Intravenous adenosine is considered the drug of choice to obtain maximum hyperemia in the measurement of the fractional flow reserve (FFR). However, comparative studies performed between intravenous and intracoronary administration have not used high doses of intracoronary adenosine. The present study compared the efficacy and safety of high doses of intracoronary adenosine to intravenous administration when calculating the FFR. Intracoronary bolus doses of 60, 180, 300, and 600 μg adenosine were compared to an intravenous administration of 140 μg/kg/min, 200 μg/kg/min, and 140 μg/kg/min plus an intracoronary bolus of 120 μg. All the cases were performed using the radial approach. FFR was assessed in 102 patients with 108 intermediate lesions by an intracoronary pressure wire. The intracoronary dose of 60 μg was associated with a significantly greater FFR compared to the intravenous infusion (0.02 ± 0.03, p = 0.001). The intracoronary doses of 300 (−0.01 ± 0.00; p = 0.006) and 600 μg (−0.02 ± 0.00; p <0.0005) were significantly associated with a smaller FFR compared to the intravenous infusion. An intracoronary dose of 600 μg revealed a significantly greater percentage of lesions with an FFR <0.80 compared to intravenous infusion at 140 μg/kg/min (37.6 vs 31.5%; p <0.05) and 200 μg/kg/min (37.6 vs 32.4%; p <0.05) and compared to intracoronary doses of 60 (26.9%) and 180 μg (31.5%). In conclusion, an intracoronary bolus dose >300 μg can be equal to or more effective than an intravenous infusion of adenosine in achieving maximum hyperemia when calculating the FFR. Its use could simplify these procedures without having an effect on safety.
Determining the fractional flow reserve (FFR) using a coronary pressure wire has been established as the preferred method to determine the functional repercussion of coronary lesions in the catheterization laboratory. For the correct calculation of the FFR, it is indispensable to achieve maximum hyperemia. Adenosine is the pharmacologic agent used most frequently to obtain maximum hyperemia. Its administration in bolus intracoronary doses is simple, inexpensive, and practically free of side effects. The use of intravenous adenosine is also safe but is more expensive and generally requires a longer preparation time and catheterization of a central vein, a limitation in procedures performed using a radial approach. However, the use of intravenous adenosine is considered the method of choice to obtain hyperemia. The verification in recent studies that higher doses of intracoronary adenosine produce a greater grade of hyperemia without compromising safety suggests that at greater doses, intracoronary adenosine could be as efficient as intravenous adenosine in obtaining maximum hyperemia. The aim of the present study was to compare the safety and efficacy of obtaining maximum hyperemia using high-dose intracoronary boluses of adenosine with intravenous administration.
Methods
From April 2011 to December 2011, all patients considered to have an indication for an intracoronary pressure wire study, because of a presentation with coronary stenosis of intermediate severity (visual estimation 40% to 70%) were included in the present study. The exclusion criteria were a procedure performed with a femoral approach and the lack of the capacity, or refusal, to provide written informed consent. All patients provided informed consent to participate in the present study, with a total of 102 patients with 108 lesions included.
All the procedures were performed using the radial approach. The left radial artery was preferred over the right, unless it was not possible to access it. Before the procedure, all patients were given aspirin (100 mg/day or a loading dose of 300 mg, if not taken previously). Immediately after catheterization, all patients received, by way of the radial artery, a “cocktail” of 5,000 IU of sodium heparin and 2.5 mg of verapamil. Before introducing the coronary pressure wire in the coronary artery, a corresponding dose of sodium heparin was administered to a total dose of 100 IU/kg. A nonionic contrast agent (iodixanol) was used in all procedures. All studies were performed through a 6F catheter guide. After the decision to perform the study with a pressure wire, an antebrachial vein (cephalic or basilic) of the ipsilateral or contralateral arm to the one with the radial access was catheterized. Through the venous catheter, a 5F arterial introducer was positioned, through which we introduced a diagnostic Judkins 4F catheter, until its distal end was localized in the right atrium. This catheter was connected to a continuous perfusion pump to ensure central administration of intravenous adenosine at the programmed dose.
The method to calculate FFR has been previously described. Before initiating the functional study, 200 μg of intracoronary nitroglycerin was administered through the guide catheter. The functional evaluation was performed using a 0.014-in. Pressure-Wire Certus or Pressure-Wire Airis (St. Jude Medical Systems AB, Uppsala, Sweden) or Volcano Primewire (Volcano, Rancho Cordova, California) pressure wire. The pressure wire was externally calibrated and then advanced to the distal tip of the catheter to verify the equalization between the pressure curves recorded through the catheter and pressure wire. The pressure wire was subsequently advanced into the coronary artery, until its sensor was positioned ≥10 mm beyond the studied lesion. The FFR was measured after a beat-to-beat analysis between the mean aortic pressures (at the distal end of the guide catheter) and the pressure distal to the lesion (measured by the pressure wire) during maximum hyperemia. This calculation was performed, assuming that R in the maximum hyperemia conditions cancelled out in the equation and that the central venous pressure was negligible and generally ignored in the original formula: FFR = [(distal pressure − central venous pressure)/resistance]/[(aortic pressure − central venous pressure)/resistance]. At least 2 measurement of FFR were performed for each intracoronary dose. When measuring the FFR with intracoronary adenosine, special care was taken to avoid wedging the catheter in the coronary ostium after administration of the bolus drug. When damping was observed, the guiding catheter was pulled back a few millimeters into the aorta after the intracoronary injection. Intravenous infusion was performed with the distal end of the catheter guide outside the coronary ostium.
