine evaluation. However, several observations cast some doubts about the ability of the former 12- to 18-g boli of adenosine to achieve maximal vasodilatation in all patients,4,6 and higher dosages have been suggested.7,8
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Therefore, this study was designed to test the hypothesis that a dose-response relationship on hyperemia exists for intracoronary adenosine doses ⬎60 g and such very high intracoronary doses may achieve a vasodilatation of the coronary microcirculation comparable with that of the standard intravenous route.
Casella et al 591
Table I. Demographic data of the study population Study cohort (50 patients, 50 lesions) 66 ⫾ 8 40/10
A total of 50 patients were prospectively enrolled. The study population consisted of 40 men and 10 women with a mean age of 66 years (SD ⫾ 8 years; range, 52–76 years). Most patients had normal left ventricular function, and only intermediate coronary lesions were assessed. Exclusion criteria included acute coronary syndromes, prior myocardial infarction in the territory supplied by the target vessel, diffuse coronary stenoses, and atrioventricular conduction abnormalities in the electrocardiogram. All patients gave informed consent to participate in the study.
Age (y) Male/female Risk factors Hypertension Diabetes Smoking Hyperlipidemia Family history of CAD Angiographic parameters 3-Vessel disease Ejection fraction (%) Percent stenosis (%) Target vessel LAD LCx RCA
Study protocol
CAD, Coronary artery disease; LAD, left anterior descending artery; LCx, left circumflex artery; RCA, right coronary artery.
Methods Study population
Coronary angiography was performed with the standard femoral approach. Heparin was administered at the beginning of the procedure (5000 units). Non-ionic contrast material was used for all patients. The heart rate and arterial pressure were continuously monitored throughout the procedure. After coronary angiography, a 0.014-inch highfidelity pressure-recording guidewire (PressureWire, Radi Medical Systems, Uppsala, Sweden) was introduced through a 6F guiding catheter into the coronary artery. Special attention was given to avoid arterial pressure wave damping or variation of the measured coronary guide pressure. The guidewire was externally calibrated and then advanced to the distal tip of the catheter, as previously described.9 Afterward, it was verified that both the catheter and the pressure wire recorded equal pressures. The pressure wire was subsequently advanced into the coronary artery with the pressure sensor placed beyond the lesion site. Distal coronary and aortic pressures were measured at baseline and at maximal hyperemia. Pressure signals were continuously recorded at a paper speed of 25 mm/s, and a beat-to-beat analysis of mean pressure was performed automatically (Radi Analyzer, Radi Medical Systems, Uppsala, Sweden). Once a stable pressure signal was obtained, baseline measurements were recorded. In all patients, intracoronary nitroglycerin (0.25 mg) was administered before coronary angiography and was repeated before FFR measurements afterward.
Pharmacological protocol All patients received multiple boli of intracoronary adenosine. Incremental doses of intracoronary adenosine (60, 90, 120, and 150 g for both coronary arteries) were administered in a randomized fashion. Subsequent doses were given after pressure curves returned to baseline values. Each bolus was followed by a flush with saline. Thereafter, adenosine via a brachial or femoral vein at a dose of 140 g/kg/min was administered as an intravenous infusion until a steady-state hyperemia was achieved for a minimal duration of 1 minute. The electrocardiogram was simultaneously recorded.
44 (88%) 17 (34%) 10 (20%) 44 (88%) 22 (44%) 22 (44%) 61.2 ⫾ 12 64.6 ⫾ 12.5 27 (54%) 10 (20%) 13 (26%)
Calculations of pressure-derived FFR FFR is defined as the ratio of the hyperemic flow in a stenotic artery to the hyperemic flow in the same artery in the hypothetical case in which there is no stenosis present.10 FFR expresses maximum hyperemic blood flow in a stenotic vessel as a fraction of normal maximal blood flow in that vessel. FFR is calculated from intracoronary and aortic pressure measurements obtained during maximal hyperemia with this equation: FFR ⫽ Pd ⫺ Pv/Pa ⫺ Pv, or FFR ⫽ Pd/Pa (when Pv is negligible), in which Pa is the mean proximal coronary pressure (mean arterial pressure), Pd is the mean distal coronary pressure, and Pv is the mean central venous pressure. In this study, the simplified formula (in which Pv is considered negligible) was applied.
