Methods

Patients were eligible for enrollment if they were aged >18 and <70 years, had angina pectoris or positive stress test results, and had undergone TRCAG using a 5Fr sheath. Patients were excluded if they had histories of taking TMZ within 4 weeks, histories of adverse effects of TMZ, histories of TRCAG or transradial percutaneous coronary intervention, negative Allen test results, renal insufficiency (serum creatinine >2.5 mg/dl), significant valvular heart disease, left ventricular dysfunction (left ventricular ejection fraction <55%), TRCAG or transradial percutaneous coronary intervention with a sheath >6Fr, or inability to follow-the protocol.

All patients who underwent TRCAG using a 5Fr sheath were randomly assigned to the TMZ group or the control group if they were not excluded. If a patient was allocated to the TMZ group, 20 mg thrice daily of TMZ was given immediately after TRCAG and continued for 10 weeks. This dose was based on a previous study that showed a reduction of endothelial dysfunction by TMZ. A 5Fr (external diameter 2.27 mm), 25-cm-long sheath (Radifocus; Terumo Corporation, Tokyo, Japan) was used for radial artery cannulation. Through the inserted radial sheath, all patients received nitroglycerin 200 μg, verapamil 100 μg, and heparin 2,000 U. At the end of TRCAG, the sheath was removed immediately, and a wrist pressure bandage was applied for 4 to 5 hours to achieve hemostasis.

An experienced vascular sonographer who was blinded to the patients’ information performed ultrasound examinations using a Vivid 7 ultrasound system (GE Vingmed Ultrasound AS, Horten, Norway) with a 12-MHz linear-array transducer. The baseline study was done on the morning of the planned TRCAG. The post-TRCAG study was done <24 hours after TRCAG. The third study was done 10 weeks after TRCAG. FMD and nitrate-mediated dilation (NMD) were measured according to the recommendations of Corretti et al. In brief, patients should not exercise; should not ingest substances that might affect FMD and NMD, such as caffeine, foods, or medications; and should not use tobacco for ≥12 hours before the study. A landmark 10 cm above the proximal wrist crease was used for the ultrasound measurement location. The baseline diameter of the radial artery was measured from 2-dimensional grayscale longitudinal images. Subsequently, a blood pressure cuff was inflated at the forearm up to 220 mm Hg for 5 minutes. After cuff release, the radial artery diameter was measured at 1, 2, and 3 minutes. All images were recorded digitally by capturing the radial artery in the longitudinal plane with electrocardiography. The opposite arm was then measured in the same fashion. After 10 minutes of FMD measurements, an exogenous nitric oxide donor, sublingual nitroglycerin (0.6 mg) was administered, and 3 minutes later, images were recorded of the right and left arms for NMD measurements. Two cardiologists (M-KK and J-HP), blinded to the participants’ clinical data, interpreted the ultrasound results using an off-line method. The maximal radial artery diameter image for analysis was chosen around the T wave on electrocardiography. A total of 7 points of measurements were performed, and the maximal and minimal values were discarded. The mean value from these 5 measurements was used for further analysis. The intraobserver (κ = 0.92) and interobserver (κ = 0.89) reproducibility for FMD were within the acceptable range. Clinical follow-up visits were scheduled at the first, fourth, and eighth weeks with office visits for all patients enrolled in the study. In addition, drug compliance and complications of the radial artery were assessed.

On the basis of the results of a previous study, we assumed that the minimal improvement of FMD would be >2.0% in the TMZ group compared to the control group. Using a 2-sided α level of 0.05 and SD of 2.5%, which was based on our pilot study showing the difference in mean FMD at 10 weeks between the TMZ group and the control group to be 5.1 ± 2.5%. We estimated that 60 patients (30 per group), on the expectation of 10% loss to follow-up, were needed to demonstrate the superiority of the TMZ group with statistical power of 80%. Sample size was calculated using PASS software (NCSS, Kaysville, Utah). Data are expressed as mean ± SD. Comparisons of data across the 3 time points (baseline vs post-TRCAG and baseline vs 10-week follow-up) were performed using Student’s 2-tailed and paired-samples t tests. Interactions between groups were examined with repeated-measures analysis of variance to evaluate the serial changes among the multiple data points. Differences in categorical variables between the 2 groups were analyzed using the chi-square test or Fisher’s exact test. All probability values were 2 sided. A p value <0.05 indicated statistical significance. Statistical analyses were performed using SPSS version 13 (SPSS, Inc., Chicago, Illinois). This study was approved by the institutional review board of the local center, and all patients gave their written informed consent.

Results

A total of 102 patents were assessed for randomization. After TRCAG using a 5Fr sheath, 60 patients were randomly allocated in a 1:1 ratio to the TMZ or the control group. In the TMZ group, 1 patient dropped out because of skin rash and palpitations 2 days after taking TMZ. In the control group, 2 patients were excluded. One patient underwent coronary artery bypass grafting, and the other was lost to follow-up ( Figure 1 ). Arterial spasm developed in 3 patients only in the TMZ group, and puncture-site hematoma developed in 7 patients (4 patients in the TMZ group and 3 patients in the control group). Fortunately, no arterial occlusions were observed during the study period.

Flow diagram during the study. CABG = coronary artery bypass grafting; FU = follow-up; TRPCI = transradial percutaneous coronary intervention.

There were no significant differences between the groups in terms of baseline clinical characteristics, including the incidence of coronary artery disease and prescribed medications at baseline and 10-week follow-up ( Table 1 ). The radial artery diameters across the study are listed in Table 2 . In the noncannulated arm, there was no difference in radial artery diameters in the 2 groups during the study period. In the 2 cannulated groups, the post-TRCAG radial artery diameter was significantly larger than the baseline radial artery diameter. At 10-week follow-up, the radial artery diameter of the cannulated arm in the control group was smaller than the baseline value. However, in the cannulated arm of the TMZ group, there was no difference in radial artery size between baseline and 10-week follow-up.

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