Intracoronary and Intravenous Adenosine 5′-Triphosphate, Adenosine, Papaverine, and Contrast Medium to Assess Fractional Flow Reserve in Humans
Background— Inducing both maximal and steady-state coronary hyperemia is of clinical importance to take full advantage of fractional flow reserve measurements. The present study compares different dosages and routes of administration of adenosine 5′-triphosphate (ATP), adenosine, contrast medium, and papaverine regarding their potential to achieve both maximal and steady-state hyperemia.
Methods and Results— In 21 patients with an isolated coronary stenosis, coronary vasodilation was induced successively by papaverine (20 mg intracoronary), adenosine (20 and 40 μg intracoronary), ATP (20 and 40 μg intracoronary), iohexol (6 mL intracoronary), adenosine or ATP through an antecubital vein (140 and 180 μg · kg−1 · min−1), or adenosine or ATP through a femoral vein (140 and 180 μg · kg−1 · min−1). Because vessel dimensions did not change, the ratio of distal coronary pressure (Pd) to aortic pressure (Pa) was used as an index of myocardial resistance. Pd/Pa was 0.77±0.21 at rest and decreased to 0.61±0.21 after papaverine. Pd/Pa decreased to a similar level with all other vasodilators, except with contrast medium (0.68±0.21; P<0.01 versus papaverine). Steady-state hyperemia could only be obtained by intracoronary papaverine and by intravenous ATP or adenosine. In another 23 patients, an intravenous infusion of ATP was varied from 0 to 280 μg · kg−1 · min−1. At doses >140 μg · kg−1 · min−1, there was neither a further decrease in Pd/Pa ratio nor a further increase in coronary flow velocities.
Conclusion— Provided sufficient dosages are used, ATP, adenosine, and papaverine (but not contrast medium) induce maximal hyperemia and are therefore suitable to assess fractional flow reserve. Only intracoronary papaverine and intravenous ATP or adenosine induce steady-state hyperemia enabling a pressure pullback maneuver that is useful in assessing diffuse coronary atherosclerosis.
Received October 28, 2002; revision received January 21, 2003; accepted January 28, 2003.
Coronary flow reserve (CFR) and fractional flow reserve (FFR) are 2 indices commonly used in clinical practice to determine the hemodynamic significance of epicardial coronary stenoses detected with an angiogram. In the catheterization laboratory, CFR is defined as maximal flow divided by baseline flow1 and can be derived from flow velocity or thermodilution.2,3 FFR is defined as the ratio of maximal flow in the stenotic territory to maximal flow in the same territory but without stenosis and can be calculated from coronary pressure measurements.4,5 A less than maximal vasodilation would underestimate CFR and overestimate FFR and might lead to erroneous clinical decision-making.
Adenosine has been validated for CFR and FFR measurements in many studies, mostly those comparing it with papaverine.6–8 However, in a more detailed dose-response study, the maximal tested dose of adenosine was 16 μg for the left coronary artery, 12 μg for the right coronary artery, and 140 μg · kg−1 · min−1 as an intravenous infusion.7 With this regimen, 16% of patients did not reach a maximal hyperemic response compared with papaverine. Another study suggested that only dosages of adenosine larger by 2 orders of magnitude ensure maximal vasodilation.9 Animal experiments also suggest that higher dosages than commonly proposed might be needed to achieve complete hyperemia.10 In certain patient subsets, the different vasodilators were reported to exert different effects on myocardial resistances.11 In addition, in animals, maximal hyperemic response, as observed after coronary occlusion, was not achieved by the pharmacological stimuli.10 In addition, a recent study established the usefulness of more prolonged vasodilation required for pressure wire pullback procedure in assessing diffuse coronary atherosclerosis.12
The aim of the present study was to compare, side-by-side, the effects of different dosages and routes of administrations of adenosine 5′-triphosphate (ATP) and adenosine with intracoronary administration of contrast medium and papaverine regarding their potential for inducing maximal and steady-state hyperemia.
