Coronary plaques can be reduced by some medications. The aim of this study was to compare the effects of 2 angiotensin II receptor blockers (olmesartan at 20 mg/day or valsartan at 80 mg/day) on coronary plaque by coronary intravascular ultrasound. One hundred hypertensive patients with stable angina pectoris who underwent elective percutaneous coronary intervention were randomly selected to receive 1 of the 2 angiotensin II receptor blockers after coronary intervention. Nontarget coronary lesions with mild to moderate stenosis were measured by volumetric intravascular ultrasound at baseline and after 6 months. After 6 months, both the olmesartan and the valsartan groups showed significant reduction of the examined coronary plaque volume (46.2 ± 24.1 mm 3 at baseline vs 41.6 ± 21.1 mm 3 at 6 months: 4.7% decrease, p = 0.0002; and 47.2 ± 32.7 mm 3 at baseline vs 42.5 ± 30.2 mm 3 at 6 months: 4.8% decrease, p = 0.002, respectively). There was no statistically significant difference of plaque regression between the 2 groups (p = 0.96). In conclusion, there was a significant decrease from baseline in the coronary plaque volume in patients with stable angina pectoris who received olmesartan or valsartan for 6 months. In addition, there was no significant difference in the reduction of plaque volume achieved by these 2 medications.
Coronary plaques can be stabilized or even reduced in size with some medications. Treatment with statins can promote coronary plaque regression. In addition, antihypertensive therapy may slow the progression of coronary atherosclerosis. Administration of the angiotensin II receptor blocker (ARB) olmesartan prevents the progression of coronary atheroma in patients who receive percutaneous coronary intervention (PCI) for stable angina, resulting in an improved clinical outcome. However, it remains unknown whether this represents a class effect or is specific to olmesartan, and there have been few studies comparing the effects of ARBs on the progression of coronary atherosclerosis. In this study, we used intravascular ultrasound (IVUS) to determine whether long-term olmesartan administration after PCI reduced coronary plaques in patients with stable angina pectoris and mild hypertension, and we performed a comparison with valsartan.
Methods
Between January 2006 and October 2010, we performed a prospective open-label, randomized, blinded end-point multicenter clinical trial at Yokkaichi Municipal Hospital, Ogaki Municipal Hospital, Chubu-Rosai Hospital, and Nagoya University Hospital in Japan. Patients with stable angina pectoris and mild hypertension were eligible if they were aged ≥20 years and had been treated with statins for >8 weeks before PCI. We excluded patients with acute coronary syndrome, those with a history of Q-wave myocardial infarction, those with a left ventricular ejection fraction <45%, those with a serum creatinine >3.0 mg/dl, and those already being treated with angiotensin-converting enzyme inhibitors, ARBs, and/or aldosterone receptor blockers at randomization. We also excluded subjects with insufficient IVUS data for evaluation.
The patients were randomized into 2 groups, 1 receiving olmesartan at 20 mg/day and 1 receiving valsartan at 80 mg/day. The study protocol was approved by the ethics committee of each hospital, and written informed consent was obtained from all patients.
Nontarget coronary lesions with mild to moderate stenosis (percent diameter stenosis <50% by quantitative coronary angiography) were measured by volumetric IVUS both at baseline and after a 6-month follow-up period. The primary end point of the study was the change of the percent plaque volume assessed by IVUS (change of the percent plaque volume [%PV] = %PV at follow up − %PV at baseline). Changes of vessel volume and luminal volume were also analyzed.
We used a Clear View system (Boston Scientific, Natick, Massachusetts) for imaging and a SCIMED (Freemont, California) motorized pullback device to perform conventional IVUS analysis according to published guidelines. By tracing the leading edge of the adventitia, the cross-sectional area (CSA) of the external elastic membrane (EEM) was measured. Then the CSA of plaque plus media was calculated as (EEM CSA − luminal CSA). The percent plaque area was defined as [(EEM area − luminal area)/EEM area] × 100. Lesion length was also evaluated by IVUS. Conventional 3-dimensional IVUS analysis was performed to determine the vessel volume, luminal volume, and total plaque volume (the sum of EEM CSA, luminal CSA, and plaque plus media CSA) at 1-mm axial intervals in the segments analyzed.
We also performed integrated backscatter (IB) IVUS in 54 patients. IB signals were obtained with a commercially available system (IB-IVUS, YD Co., Ltd., Nara, Japan) connected to the IVUS imaging system. As previously reported, the IB value for each tissue component was calculated as the average power (measured in decibels) of the backscattered signal from a small volume of tissue using fast-Fourier transformation. The IB data were then used to divide plaque into 3 histologic categories: a fibrous tissue area, a lipid tissue area, and a high signal area (partial calcification). In patients undergoing IB-IVUS analysis, adiponectin and malondialdehyde-modified low-density lipoprotein levels were also evaluated.
Statistical analysis was performed using SAS version9.2 (SAS Institute, Cary, North Carolina). The mean ± SD were calculated for continuous variables. Results were compared using the Student’s t test for continuous variables and Fisher’s exact test for categorical variables. For the IB-IVUS data, analysis of covariance was used to adjust for baseline differences between the 2 groups. In all analyses, p <0.05 was considered significant.