A protocol of increasing doses of intracoronary adenosine boluses (60, 180, 300, and 600 μg) was used for all patients. Two measurements of FFR were performed per dose. Each bolus was followed by a flush of saline. The beat-to-beat measurement of FFR was started 3 seconds after bolus administration. The administration of the next bolus was not performed until the pressure curves returned to the baseline values. After the end of the protocol for intracoronary bolus administration, intravenous infusion of adenosine was begun at 140 μg/kg/min. After the measurement of FFR 2 minutes after beginning the intravenous infusion, 2 intracoronary boluses of 120 μg adenosine were administered without stopping the intravenous infusion, using the same technique used with the initial boluses administered. The protocol was ended by increasing the intravenous infusion to 200 μg/kg/min. In the event of a pause of >3 seconds after an intracoronary bolus dose of adenosine, no additional doses were administered.
Quantitative analysis was performed offline by an experienced interventional cardiologist, who was unaware of the functional study results, using MEDIS QAngio XA, version 7.1 (Medis Medical Imaging Systems, Leiden, The Netherlands) software.
Continuous variables are presented as median ± SD and categorical variables as absolute values or percentages. The data for the mean arterial pressure and cardiac frequency, before and after adenosine intravenous infusion, and the FFR values measured at different doses of bolus intracoronary adenosine were analyzed using the Student t test for paired multiple comparisons. The change in the percentage of patients with FFR <0.80 for each dose of adenosine was analyzed using the Cochran Q test for paired categorical measures. The results were considered statistically significant when p <0.05. The software SPSS, version 15.0 for Windows (SPSS, Chicago, Illinois) was used.
Results
In the present study, 108 lesions in 102 patients were included. The baseline patient characteristics and lesions studied are reported in Tables 1 and 2 . In 94 patients (92.2%), the infusion was performed in the right atrium. In the remaining 8 patients (7.8%), the infusion was performed through an antebrachial vein. In 101 of the lesions (93.5%), all the doses of intracoronary adenosine were administered successfully. In 7 patients, the protocol of intracoronary adenosine administration could not be performed completely because of transient atrioventricular block of >3 seconds (mean 4.9 ± 1.2). The dosages causing an atrioventricular block of >3 seconds are reported in Figure 1 . All episodes of atrioventricular block were spontaneously self-limiting or resolved by encouraging the patient to cough. All patients experienced some degree of thoracic discomfort with high-dose intracoronary adenosine. This discomfort was well tolerated by the patients and showed a very difficult possibility of evaluation because of the very short duration of the intracoronary adenosine effect. All cases (100%) reported some degree of thoracic discomfort with intravenous infusion of adenosine. In none of these cases was it necessary to discontinue the study before obtaining an FFR value. A significant decrease in systolic (141 ± 30 vs 129 ± 27 mm Hg; p <0.0005), diastolic (67 ± 15 vs 63 ± 15 mm Hg; p <0.0005), mean arterial pressure (92 ± 18 vs 86 ± 16 mm Hg; p <0.0005), and heart rate (71 ± 13 vs 80 ± 13 beats/min; p <0.0005) was observed with intravenous adenosine. These hemodynamic variations were not clinically relevant in any of the cases. One patient (0.98%) developed 1 episode of paroxysmal atrial fibrillation that was self-limiting, starting with the infusion of adenosine at 140 μg/kg/min. No complications were observed when advancing the guide or at the site of venous access, and no other complication was associated with the study with a pressure wire.