Group 1 consisted of 21 patients (4 women; mean age, 58±8 years) with normal left ventricular function and in whom a one-vessel angioplasty was scheduled. The stenosis to be treated was located in the left anterior descending (n=6), the left circumflex (n=4), or right coronary artery (n=11).
Group 2 consisted of 12 patients (4 women; mean age, 60±9 years) scheduled for a one-vessel angioplasty. The stenosis to be treated was located in the left anterior descending (n=2), the left circumflex (n=1), or the right coronary artery (n=9). Left ventricular function was normal in 8 patients. In 4 other patients, there was a hypokinesia in the territory, depending on the stenosis under study.
Group 3 consisted of 11 patients (2 women; mean age, 58±11 years) scheduled for angioplasty and in whom pressure and flow velocity measurements were obtained in the contralateral, nonstenotic, coronary artery (6 left anterior descending arteries and 5 right coronary arteries). The study protocol was approved by the medical ethics committees of the OLV Hospital, Aalst, Belgium, and of the Catharina Hospital, Eindhoven, the Netherlands. Informed consent was obtained from all patients.
Figure 1 outlines the study protocols applied in the 3 groups of patients.
After insertion of a femoral sheath, a 6 or 7F guiding catheter was advanced into the coronary ostium. At least 30 s after administration of 0.2 mg of intracoronary isosorbide dinitrate, a high quality angiogram was obtained. A pressure monitoring guidewire (PressureWire, Radi Medical) was first advanced up to the tip of the guiding catheter to ensure that the pressures recorded by the guiding catheter (aortic pressure, Pa) and by the Pressure Wire were identical. The wire was then advanced in the distal part of the vessel (distal coronary pressure, Pd). Heart rate, Pa, and Pd were continuously recorded and digitally stored. FFR was calculated by dividing mean Pd by mean Pa during maximal hyperemia. The time to maximal vasodilation (time needed to reach <90% of the minimal value of Pd/Pa after the injection of the vasodilator) and the plateau phase (the time during which Pd/Pa ratio remained at <90% of its minimal value) were computed. In group 3, Pd and flow velocity (FloWire, Jomed) were measured simultaneously.
In group 1, the following intracoronary hyperemic stimuli were successively administered as a bolus: papaverine 20 mg (n=21), adenosine 20 μg (n=21) and 40 μg (n=19), ATP 20 μg (n=21) and 40 μg (n=18), and Iohexol 6 mL (n=21). Thereafter, the following intravenous stimuli were administered: adenosine via the femoral vein at 140 (n=19) and 180 μg · kg−1 · min−1 (n=19), ATP via the femoral vein at 140 (n=21) and 180 μg · kg−1 · min−1 (n=18), adenosine via the antecubital vein at 140 (n=18) and 180 μg · kg−1 · min−1 (n=18), and ATP via the antecubital vein at 140 (n=17) and 180 μg · kg−1 · min−1 (n=17). In 17 patients, a second intracoronary bolus of papaverine was given at the end of the protocol. The next hyperemic stimulus was given when Pa, Pd, and heart rate had returned to their baseline value (except between the dosages of 140 and 180 μg · kg−1 · min−1 for the various intravenous routes of administration of ATP and adenosine). In the latter cases, the dosage of ATP or adenosine was merely increased to 180 μg · kg−1 · min−1 after a steady-state at 140 μg · kg−1 · min−1 had been reached.
In group 2, a dose-response curve was obtained by computing the Pd/Pa ratio at baseline and during intravenous femoral infusion of ATP at dosages varying between 0 and 280 μg · kg−1 · min−1.
In group 3, a dose-response curve was obtained by simultaneously measuring flow velocities and the Pd/Pa ratio in a nonstenotic artery at baseline and during intravenous femoral infusion of ATP at dosages varying between 0 and 280 μg · kg−1 · min−1.