This study was planned to assess the difference of %PV between olmesartan and valsartan as an indicator of the regression of coronary atherosclerosis. With the assumption of an SD of 4.7, a 2.7% difference in the treatment groups, a power of 0.8, and a level of significance of 0.025 (1-sided), at least 48 patients were needed in each group. Taking dropouts into consideration, 50 patients per group (100 in total) were planned for enrollment in the study.
Results
One hundred patients with stable angina pectoris who underwent elective PCI were enrolled. In 94 patients (45 in the olmesartan group and 49 in the valsartan group), volumetric IVUS was performed at the 6-month follow-up. The others who did not undergo follow-up angiography and refused repeat IVUS had no symptoms of myocardial ischemia.
Table 1 shows the baseline clinical characteristics of the 2 groups, which were well matched between groups. In both groups, the test drug significantly reduced blood pressure ( Table 2 ).
| Variable | All (n = 94) | Olmesartan Group (n = 45) | Valsartan Group (n = 49) | Between-Group p ∗ |
|---|---|---|---|---|
| Age (yrs) | 67.9 ± 8.7 | 68.3 ± 7.2 | 67.5 ± 10 | 0.69 |
| Male | 68 (73%) | 31 (69%) | 37 (77%) | 0.48 |
| Body mass index (kg/m 2 ) | 24.2 ± 3.1 | 24.2 ± 3.2 | 24.1 ± 3.0 | 0.89 |
| Diabetes mellitus | 39 (42%) | 19 (43%) | 20 (42%) | 1.00 |
| Current smoker | 28 (31%) | 14 (32%) | 14 (30%) | 1.00 |
| Previous coronary angioplasty | 32 (35%) | 13 (30%) | 19 (40%) | 0.38 |
| Previous coronary bypass | 2 (2%) | 0 | 2 (4%) | 0.50 |
| Previous myocardial infarction | 18 (20%) | 7 (16%) | 11 (23%) | 0.44 |
| Systolic BP (mm Hg) | 147.0 ± 8.7 | 147.8 ± 7.4 | 146.3 ± 9.7 | 0.40 |
| Diastolic BP (mm Hg) | 77.1 ± 9.8 | 78.4 ± 9.8 | 75.9 ± 9.8 | 0.22 |
| Creatinine (mg/dl) | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.1 | 0.77 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 67.9 ± 14.8 | 68.1 ± 16.9 | 67.7 ± 12.6 | 0.89 |
| Total cholesterol (mg/d) | 178.0 ± 32.5 | 179.3 ± 35.6 | 176.7 ± 29.6 | 0.70 |
| LDL (mg/dl) | 101.3 ± 20.9 | 98.7 ± 20.9 | 103.8 ± 20.8 | 0.25 |
| HDL (mg/dl) | 48.1 ± 11.6 | 50.5 ± 13.1 | 45.9 ± 9.6 | 0.06 |
| Logarithmic transformed triglyceride (mg/dl) | 4.8 ± 0.5 | 4.9 ± 0.5 | 4.8 ± 0.4 | 0.59 |
| Hemoglobin A 1c (%) | 6.1 ± 1.3 | 6.0 ± 1.0 | 6.2 ± 1.5 | 0.49 |
| LVEF (%) | 66.9 ± 8.5 | 67.1 ± 10.0 | 66.7 ± 6.8 | 0.85 |
| Medication | ||||
| Calcium antagonist | 48 (52%) | 20 (46%) | 28 (58%) | 0.30 |
| Beta blockers | 18 (20%) | 8 (18%) | 10 (21%) | 0.80 |
| Eicosapentaenoic acid | 4 (4%) | 2 (4%) | 2 (4%) | 1.00 |
| Insulin | 6 (6%) | 5 (11%) | 1 (2%) | 0.10 |
| Sulfonylurea | 13 (14%) | 6 (13%) | 7 (14%) | 1.00 |
| Pioglitazone | 12 (13%) | 6 (13%) | 6 (12%) | 1.00 |
| Other diabetes medications | 15 (16%) | 6 (13%) | 9 (18%) | 0.58 |
| Culprit coronary artery | ||||
| Left anterior descending | 43 (47%) | 22 (49%) | 21 (44%) | 0.68 |
| Left circumflex | 22 (24%) | 12 (27%) | 10 (20%) | 0.63 |
| Right coronary | 33 (36%) | 13 (29%) | 20 (41%) | 0.28 |
| AHA/ACC type | ||||
| A | 22 (24%) | 11 (24%) | 11 (22%) | 1.00 |
| B 1 | 27 (29%) | 14 (31%) | 13 (27%) | 0.65 |
| B 2 | 31 (33%) | 14 (31%) | 17 (35%) | 0.83 |
| C | 14 (15%) | 6 (13%) | 8 (16%) | 0.78 |
∗ Unpaired t -test or Fisher’s exact test (olmesartan group vs valsartan group).
