Role of statins, phosphodiesterase inhibitors, and thiazolidinediones
In a recent meta-analysis of eight trials, 919 patients (461 patients in the statin group and 458 in the placebo group) were studied with IVUS.40
There was no significant difference between the two groups in terms of their plaque characteristics at baseline. However, there was a statistically significant mean difference in coronary atheroma volume between the statin therapy and the placebo arms, which was −3.573 (95% CI −4.46 to −2.68; P
< 0.01). This suggests that statins have the potential to induce plaque reversal.
One small study analyzed the effects of rosuvastatin combined with ramipril on atheroma volume and its mechanism in patients with intermediate CAD.41
In this study, 21 patients received rosuvastatin (20 mg daily) and 19 patients received rosuvastatin along with ramipril (20 mg and 10 mg, respectively) for 9 to 12 months. The study focused on measurement of TAV per 10 mm segment along with lipids, metabolic parameters (adiponectin, insulin sensitivity), and biomarkers (high-sensitivity [hs]-CRP, matrix metalloproteinase-9) at baseline and end of study. There was decrease in the TAV in both groups, with reduction in the CRP levels in the combination treatment group.
Takayama and colleagues studied the effect of rosuvastatin on plaque volume on 126 patients with stable CAD on lipid-lowering therapy at 37 centers in a 76-week open-label study.42
Subjects received rosuvastatin 2.5 mg per day (with the potential to be increased at 4-week intervals to up to 20 mg per day). The primary end point of percent change of plaque volume, as evaluated by IVUS was −5.1% ± 14.1% in the rosuvastatin group (P
Hibi et al studied effects of statin treatment on plaque regression in patients with polyvascular disease versus those with CAD alone.43
They studied 252 patients (at 33 centers) with a history of an ACS, who underwent percutaneous intervention to localize the lesion followed by treatment with atorvastatin (20 mg per day) or pitavastatin (4 mg per day). Both groups showed regression of plaques, as assessed by IVUS at baseline and at 8–12 months follow-up. A sub-analysis of this study showed that aggressive lipid lowering by pitavastatin and atorvastatin results in marked regression of atherosclerotic coronary lesions after ACS. The study involved data from 251 patients (73 were diabetic) and the authors studied the association of lipid levels after statin therapy with regression of atherosclerotic coronary lesions and major cardiovascular events in patients after ACS. The results showed that decrease in LDL-C, non-HDL-C, LDL-C/HDL-C ratio, and apo B levels were all associated with a progressively smaller plaque burden. In diabetic patients, further reduction of these parameters was associated with a significantly greater reduction in plaque volume.44
In a prospective randomized comparative study using rosuvastatin 20 mg (n = 65) and atorvastatin 40 mg (n = 63), IVUS was used at baseline and at 11-month follow-up, to show effective plaque regression. TAV and percent atheroma volume (PAV) was measured. Plaque was decreased in 99 of 128 patients (77%; 85% [55/65] in the rosuvastatin group vs 70% [44/63] in the atorvastatin group). Both groups showed change in TAV: −4.4 ± 7.3 mm3
for the rosuvastatin group and – 3.68 ± 6.8 mm3
for the atorvastatin group (P
= 0.5). The difference in PAV between the two groups was not statistically significant (P
= 0.14). These results demonstrate that both statins are effective in reducing plaque burden.45
Tani et al studied the effect of pravastatin on atherosclerotic plaque in a 6-month prospective study of 64 patients. Pravastatin reduced plaque volume, as measured by volumetric intravascular ultrasonography, by 12.6% (P
< 0.0001 vs baseline).46
The authors also found a significant reduction in the apoB/apoA-1 ratio (P
< 0.0001 vs baseline).
The effect of atorvastatin on MRI changes in atherosclerotic plaques in the thoracic and abdominal aorta was studied in a prospective study in which 87 patients with hypercholesterolemia were administered either atorvastatin (n = 42) or atorvastatin plus etidronate (n = 47) for 12 months.47
LDL levels and wall thickness in the thoracic aorta were reduced in both groups (−15% and −14% for the combination therapy and monotherapy group, respectively; P
< 0.001 vs baseline for both groups). However, only patients in the combination group had a reduction in wall thickness of the abdominal aorta (−14%; P
< 0.001 vs baseline).
The SECURE study was an ongoing Phase IV double-blind randomized controlled multicenter clinical trial of patients who were given either a combination of cilostazol and probucol or cilostazol alone.48
Plaque volume and composition using IVUS was studied as the primary end point at baseline and 9-month follow-up. This study has been completed and results are awaited.
Kovarnik et al randomized 89 patients to receive either atorvastatin 80 mg plus ezetimibe 10 mg or standard treatment per the patients’ general practitioner for 12 months.49
The authors found a decrease in the coronary artery PAV (−0.4%) in the group on combination treatment versus an increase (+ 1.4%) in the other group (P
= 0.014), as measured by IVUS. There was also an increased frequency of combined atherosclerosis regression (increased lumen volume plus decreased PAV) in patients taking both medications (40.5%) compared with the group on monotherapy (14.9%) (P
A recent study used cardiovascular magnetic resonance (MR) to study volumetric carotid plaque measurement on 26 subjects who had carotid plaques greater than 1.1 mm and coronary or cerebrovascular atherosclerotic disease (mean age 67 ± 2 years, 7 females).50
The subjects underwent evaluation with 3 Tesla MR (T1, T2, proton density, and time of flight sequences) and two-dimensional ultrasound at baseline and after 6 months of statin therapy. Plaque volume as measured by MR decreased by 5.8% ± 2% (1036 ± 59 to 976 ± 65 mm3
= 0.018) while mean plaque volume, as measured by ultrasound, was unchanged (1.12 ± 0.06 vs 1.14 ± 0.06 mm; P
= not significant). Those patients (n = 13) who had an initiation or increase of statins had −8.8% ± 2.8% change (P
= 0.001), as compared with an insignificant change in patients (n = 13) who were on statin maintenance.
