Comparison of fimasartan and amlodipine therapy on carotid atherosclerotic plaque inflammation

Background The renin‐angiotensin system plays an important role in promoting atherosclerotic plaque inflammation, which may be inhibited by angiotension‐II receptor blockers. Hypothesis We investigated the effects of fimasartan and amlodipine therapy on carotid atherosclerotic plaque inflammation using 18F‐fluorodeoxyglucose (18FDG) positron emission tomography (PET) imaging. Methods Fifty patients with acute coronary syndrome (ACS) and at least one lesion with 18FDG uptake in the carotid artery (target‐to‐background ratio [TBR] ≥ 1.6) were randomly assigned to receive either fimasartan (60 mg once a day) or amlodipine (5 mg once a day). 18FDG PET examinations were performed in all patients at baseline and 6 months. The primary endpoint was the percent change in the index vessel TBR for the most diseased segment (MDS TBR). Results The two groups had similar baseline characteristics. At the 6‐month follow‐up, index vessel and aorta MDS TBR significantly decreased in both groups. However, the percent change in index vessel MDS TBR was similar between the two groups (−9.33 ± 14.2% vs −7.73 ± 19.1%, respectively, P = 0.9). No significant difference was found for the percent change in the whole vessel TBR for the index vessel between the two groups, with similar findings for changes in MDS TBR or whole vessel TBR for the aorta. Total cholesterol, low‐density lipoprotein cholesterol levels, and blood pressure improved to a similar degree in both groups. Conclusions Fimasartan and amlodipine reduce carotid atherosclerotic plaque inflammation similarly in patients with ACS, offering the same level of effectiveness.


| INTRODUCTION
The renin-angiotensin system (RAS) may promote atherosclerotic processes by the inducing of inflammation, endothelial dysfunction, and low-density lipoprotein (LDL) oxidation. [1][2][3] Several studies have shown upregulation of tissue angiotensin converting enzyme and angiotension-II receptor type 1 (AT1 receptor) in human atherosclerotic plaques, 4,5 suggesting a potential role of tissue RAS in atherogenesis through local angiotension-II effects. [6][7][8] Angiotensin-II may promote atherosclerotic plaque inflammation, 3 and AT1 receptor blockers suppress plaque progression and induce plaque stabilization. 9,10 However, beneficial antiatherosclerotic properties of AT1 receptor blockers beyond blood pressure control have not yet been established. Although AT1 receptor blockers and calcium channel blockers are commonly used in patients with atherosclerotic cardiovascular disease, little is known about the comparative effects of these two agents on atherosclerotic plaque inflammation. Fimasartan, a potent AT1 receptor blocker, has been shown to have antiatherosclerotic effects in a rabbit model of atherosclerosis. 11 We hypothesized that fimasartan is superior to amlopidine in reducing atherosclerotic plaque inflammation despite similar blood pressure reduction efficacy.
The present study compared the effects of fimasartan and amlodipine therapy on carotid atherosclerotic plaque inflammation in patients with acute coronary syndrome (ACS) using 18  2.2 | 18 FDG PET/CT examination Baseline 18 FDG PET/CT scans were performed within 2 days of coronary angiography or percutaneous coronary intervention (3-5 days after admission). Eligible patients meeting all the inclusion and none of the exclusion criteria were randomized at 1:1 ratio to receive either fimasartan (60 mg once a day for 6 months) or amlodipine (5 mg once a day for 6 months). All patients were required to take standard medications including antiplatelet agents and cholesterol-lowering drugs and were requested to have a follow-up 18 FDG PET/CT examination at 6 months. Biochemical laboratory tests were also required at admission and at 6-month follow-up. The study protocol was approved by our Institutional Review Committee, and written informed consent was obtained from all patients.
All patients underwent vascular 18

| Image analysis
Image analysis was performed on a dedicated workstation. 18  SUVs for each region were derived by averaging SUVs of all artery slices within an arterial territory. The SUVs were normalized to blood 18 FDG activity by dividing them by the average blood ROI (calculated from at least six venous ROI measurements) estimated from the superior vena cava, yielding an arterial TBR.
The most diseased segment (MDS) TBR was measured by centering on the slice of the artery that showed the highest 18 FDG activity, and then averaging five contiguous segments (approximately, 1.5 cm extent), combined with immediate inferior and superior neighbors.
Whole vessel TBR was measured as the average of maximal TBR activity for all axial slices. Whole vessel 18 FDG uptake (TBR) was measured in the three target arteries (right and left carotid and aorta) and used to indicate 18 FDG defined atherosclerotic inflammation activity.
Cardiac catheterization may have variable impact on 18 FDG uptake of the ascending aorta due to catheter induced aortic injury, and the carotid artery with the highest 18 FDG uptake at baseline was chosen as the index vessel. 13

| Statistical analysis
Sample size of approximately 22 patients per treatment group was estimated to yield 90% power (assuming 15% SD in both fimasartan and amlodipine groups) for detecting a difference of 15% with a significance level of 0.05, using a two-sided test. With 10% anticipated dropout rate, the planned enrollment was 25 patients per treatment group (total 50 patients). Continuous variables were expressed as means AE SDs or medians with interquartile ranges, whereas categorical variables were expressed as frequencies. Continuous variables were compared using the paired t test or Wilcoxon rank sum test for changes in each group, and unpaired t test or Mann-Whitney U test for differences between groups. Statistical significance was defined as two-sided P < 0.05.