| Variable | Value |
|---|---|
| Age (yrs) | 66.9 ± 10.5 |
| Women | 25 (24.5%) |
| Height (cm) | 167.1 ± 7.2 |
| Weight (kg) | 79.0 ± 14.2 |
| Body mass index (kg/m 2 ) | 1.8 ± 0.2 |
| Systolic blood pressure (mm Hg) | 147.1 ± 29.5 |
| Diastolic blood pressure (mm Hg) | 78.7 ± 15.4 |
| Heart rate (beats/min) | 71.9 ± 14.2 |
| Diabetes | 37 (36.3%) |
| Hypertension | 79 (77.5%) |
| Dyslipidemia | 63 (61.8%) |
| Smoking | 59 (57.8%) |
| Previous myocardial infarction | 21 (20.6%) |
| Previous coronary revascularization | 34 (33.3%) |
| Previous stroke | 8 (7.8%) |
| Stable angina pectoris | 27 (26.5%) |
| Acute coronary | 57 (55.8%) |
| Valvulopathy | 4 (3.9%) |
| Dilated myocardial cardiomyopathy | 5 (4.9%) |
| Silent ischemia | 9 (8.8%) |
| Left ventricular ejection fraction | 52.96 ± 14.00 |
| Arterial access | |
| Left radial artery | 98 (96.3%) |
| Right radial artery | 4 (3.7%) |
| Diseased vessels (n) ∗ | 0.80 ± 1.01 |
| 0 | 51 (50.0%) |
| 1 | 26 (25.5%) |
| 2 | 15 (14.7%) |
| 3 | 10 (9.8%) |
| Lesions (n) ∗ | 1.06 ± 0.28 |
∗ Angiographic stenosis >70% in lesions other than studied lesion.
| Characteristic | Value |
|---|---|
| Lesion type | |
| De novo lesion | 103 (95.4%) |
| In-stent restenosis lesion | 5 (4.6%) |
| Lesion type | |
| A | 26 (24.1%) |
| B1 | 17 (15.7%) |
| B2 | 46 (42.6%) |
| C | 19 (17.6%) |
| Studied vessel | |
| Left anterior descending | 59 (54.6%) |
| Circumflex | 29 (26.9%) |
| Right coronary | 18 (16.7%) |
| Left main | 2 (1.9%) |
| Localization | |
| Ostial | 2 (1.9%) |
| Proximal | 39 (36.1%) |
| Media | 45 (41.7%) |
| Distal | 22 (20.4%) |
| Quantitative analysis | |
| Reference diameter (mm) | 2.96 ± 0.63 |
| Minimum luminal diameter (mm) | 1.55 ± 0.39 |
| Lesion length (mm) | 15.79 ± 8.62 |
| Diameter stenosis (%) | 52.60 ± 8.27 |
The intracoronary adenosine bolus dose of 60 μg obtained FFR values significantly greater than those obtained with the intravenous adenosine infusion (difference in FFR 0.02 ± 0.03; 95% confidence interval 0.01 to 0.01; p = 0.001). Bolus doses of 300 and 600 μg resulted in FFR values significantly smaller than those obtained with intravenous adenosine. An intravenous adenosine infusion of 200 μg/kg/min was not associated with FFR values significantly smaller than those obtained with infusion at 140 μg/kg/min. The addition of a bolus intracoronary dose of adenosine during intravenous infusion did show an association with a significantly lower FFR than that observed with the 140-μg/kg/min and 200-μg/kg/min doses but significantly greater than that obtained with a bolus intracoronary dose of 600 μg ( Table 3 and Figure 2 ).
| Variable | Standard Intravenous Perfusion (140 μg/kg/min) | Intravenous Perfusion (200 μg/kg/min) | Intravenous Perfusion (140 μg/kg/min) Plus 120-μg Intracoronary Adenosine | ||||||
|---|---|---|---|---|---|---|---|---|---|
| FFR Difference | 95% CI | p Value | FFR Difference | 95% CI | p Value | FFR Difference | 95% CI | p Value | |
| Intracoronary bolus dose (μg) | |||||||||
| 60 | 0.02 ± 0.00 | 0.01–0.03 | 0.001 | 0.02 ± 0.00 | 0.01–0.03 | 0.000 | 0.03 ± 0.00 | 0.02–0.03 | 0.000 |
| 180 | −0.00 ± 0.00 | −0.01–0.00 | 0.256 | −0.00 ± 0.00 | −0.01–0.01 | 0.625 | 0.01 ± 0.00 | 0.00–0.01 | 0.049 |
| 300 | −0.01 ± 0.00 | −0.02–0.00 | 0.006 | −0.01 ± 0.00 | −0.02–0.00 | 0.035 | 0.00 ± 0.00 | −0.00–0.01 | 0.902 |
| 600 | −0.02 ± 0.00 | −0.02–0.01 | 0.000 | −0.01 ± 0.00 | −0.02–0.01 | 0.000 | −0.01 ± 0.00 | −0.01–0.00 | 0.020 |
| Intravenous perfusion | |||||||||
| Standard (140 μg/kg/min) | — | — | — | 0.00 ± 0.00 | −0.00–0.01 | 0.066 | 0.01 ± 0.00 | 0.01–0.02 | 0.000 |
| 200 μg/kg/min | −0.00 ± 0.00 | −0.01–0.00 | 0.066 | — | — | — | 0.01 ± 0.00 | 0.00–0.01 | 0.005 |
| Standard (140 μg/kg/min) plus 120-μg intracoronary adenosine | −0.01 ± 0.00 | −0.02–0.01 | 0.000 | −0.01 ± 0.00 | −0.01–0.00 | 0.005 | — | — | — |
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