Several studies have demonstrated the correlation of heart rate (HR) and image quality in coronary computed tomography angiography. Beta-blocker administration is critical because of its negative inotropic effect. Ivabradine is a selective HR-lowering agent that exclusively inhibits the I f current in sinoatrial node cells without having any effect on cardiac contractility or atrioventricular conduction. A total of 120 patients were randomized to oral premedication with ivabradine 15 mg or metoprolol 50 mg. HR and blood pressure (BP) were measured before the administration of premedication and immediately before coronary computed tomographic angiography. The mean time between premedication administration and follow-up was 108 ± 21.5 minutes for ivabradine and 110 ± 22.2 minutes for metoprolol (p = NS). When comparing groups, there were no significant differences in reduction of HR (−11.83 ± 8.6 vs −13.20 ± 7.8 beats/min, p = NS) and diastolic BP (−5.05 ± 14.2 mm Hg vs −4.08 ± 10.8 mm Hg, p = NS), whereas the decrease of systolic BP was significantly lower in patients who received ivabradine compared to those in the metoprolol group (−3.95 ± 13.6 vs −13.65 ± 17.3 mm Hg, p <0.001). In the subgroup of patients who were receiving long-term β-blocker therapy, significantly stronger HR reduction was achieved with ivabradine (−13.19 ± 5.4 vs −10.04 ± 6.0 beats/min, p <0.05), while the decrease in systolic BP was less (−2.00 ± 13.6 vs −15.04 ± 20.8 mm Hg, p <0.05) compared to metoprolol. In conclusion, ivabradine decreases HR before coronary computed tomographic angiography sufficiently, with significantly less depression of systolic BP compared to metoprolol.
Ivabradine, a novel drug, selectively inhibits the I f current, which is a mixed K + -Na + inward current activated by hyperpolarization and contributes importantly to the activity of the sinoatrial node. It slows the diastolic depolarization slope of the sinoatrial cells and reduces heart rate (HR) at rest and during exercise without affecting myocardial contractility. The primary object of the present trial was to examine the effects of ivabradine on HR and blood pressure (BP) compared to the β blocker metoprolol when used as single-dose oral premedication before cardiovascular computed tomography.
Methods
A total of 281 consecutive patients referred for coronary computed tomographic angiography because of suspected coronary artery disease or progression of known coronary artery disease were screened for the present study. Patients’ medical histories were recorded, and after a rest period of 10 minutes in the sitting position, hemodynamic parameters (HR and systolic and diastolic BP) were obtained using a commercially available automatic BP monitor (MBO Digital 16, MBO International Electronic GmbH, Germany). Exclusion criteria were HR ≤60 beats/min (n = 115), systolic BP <100 mm Hg (n = 2), atrial fibrillation (n = 21), frequent premature heartbeats (n = 8), previous pacemaker implantation (n = 3), long-term therapy with a cardiotropic calcium channel blocker (n = 1), serum creatinine level >1.5 mg/dl (n = 5), and chronic obstructive pulmonary disease (n = 6). The final study population comprised 120 patients. The present research protocol complies with the Declaration of Helsinki and was approved by the institutional review board. All patients gave written informed consent.
Patients eligible for the trial were randomized in blocks of 20 patients in a 1:1 ratio to immediate oral premedication with either ivabradine 15 mg or metoprolol 50 mg, a cardioselective β blocker, and instructed to refrain from activities that may alter cardiac parameters or intestinal absorption (e.g., extensive physical activity, eating or drinking). After 109 ± 21.8 minutes, patients were remonitored for HR and BP, and coronary computed tomographic angiography was begun.
Patients were scanned in the supine position. If HR was >60 beats/min during a test breath hold command immediately before the scan, additional medication (5 to 20 mg metoprolol) was administered intravenously until a HR of ≤60 beats/min was reached. Moreover, all patients received 0.8 mg nitrogylcerin sublingually before the examination. Nonenhanced scans were not performed routinely. The first 35 patients were scanned using a 64-slice, single-source computed tomographic scanner (Somatom Sensation 64; Siemens Medical Systems, Erlangen, Germany) with slice collimation of 64 × 0.6 mm by means of a z-flying focal spot, rotation time of 370 ms, tube voltage of 120 kV, tube current–time product of 680 mAs/rotation, and pitch of 0.2. Tube current modulation was not routinely performed. The test bolus technique was used to determine the circulation time with 12 ml of contrast material (iopamidol 370 mg, Scanlux; Sonochemia, Vienna, Austria) followed by a chaser bolus of 50 ml of saline. For the contrast-enhanced series, the amount of contrast agent was adapted to the estimated scan length, followed by another chaser bolus of 50 ml saline at a flow rate of 5.0 to 8.0 ml/s, conditioned by patients’ body weight.