Quantitative Coronary Angiography
After intracoronary nitrates but before the first vasodilatory stimulus, quantitative coronary angiography of the stenotic segment was performed in all patients. During the last vasodilatory stimulus, angiography was repeated in the same projection in 13 patients in group 1 and in all patients from group 2. Reference diameter, minimum lumen diameter, and diameter stenosis were calculated using the guiding catheter as a scaling device.13 In group 3, the reference diameter of the artery was measured 3 to 4 mm distal to the tip of the Doppler guidewire before the first and during the last vasodilatory stimulus.
Data are expressed as mean±SD. Statistical comparisons between the values of Pd/Pa and changes in Pa and in heart rate were made by ANOVA, followed by the Newman-Keuls test. Changes in vessel dimensions before and at the end of the study protocol were analyzed by Student’s paired t test. A probability value <0.05 was considered statistically significant. The variability (Var) between the Pd/Pa values with the different vasodilators in a given patient (intrapatient variability) were calculated.
Hemodynamic and Angiographic Characteristics
The wide range of values of FFR illustrates the wide range of the severity of the stenoses studied in groups 1 and 2 (Table 1). There was no difference in average vessel dimensions before the first and during the last hyperemic stimulus, suggesting that the epicardial vessels were fully dilated after intracoronary nitrates. No correlation was found between individual changes in minimum lumen diameter, diameter stenosis, and the difference in Pd/Pa ratio between the different pharmacological stimuli.
Effects of the Different Vasodilators on Pd/Pa (Group 1)
Figure 2 shows the individual values of Pd/Pa ratio at baseline (ie, before the first injection of papaverine) and at peak action of the different vasodilators administered by the different routes. The mean values of Pd/Pa ratios with the different vasodilatory stimuli are given in Table 2. There was no significant difference in minimal Pd/Pa ratio between papaverine, adenosine, and ATP, given either intracoronarily or intravenously. In contrast, the intracoronary bolus administration of 6 mL of Iohexol did produce a significantly weaker effect than all other stimuli.
This was particularly pronounced in stenoses with a papaverine-induced FFR >0.55. Likewise, there were no significant differences between the different intravenous routes of administration (brachial or femoral) of adenosine or ATP. However, when considering only patients with an FFR between 0.70 and 0.86 (n=11), there was a small but significant difference between the mean of all FFR values obtained by intracoronary and intravenous adenosine or ATP (0.78±0.01 versus 0.75±0.01 for intracoronary and intravenous routes, respectively; P=0.02). In the latter patients, FFR values obtained by the intracoronary administration of 20 μg of adenosine or ATP was not significantly larger than the values obtained after the intracoronary administration of 40 μg (0.79±0.01 versus 0.76±0.01, respectively; P=NS).
The intrapatient variability in Pd/Pa value for the different vasodilators (with the exception of contrast medium) was 8±4% (range, 3% to 19%) for all group 1 patients and 7±4% (range, 3% to 15%) for the patients with a FFR between 0.70 and 0.86.
The mean time to maximal vasodilation and the mean duration of the plateau phase for each vasodilatory stimulus are given in Table 2. There was no significant difference between the time to maximal vasodilation for intracoronary papaverine, adenosine, and ATP. The plateau phase after intracoronary papaverine was significantly longer than that after both intracoronary adenosine and ATP at 20 and 40 μg. In patients with an FFR>0.75 (n=9), adenosine and ATP hardly induced a plateau phase.
Systemic Effects of the Different Vasodilators (Group 1)
All vasodilators produced a significant decrease in blood pressure, but the decrease was significantly more pronounced with the intravenous than with the intracoronary routes of administration (Figure 3). Intravenous (brachial and femoral) administration of adenosine or ATP (at 140 and 180 μg · kg−1 · min−1) produced a significant increase in heart rate, but the intracoronary administration of papaverine, adenosine, or ATP did not (Figure 3).