| RESULTS
A total of 146 patients with ACS were screened for enrollment  (Table 2). At 6-month followup, total cholesterol and LDL cholesterol levels significantly decreased in both groups (P < 0.001). High-sensitivity C-reactive protein levels  significantly decreased in the fimasartan group (P = 0.017), but not in the amlodipine group (P = 0.068). Triglyceride and HDL cholesterol levels did not significantly change in both groups. Figure 2 shows representative images of improved 18 FDG uptake in carotid plaque after fimasartan or amlodipine therapy, and Table 3 shows 18

| DISCUSSISON
Among patients with ACS and carotid artery disease, we found that MDS TBR of the carotid arteries and aorta significantly decreased in  but not in the amlodipine group whereas those of aorta decreased in both groups. However, this effect did not differ significantly between the two groups, suggesting similar effects from both agents on atherosclerotic plaque inflammation. Improvement in total cholesterol, LDL cholesterol, and high sensitivity C-reactive protein was also observed without between group differences.
Inflammation derives the atherosclerotic process, providing an important target for in-vivo atherosclerosis imaging studies. 18 FDG accumulates in atherosclerotic plaques in proportion to macrophage concentration, and arterial uptake correlates with arterial inflammatory burden. 12,13 The 18 FDG PET signal is reproducible, providing a useful tool to assess serial changes of atherosclerotic plaque inflammation. Whole vessel TBR assesses both diseased and healthy segments, whereas MDS TBR reflects inflammatory activity of the diseased segment. The latter is more commonly used to evaluate therapeutic intervention impacts on atherosclerotic plaque inflammation.
The present study showed that inflammatory indexes by 18  Antiatherosclerotic effects of RAS blockers appear to be independent of blood pressure reduction and may be in part due to RAS attenuation. 14 Tissue RAS produces local angiotensin-II that exerts various actions on the cardiovascular system. 15 The ongoing telmisartan alone and in combination with ramipril global endpoint (ONTARGET) trial showed that telmisartan was an equally effective alternative to ramipril to prevent cardiovascular events. 16 The impact of olmesartan on the progression of coronary atherosclerosis: evaluation by intravascular ultrasound (OLIVUS) trial showed that olmesartan led to a significant coronary plaque regression compared with the control group over the 14-month follow-up period. 10 High-dose fimasartan treatment suppressed atherosclerotic plaque development, lipid deposition, macrophage infiltration in a rabbit model of atherosclerosis. 11 However, the present study showed no significant difference between fimasartan and amlodipine in reducing carotid atherosclerotic plaque inflammation assessed by 18  Amlodipine is a long-acting calcium channel blocker commonly used as an antihypertensive and antianginal, and anti-inflammatory effects and antioxidant properties have been suggested. 17 The prospective randomized evaluation of the vascular effects of norvasc trial (PREVENT) trial showed that amlodipine reduced carotid intima-media thickness progression rate despite having no effect on angiographic progression of coronary atherosclerosis. 18 The comparison of amlodipine vs enalapril to limit occurrences of thrombosis (CAMELOT) study showed that major adverse cardiovascular events were similarly reduced for both amlodipine and enalapril treated patients. 19 The present study showed that atherosclerotic plaque inflammation similarly decreased in both groups with no blood pressure differences. These findings are inconsistent with those from other calcium channel blocker clinical trials, 20 suggesting that amlodipine may have additional beneficial effects not mediated through blood pressure reduction.
Several classes of antihypertensive drugs have been used to control blood pressure, but optimal pharmacological agent choice is not yet fully established. Two clinical trials showed angiotensin converting enzyme inhibitor benefits for patients with coronary artery disease and normal or borderline blood pressure, whereas other trials showed no additional benefits beyond blood pressure. [6][7][8] The antihypertensive and lipid lowering to prevent heart attack trial (ALLHAT) showed no differences of major cardiovascular events among lisinopril, diuretic, and amlodipine therapies. 21 The valsartan antihypertensive long-term use evaluation (VALUE) study showed similar event reduction for valsartan compared with amlodipine. 22 The present study showed similar reductions of carotid or aorta inflammation, consistent with previous clinical trials that did not show superior outcomes for antihypertensive agents that modulate the RAS.
This study has several limitations. First, the analysis was limited by the small number of patients, which may have impacted the power to detect subtle differences in arterial inflammation. Second, our study was an open label, single center study, which is subject to inherent limitations. However, we tried to minimize these limitations by using blind 18 FDG PET/CT evaluations.