Coronary angiography The coronary angiogram was reviewed before coronary pressure was measured. Percent diameter stenosis was calculated with the guiding catheter as a scaling device.11
Statistical analysis Data are presented as the mean plus or minus SD. The Student paired t test was used to compare FFR values after different intracoronary adenosine doses and routes. Because this was an exploratory study, no correction for the performance of multiple statistical tests was applied. Results were considered statistically significant when the P value was ⬍.05.
Results Patient characteristics All 50 patients were included in the analysis. Demographic data are presented in Table I. Procedural suc-
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Figure 1
FFR values for different doses and routes (intracoronary and intravenous) of adenosine.
Figure 2
Figure 3
Percentage of patients having a FFR less than the cutoff value of 0.75 with increasing doses of adenosine.
Table II. Major side effects of different dosages and routes of administration of adenosine
Angina Dyspnoe Nausea A-V block
60 g
90 g
120 g
150 g
Ado IV
0 0 0 4 (8%)
0 0 0 3 (6%)
0 0 0 5 (10%)
0 0 0 8 (16%)
13 (26%) 8 (16%) 1 (2%) 3 (6%)
Ado IV, Intravenous adenosine.
Difference in mean FFR for different intracoronary doses compared with standard intravenous administration. The differences decrease with increasing intracoronary doses, and get non-significant for an intracoronary dose of 150 g.
cess was 100% for advancing the pressure wire distal to the stenosis. There were no procedure-related complications. Several systemic adverse effects (Table II) were observed during intravenous adenosine administration, whereas intracoronary boli elicited an asymptomatic transient atrioventricular block in as much as 16% of patients. Thirty-two patients (64%) underwent percutaneous coronary intervention (PCI) after FFR measurements.
FFR measurements At rest, the mean aortic and distal coronary blood pressure and the heart rate were not significantly different with the separate injections. The dose-response relationship in different adenosine doses and routes of administration and FFR are shown in Figure 1. The
mean FFR decreased with all doses, but the lowest values were achieved with the 150 g dose and with intravenous adenosine. For absolute values, in 25 patients (50%), the FFR values decreased when intracoronary doses ⬎60 g were administered. Thus, there was a clear dose-response relationship between intracoronary adenosine and FFR values. In addition, in 38 patients (76%), intravenous adenosine further decreased FFR. This decrease ranged from 0.01 to 0.23. This clearly demonstrates the potential overestimation of FFR values when calculated with intracoronary adenosine alone. The absolute mean difference between FFRic and FFRiv decreased with increasing intracoronary doses and was non-significant only for the 150-g dose (Figure 2). With the 60-g intracoronary adenosine dose, 32% of FFR values were less than the cutoff point of 0.75. Higher doses increased this percentage to 40%, 41%, 41%, and 46% for 90 g, 120 g, 150 g, and the intravenous administration, respectively (Figure 3). Five patients (10%) with a FFR value ⬎0.75 and 3 subjects (6%) with a FFR value ⬎0.80 with the 60-g intracoronary bolus reached a value below the cutoff point of 0.75 with the intravenous administration. This further reduction of FFR determined a change of strategy in
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Table III. Incremental effects of intravenous adenosine in patients with borderline values after intracoronary 60 g adenosine Patient 1 2 3 4 5 6 7 8
FFRic 60 g
FFRiv
Side effects with FFRiv
Strategy after FFRiv
0.75 0.78 0.75 0.75 0.75 0.80 0.81 0.82
0.74 0.55 0.74 0.71 0.68 0.76 0.78 0.79
Angina Angina Angina Angina
PCI PCI PCI PCI PCI PCI PCI deferred PCI deferred
ic, Intracoronary; iv, intravenous; FFR, fractional flow reserve; PCI, percutaneous coronary intervention.
most patients. All 5 subjects with FFRic values ⬎0.75 underwent coronary interventions after FFRiv measurement. Likewise, 1 of the 3 patients with FFRic values ⬎0.80 was treated with coronary angioplasty after FFRiv measurement. (Table III). Presence or absence of cardiovascular risk factors did not affect the results in any of the 5 dose-categories studied.
Discussion This study suggests that the administration of very high intracoronary adenosine boli is safe. Although a dose-response relationship is observed with higher intracoronary doses, intravenous adenosine was more potent in achieving maximal hyperemia. This is of particular relevance in subjects with borderline FFR results (0.75– 0.80). In such cases, an overestimation of FFR and an underestimation of lesion severity, because of suboptimal hyperemia, would result in false-negative values, with the consequence of deferring PCI in patients with functionally significant stenosis.