Dose-Effect Relationship of Intravenous ATP (Groups 2 and 3)
Reference diameter, minimum lumen diameter, and percent diameter stenosis (group 2) and reference diameter (group 3) did not change before and during the highest dosage of intravenous ATP infusion (Table 1). In group 2, Pd/Pa decreased significantly from 0.93±0.06 at baseline to 0.84±0.16 and to 0.78±0.14 during the intravenous infusion of 70 and 140 μg · kg−1 · min−1 of ATP, respectively, but did not decrease further when the dosage was increased to 210 (0.77±0.17) or 280 μg · kg−1 · min−1 ATP (0.77±0.14; Figure 4). In contrast, a continued decrease in mean blood pressure occurred (96±14, 88±14, 75±15, 66±13, and 58±15 mm Hg, respectively; all P<0.05) when ATP was progressively increased from 0 to 280 μg · kg−1 · min−1 (Figure 4).
An example of simultaneous pressure and coronary flow velocity tracing in a nonstenotic artery as performed in group 3 patients is given in Figure 5. As shown in Figure 6, coronary flow velocity increased significantly from 21±3 cm/s at baseline to 28±6 cm/s and 50±4 cm/s during the intravenous infusion of 70 and 140 μg · kg−1 · min−1 ATP, respectively, but did not increase further when the dosage was increased to 210 (51±4 cm/s) or 280 μg · kg−1 · min−1 ATP (47±4 cm/s). This increase in flow velocities was mirrored by a decrease in Pd/Pa ratio and in the ratio of Pd/average flow velocity, thus suggesting that myocardial resistance does not decrease further with dosages of ATP >140 μg · kg−1 · min−1.
The present study, which was conducted in patients with a wide range of stenosis severity, is the first to compare, side-by-side, several routes of administration of the presently available coronary vasodilators in humans. The results can be summarized as follows: (1) ATP and adenosine administered either intracoronarily (at least 20 μg) or intravenously (at least 140 μg · kg−1 · min−1), but not contrast medium, have the same vasodilatory effects as intracoronary papaverine (20 mg); (2) only intracoronary papaverine and intravenous ATP or adenosine induce steady-state hyperemia enabling a pressure pullback maneuver; and (3) in contrast to animal data, higher dosages of intravenous ATP beyond the currently recommended dosage do not further increase coronary blood flow in humans.
Pd as an Index of Myocardial Resistance
In the presence of an epicardial stenosis, pharmacological vasodilation of resistance vessels induces a decrease in coronary pressure distal to the stenosis and an increase in trans-stenotic pressure gradient and in trans-stenotic flow. At constant Pa, changes in Pd can mainly be due to changes in the severity of the epicardial stenosis (ie, changes in epicardial resistance), changes in myocardial resistance, or a combination of both. In cases with a fixed stenosis, changes in Pd are related to changes in myocardial resistance. In the present study, no changes were observed in stenosis dimensions before and at the end of the study protocol. Therefore, changes in Pd (corrected for possible changes in Pa) can be considered an index of changes in myocardial resistance. In addition, the Pd/Pa ratio during papaverine was similar before and at the end of the protocol, suggesting that the administration of the different vasodilators by itself did not induce any change in the capacity of the myocardial resistive vessels to dilate.
ATP is a precursor of adenosine and would therefore be expected to last longer than adenosine. The safety of ATP has been established in humans.14–16 In canines, ATP seems to be slightly more potent than adenosine, and it was shown that coronary blood flow could be further augmented with an increase of the dosage.10 However, in humans, the present data indicate equipotency of ATP and adenosine and do not confirm a longer lasting effect. Increasing the dosages of ATP beyond the recommended dosage of 140 μg · kg−1 · min−1 did not induce a further decline of the resistance index but induced a marked decline in systemic blood pressure in some patients. Taken together, the latter findings confirm that FFR is independent of systemic blood pressure or, stated another way, that during maximal hyperemia, Pd is proportional to Pa.