The remaining 85 patients were scanned using a dual-source scanner (Somatom Definition; Siemens Medical Systems), which is equipped with 2 x-ray tubes and 2 detectors mounted on a single gantry at an angle of 90°. The scan parameters were as follows: slice collimation of 2 × 64 × 0.6 mm by means of a z-flying focal spot, rotation time of 330 ms, tube voltage of 120 kV, tube current–time product of 340 mAs/rotation, and pitch 0.2 to 0.39 adapted to HR. Tube current modulation was used in all patients. The protocol for contrast media administration was the same as with the single-source scanner.
Image quality was assessed for all coronary segments according to a modified 15-segment American College of Cardiology and American Heart Association classification using a 4-point grading scale: 3 = excellent (no artifacts), 2 = good (minor artifacts), 1 = diagnostic (moderate artifacts), and 0 = uninterpretable (major artifacts with severe image degradation due to coronary motion or severe blurring caused by extensive calcification or stents).
Statistical analysis was performed using commercially available software (SPSS version 17; SPSS, Inc., Chicago, Illinois). Continuous variables are expressed as mean ± SD and categorical values as frequencies or percentages. Student’s t tests were used to assess differences in continuous variables, and chi-square tests were applied to categorical values. HR and BP values were compared at enrollment and before the scans for all patients and in a subgroup analysis for patients with and without long-term β-blocker therapy.
Results
Patients’ baseline characteristics are summarized in Table 1 . HR was not different between patients with and without permanent β-blocker therapy (72.9 ± 9.3 vs 76.6 ± 10.0 beats/min, respectively). After premedication, HR and systolic and diastolic BP decreased significantly by 12.5 ± 8.2 beats/min, 8.8 ± 16.2 mm Hg, and 4.5 ± 12.6 mm Hg, respectively. When comparing groups, the administration of ivabradine was as sufficient as metoprolol in terms of HR reduction, while systolic BP was found to be significantly less affected ( Figure 1 ) .
| Variable | All Patients | Ivabradine | Metoprolol |
|---|---|---|---|
| Number of patients | 120 | 60 (50%) | 60 (50%) |
| Age (years) | 57 ± 12 | 55 ± 13 | 60 ± 12 |
| Women | 50 (42%) | 24 (40%) | 26 (43%) |
| Body mass index (kg/m 2 ) | 27 ± 4 | 27 ± 4 | 27 ± 4 |
| Long-term β-blocker therapy | 68 (43%) | 26 (43%) | 26 (43%) |
| Time delay (minutes) | 109 ± 21 | 108 ± 21 | 110 ± 22 |
| HR (beats/min) | 75 ± 9 | 76 ± 10 | 74 ± 9 |
| Systolic BP (mm Hg) | 140 ± 20 | 138 ± 16 | 143 ± 22 |
| Diastolic BP (mm Hg) | 86 ± 13 | 86 ± 13 | 86 ± 14 |
| Hypertension ⁎ | 79 (66%) | 38 (63%) | 41 (68%) |
| Hyperlipidemia † | 70 (58%) | 33 (55%) | 37 (62%) |
| Diabetes mellitus | 11 (9%) | 6 (10%) | 5 (8%) |
| Smoker | 69 (58%) | 36 (60%) | 33 (55%) |
| Previous stent implantation | 12 (10%) | 8 (13%) | 4 (7%) |
| Previous coronary bypass | 5 (4%) | 3 (5%) | 2 (3%) |
⁎ BP at rest >140/90 mm Hg or permanent antihypertensive medication.
† Serum cholesterol level >200 mg/dl or permanent lipid-lowering therapy.
In a subgroup analysis including only patients without long-term β-blocker therapy, we found significantly less reduction in HR and systolic BP in the ivabradine group, while diastolic BP depression did not differ between the premedication arms ( Figure 2 , Table 2 ). When including only patients who were already receiving permanent β blockers, ivabradine was found to be significantly more effective in reducing HR, while systolic BP was less affected compared to metoprolol ( Figure 2 ). Again, there was no statistically relevant impact on diastolic BP when comparing groups.
| Premedication Long-term β-blocker therapy | Ivabradine | Metoprolol | ||
|---|---|---|---|---|
| No | Yes | No | Yes | |
| Before premedication | 76 ± 11 | 74 ± 9 | 76 ± 8 | 71 ± 9 |
| After premedication | 65 ± 7 | 61 ± 8 | 60 ± 6 | 61 ± 8 |
| During scan | 58 ± 8 | 56 ± 8 | 60 ± 8 | 61 ± 9 |
| Difference between before medication and during scan | −18 ± 9 | −16 ± 7 | −16 ± 8 | −10 ± 10 |
| p = NS | p < 0.05 | |||
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