Clinical relevance of FFR and inducible coronary hyperemia Physiologic lesion assessment is a reliable method for assessing stenosis severity and a better indicator for the necessity of interventions than angiography alone.12 Of the different methods, FFR has several advantages in clinical practice. Namely, this measure is independent of hemodynamic variation,13 has an unequivocal normal value of 1.0 for each vessel,9 and has an ischemic threshold value of 0.75 tightly related to non-invasive indexes of inducible ischemia.1,14 However, even for FFR calculation, it is critical to achieve a maximal decrease in myocardial resistance for an accurate estimate of its value. With submaximal hyperemia, FFR will be artificially high, and therefore it underesti-
mates the functional severity of the lesion. However, the standard for induction of maximal pharmacological hyperemia has not yet been established. Equivalent results have been reported with intravenous and intracoronary adenosine, adenosine triphosphate, dipyridamole, and papaverine.2,12,15 Currently, intravenous adenosine or intracoronary papaverine is considered to be the gold standard for the induction of maximal coronary hyperemia.4,5 Unfortunately, in the catheterization laboratory, intravenous adenosine has several potential disadvantages compared with intracoronary boli. The latter is much easier to administer, has an extremely rapid onset of action, and has a short halflife, which makes it ideal for repetitive measurements. Furthermore, intracoronary adenosine is associated with fewer systemic adverse effects. No major adverse events related to the intracoronary drug administration have been reported from multiple large trials measuring FFR.16 However, intravenous adenosine may achieve a more complete and stable vasodilatation and is more convenient for the assessment of tandem lesions or diffuse coronary artery disease.
Insufficient maximal hyperemia with conventional intracoronary doses The ischemic threshold value of 0.75 has been validated with intravenous adenosine,1,9 but in clinical practice intracoronary adenosine is often preferred. According to previous protocols of FFR measurements, intracoronary adenosine is administered in a single bolus of 8 to 12 g in the right coronary artery and 15 to 18 g in the left coronary artery. However, it has been reported17 that intracoronary adenosine fails to produce maximal hyperemia in approximately 10% to 15% of cases. This suboptimal hyperemia may be caused by an atypical response to adenosine in some patients or, more convincingly, by inadequate dosing of the drug. A clear dose-response relationship for intracoronary adenosine doses as high as 100 g has been demonstrated in animals and humans.6,8,18 Di Segni et al18 observed that incremental doses (as high as 54 g for the left coronary artery and as high as 42 g for the right coronary artery) of intracoronary adenosine attained further vasodilatation and more accurate coronary flow velocity reserve (CVR) measurements. Similar findings were observed by Murtagh et al8 when assessing FFR of intermediate lesions with doses as high as 48 g. Therefore, at present, larger dosages (30 – 40 g for the right coronary artery and 40 – 80 g for the left coronary artery) are recommended.15,19 However, even with these higher doses, Jeremias et al17 demonstrated that intracoronary FFR overestimates intravenous FFR in 8.3% of patients. Our study demonstrates that very high intracoronary doses may limit such a difference. Because a former experience from our group demonstrated a clear dose-response relation-
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ship of FFR with doses as high as 60 g,7 we used a baseline adenosine dose of 60 g. However, in this study, despite this very high baseline dose, 10% of vessels with an initial FFR value ⬎0.75 had a subsequent value less than the cutoff point when additional higher doses of intracoronary adenosine or intravenous adenosine were administered. Thus, the threshold value of FFR requested for clinical decision-making was achieved in a subgroup of patients with incremental adenosine doses much higher than the recommended standard dose. This finding may be very important when assessing lesions with borderline values or results of interventions.
Limitations We did not study patients with a decreased sensitivity of the vascular system. Therefore, our results cannot be extrapolated to this patient population. It is speculated that higher doses of vasodilating drugs may be needed to yield a near maximal hyperemic response in patients with microvascular disorders and other conditions possibly accompanied by decreased sensitivity of the vascular system to adenosine. Arterial hypertension, diabetes mellitus, and myocardial infarction impair vasodilatation of the peripheral microvasculature. These pathologies affect a well-represented population in the real world, as suggested from the extremely high prevalence of hypertension and diabetes mellitus in this study. In addition, although very high intracoronary adenosine boli could be an acceptable alternative to intravenous adenosine, intracoronary adenosine produces a plateau hyperemic phase of approximately 4 seconds, which corresponds to 3 to 6 beats, but not to a true steady state. This absence of a prolonged hyperemic state is a strong limitation to FFRic measurement in case of mild to moderate tandem stenoses or in cases of diffuse disease when a pullback maneuver of the pressure wire is necessary to detect the exact location of the critical lesion. Finally, although CVR was not measured in this study, it is reasonable to assume a similar dose-response relationship on hyperemia for CVR assessment as well. This finding has already been demonstrated18 and implies that, at less than maximal vasodilation, CVR would be underestimated and therefore results in an over-assignment of lesions as abnormal.