| Variable | Olmesartan Group (n = 45) | Valsartan Group (n = 49) | Between-Group p ∗ |
|---|---|---|---|
| Systolic BP (mm Hg) | |||
| Baseline | 147.8 ± 7.4 | 146.3 ± 9.7 | 0.40 |
| 6 mo later | 129.8 ± 8.6 | 130.5 ± 10.8 | 0.75 |
| Difference | −18.9 ± 8.1 | −16.3 ± 8.3 | 0.14 |
| Within-group p † | <0.0001 | <0.0001 | |
| Diastolic BP (mm Hg) | |||
| Baseline | 78.4 ± 9.8 | 75.9 ± 9.8 | 0.22 |
| 6 mo later | 70.6 ± 11 | 72.3 ± 7.7 | 0.42 |
| Difference | −8.5 ± 11.8 | −3.9 ± 10.7 | 0.06 |
| Within-group p † | <0.0001 | 0.017 |
∗ Unpaired t test (olmesartan group vs valsartan group).
There were no significant differences of IVUS findings between the 2 groups at baseline ( Table 3 and Figure 1 ). At follow-up evaluation after 6 months, plaque volume showed a statistically significant decrease in the olmesartan group (p = 0.0002) and in the valsartan group (p = 0.002). However, there was no significant difference of reduction of plaque volume between the 2 groups (p = 0.96). There was a consistent trend for a reduction of vessel volume in the coronary arteries after treatment with olmesartan, but it did not reach statistical significance (p = 0.052). In both the olmesartan group and the valsartan group, there were no significant differences of luminal volume between baseline and after 6 months of treatment (p = 0.56 and p = 0.39, respectively).
| Variable | Olmesartan Group (n = 45) | Valsartan Group (n = 49) | Between-Group p ∗ |
|---|---|---|---|
| Plaque volume (mm 3 ) | |||
| Baseline | 46.2 ± 24.1 | 47.2 ± 32.7 | 0.87 |
| 6 mo later | 41.6 ± 21.1 | 42.5 ± 30.2 | 0.87 |
| Difference | −4.7 ± 7.7 | −4.8 ± 10.3 | 0.96 |
| Within-group p † | 0.0002 | 0.002 | |
| PPV (%) | |||
| Baseline | 40.6 ± 12.2 | 43.4 ± 12.5 | 0.28 |
| 6 mo later | 38.2 ± 11.5 | 40.6 ± 12.0 | 0.32 |
| Difference | −2.5 ± 5.5 | −2.8 ± 8.9 | 0.84 |
| Within-group p † | 0.004 | 0.03 | |
| Normalized TPV (mm³) | |||
| Baseline | 54.1 ± 29.8 | 58.5 ± 41.1 | 0.56 |
| 6 mo later | 48.6 ± 26.6 | 52.4 ± 37.8 | 0.58 |
| Difference | −5.5 ± 7.9 | −6.0 ± 13.0 | 0.79 |
| Within-group p † | <0.0001 | 0.002 | |
| Vessel volume (mm 3 ) | |||
| Baseline | 115.7 ± 52.5 | 105.5 ± 59.0 | 0.38 |
| 6 mo later | 109.9 ± 49.1 | 103.4 ± 61.5 | 0.58 |
| Difference | −5.8 ± 19.6 | −2.1 ± 19.8 | 0.36 |
| Within-group p † | 0.052 | 0.47 | |
| Lumen volume (mm 3 ) | |||
| Baseline | 69.7 ± 36.5 | 58.3 ± 33.2 | 0.12 |
| 6 mo later | 68.3 ± 34.4 | 60.5 ± 37.0 | 0.29 |
| Difference | −1.4 ± 16.2 | 2.1 ± 17.2 | 0.31 |
| Within-group p † | 0.56 | 0.39 |
∗ Unpaired t test (olmesartan group vs valsartan group).
IB-IVUS was also performed in 54 patients (27 in the olmesartan group and 27 in the valsartan group; Table 4 ). At the 6-month follow-up evaluation, the reduction of lipid tissue volume from baseline was statistically significant in the olmesartan group (p = 0.036), but it was not significant in the valsartan group (p = 0.50). There was a significant difference in the change of lipid volume (% change) between the olmesartan group and the valsartan group (p = 0.04). At the follow-up evaluation, the reduction of fibrous tissue volume from baseline was significant in the valsartan group (p = 0.037), but it was not significant in the olmesartan group (p = 0.10). There was a significant difference in the change of fibrous tissue volume (% change) between the olmesartan group and the valsartan group (p = 0.03). In the olmesartan group, adiponectin levels significantly increased (2.19 ± 0.61 at baseline vs 2.30 ± 0.56 at 6 months, p = 0.02), but not in the valsartan group (2.10 ± 0.47 at baseline vs 2.15 ± 0.54 at 6 months, p = 0.06). Also, modified low-density lipoprotein levels significantly decreased in the olmesartan group (111.7 ± 52.9 at baseline vs 92.8 ± 35.3 at 6 months, p = 0.036) but not in the valsartan group (103.8 ± 30.1 at baseline vs 93.6 ± 22.9 at 6 months, p = 0.16).