Dosages and Routes of Administration
The effects of ATP, adenosine, and contrast medium were compared with a bolus administration of 20 mg of papaverine. This slightly higher dosage than that usually recommended was chosen to ensure a truly maximal pharmacological vasodilation. In the present study, an intracoronary bolus of 20 and 40 μg of ATP or adenosine induced similar effects. However, in patients with an FFR between 0.70 and 0.86 (ie, those in whom achieving maximal hyperemia is crucial), there was a trend toward a lower Pd/Pa ratio with a 40 μg bolus of ATP. Because spillover in the aorta of the drugs given as an intracoronary bolus is common and cannot be controlled for, it might therefore be preferable to give larger dosages (20 to 40 μg) than the recommended intracoronary dosages (12 to 16 μg). For the intravenous route, the vasodilatory action of 140 μg · kg−1 · min−1 of both ATP and adenosine could not be surpassed by increasing the perfusion rate to 180, 210, or 240 μg · kg−1 · min−1. Using positron emission tomography, Kaufmann et al17 also found, in a small number of patients, that coronary resistance did not further decrease when the intravenous infusion of adenosine was increased from 140 to 170 and 200 μg · kg−1 · min−1. In 3 patients, intravenous administration of ATP or adenosine produced wide fluctuations of coronary resistance. This was not observed when ATP or adenosine was given via the femoral vein. The latter route of administration at a dosage of 140 μg · kg−1 · min−1 is therefore preferred when steady-state vasodilation is crucial. This is particularly true when a pullback maneuver of the pressure sensor to detect the exact location of abnormal resistance along the epicardial vessel has to be done. When given as an intracoronary bolus, ATP and adenosine produce a plateau hyperemic phase of ≈4 s, which corresponds to 3 to 6 beats but not to a true steady state. This absence of prolonged hyperemic state is particularly striking in case of mild to moderate stenoses, in which the measurements of hyperemic physiological indices is of critical importance for clinical decision-making.
The use of the Pd/Pa ratio as an index of myocardial resistance without direct measurement of coronary flow warrants a word of caution. First, it relies on the assumption that the epicardial stenosis does not change. The design of the study cannot exclude that some minor changes occurred with other vasodilatory stimuli than papaverine. Major changes are unlikely because vasodilatory stimuli had been preceded by the administration of intracoronary nitrates. However, given the small minimum luminal diameters involved and potentially steep pressure/flow relations at such small diameters,18 concern is raised about the interpretation of changes in Pd/Pa in an individual patient when neither flow nor stenosis geometry are known. Second, the Pd/Pa ratio does not entirely account for back pressure and zero-flow pressure, which might play a role in resistance to flow at very low Pa, like that seen in group 2 patients during infusion of high dosages of ATP. In group 3 patients, in whom such pronounced decreased in systemic pressure was not observed, flow velocity did not increased further nor did Pd/Pa decrease further beyond 140 μg · kg−1 · min−1.
Given the relatively small sample size, we could not exclude the possibility that in some subsets of patients (left ventricular hypertrophy, post-infarction), a particular pharmacological stimulus or route of administration may not totally exhaust myocardial resistance.
Summary and Clinical Implications
An intracoronary bolus of ATP or adenosine (20 to 40 μg) induces a similar degree of hyperemia as in intracoronary bolus of 20 mg papaverine in humans. However, and in contrast to intracoronary papaverine, intracoronary ATP and adenosine often fail to induce true steady-state hyperemia. Only intracoronary papaverine (20 mg) and intravenous ATP or adenosine (140 μg · kg−1 · min−1) induce complete, true steady-state hyperemia to enable a pressure pullback maneuver. The latter is the easiest means for assessing (segment by segment) the conductance of the epicardial artery, especially in cases with diffuse disease.
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