Conclusions This study suggests a dose-response relationship on hyperemia for intracoronary adenosine doses ⬎60 g. The administration of very high intracoronary adenosine doses is safe and associated with fewer systemic adverse effects than standard intravenous adenosine. However, intravenous adenosine with a dose of 140 g/kg/min produced a more pronounced hyperemia
than intracoronary adenosine in moat patients and should be the preferred mode of application for the assessment of FFR, when available.
References 1. Pijls NHJ, 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;334:1703– 8. 2. Casella G, Klauss V, Stempfle H-U, et al. Beyond morphology: new coronary physiologic approaches to interventions. G Ital Cardiol 1999;29:174 – 81. 3. van der Voort PH, van Hagen E, Heyndrickx 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. 4. Wilson RF, Wyche K, Christensen BV, et al. Effects of adenosine on human coronary circulation. Circulation 1990;82:1595– 606. 5. Kern MJ, Deligonul U, Tatineni S, et al. Intravenous adenosine: continuous infusion and low dose bolus administration for determination of coronary vasodilator reserve in patients with and without coronary artery disease. J Am Coll Cardiol 1991;18:718 –29. 6. Jeremias A, Filardo SD, Whitbourn RJ, et al. Effect of intravenous and intracoronary adenosine 5’-triphosphate as compared with adenosine on coronary flow and pressure dynamics. Circulation 2000;101:318 –23. 7. Casella G, Rieber J, Schiele TM, et al. A randomized comparison of 4 doses of intracoronary adenosine in the assessment of fractional flow reserve. Z Kardiol 2003;92:627–32. 8. Murtagh B, Higano S, Lennon R, et al. Role of incremental doses of intracoronary adenosine for fractional flow reserve assessment. Am Heart J 2003;146:99 –105. 9. Pijls NH, van Gelder B, van der Voort P, et al. Fractional flow reserve: a useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation 1995;92: 3183–93. 10. Pijls NH, van Son JA, Kirkeeide RL, et al. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty. Circulation 1993;87:1354 – 67. 11. Rieber JH, Serruys PW, Kooijman CJ, et al. Assessment of short-, medium-, and long-term variations in the arterial dimensions from computer assisted quantitation of coronary cineangiograms. Circulation 1985;71:280 – 8. 12. Kern MJ, de Bruyne B, Pijls NH. From research to clinical practice: current role of intracoronary physiologically based decision making in the cardiac catheterization laboratory. J Am Coll Cardiol 1997;30:613–20. 13. de Bruyne B, Bartunek J, Sys SU, et al. 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;94:1842–9. 14. de Bruyne B, Bartunek J, Sys SU, et al. Relation between myocardial fractional flow reserve calculated from coronary pressure measurements and exercise-induced myocardial ischaemia. Circulation 1995;92:39 – 46.
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15. de Bruyne B, Pijls NHJ, Barbato E, et al. Intracoronary and intravenous adenosine 5’-triphosphate, adenosine, papaverine, and contrast medium to assess fractional flow reserve in humans. Circulation 2003;107:1877– 83. 16. Pijls NHJ, Klauss V, Siebert U, et al. Coronary pressure measurements after stenting predicts adverse events at follow-up: a multicenter registry. Circulation 2002;105:2950 – 4. 17. Jeremias A, Whitbourn RJ, Filardo SD, et al. Adequacy of intracoronary versus intravenous adenosine-induced maximal coronary
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hyperemia for fractional flow reserve measurements. Am Heart J 2000;140:651–7. 18. Di Segni E, Higano ST, Rihal CS, et al. Incremental doses of intracoronary adenosine for the assessment of coronary velocity reserve for clinical decision making. Cathet Cardiovasc Intervent 2001;54:34 – 40. 19. Pijls NHJ, de Bruyne B. Maximum hyperemic stimuli. In: Coronary pressure. 2nd ed. Dordrecht, The Netherlands; Kluwer Academic Publishers; 2000. p. 97–107.