Nicholls et al compared serial intravascular ultrasonography in 1039 patients with coronary disease, at baseline and after 104 weeks of treatment with either atorvastatin, 80 mg daily, or rosuvastatin 40 mg daily.51
In the atorvastatin group, the atheroma volume decreased by 0.99% (95% CI −1.19 to −0.63) and 1.22% (95% CI −1.52 to −0.90) in rosuvastatin group (P
= 0.17). The normalized TAV was −6.39 mm3
(95% CI, −7.52 to −5.12) with rosuvastatin and −4.42 mm3
(95% CI, −5.98 to −3.26) with atorvastatin (P
= 0.01). The side-effect profiles were acceptable in both groups.
A previous review of four prospective randomized trials showed significant regression in coronary atherosclerosis associated with the lowering of LDL-C levels and an increase in HDL.52
This post-hoc analysis included 1455 patients with angiographic CAD who underwent serial intravascular ultrasonography while receiving statin treatment for 18 to 24 months.
In their 6-month study, Yang and colleagues studied the effect of pioglitazone on coronary plaque area and plaque burden in patients with impaired glucose tolerance and CAD who were taking atorvastatin 20 mg daily for 3 months, followed by 10 mg daily for the next 3 months.53
At the completion of treatment, they underwent IVUS. Compared with the control group, 6 months’ treatment with pioglitazone significantly decreased coronary plaque burden (50.7 ± 11.1 vs 64.1% ± 10.3%; P
< 0.05), decreased plaque area (6.22 ± 2.03 vs 8.31 ± 4.29; P
< 0.05), decreased thin-cap fibroatheroma prevalence (11% vs 22%; P
< 0.05), and decreased percentage of necrotic core area (16% ± 8% vs 31% ± 7%; P
< 0.05). Incidentally, the patients taking pioglitazone had significantly lower hs-CRP and endothelin-1 levels and higher adiponectin levels.
Another study of 26 patients evaluated the effect of pioglitazone on coronary plaque structure. IVUS was used to demonstrate that pioglitazone reduced plaque burden without LDL-C reduction in patients suffering from diabetes and impaired glucose tolerance.54
Thirteen patients received pioglitazone 15 mg per day for an initial 14 days after percutaneous coronary intervention followed by 30 mg per day with the remaining patients as control. At the end of 6 months, the pioglitazone group had significantly reduced plaque volume (101.3 ± 32.1 to 94.6 ± 33.6 mm3
, −7.2%; P
= 0.0023). Serum cholesterol levels were also significantly improved in the pioglitazone group; they had lower triglyceride and CRP levels and higher HDL levels at the end of the study.
Yet another study has shown significant reduction in plaque volume with the use of pioglitazone and statin combination therapy using IVUS and IVUS-virtual histology.55
Analysis of 29 plaques in 25 diabetic patients who were treated with 80 mg of atorvastatin plus 30 mg of pioglitazone daily for 6 months was performed. Mean elastic external membrane volume was significantly reduced between baseline and follow-up (343.9 vs 320.5 mm3
< 0.05), as was mean TAV (179.3 vs 166.6 mm3
< 0.05). Change in TAV showed a 6.3% mean reduction. However, areas of the necrotic core increased from 9% to 14% (P
< 0.05) in spite of fibrous tissue and calcium decreasing over the 6 months of follow-up.
In a prospective study of 140 patients aged 50–75 years old (64 males and 76 females), the effects of aggressive lipid lowering with atorvastatin on the echogenicity of carotid plaques was studied. All subjects had moderate-grade carotid artery disease (symptomatic and asymptomatic) but without the indication for surgical intervention and did not suffer from CHD, renal failure, hypothyroidism, or osteoporosis. Group A (n = 70) received atorvastatin 10 mg or 20 mg (target LDL-C < 100 mg/dL) and Group B (n = 70) received atorvastatin 80 mg (target LDL-C < 70 mg/dL). There were no significant differences between groups at baseline and none of the subjects had ongoing use of statins. Group B had a higher augmentation of the grayscale median on carotid ultrasound at the end of 12 months (from 66.39 ± 23.66 to 100.4 ± 25.31) than group A (from 64.4 ± 23.62 to 85.39 ± 20.21) (P
= 0.024). No change in the degree of carotid stenosis was noted in either treatment arm. Along with enhanced carotid plaque echogenicity, atorvastatin showed significant reduction in serum hs-CRP, osteopontin, and osteoprotegrin (novel cardiovascular biomarkers belonging to the tumor necrosis factor family) levels in a dose-dependent manner (P
In the 2-year Dietary Intervention Randomized Controlled Trial – Carotid (DIRECT-Carotid) study, participants were randomized to a low-fat, Mediterranean, or low-carbohydrate diet. The change in carotid plaque caliber was evaluated using CIMT (measured with standard B-mode ultrasound) and carotid vessel wall volume (VWV; measured with carotid three-dimensional ultrasound). After 2 years of dietary intervention, the observation was a significant 5% regression in mean carotid VWV (−58.1 mm3
; 95% CI −81.0 to −35.1 mm3
< 0.001), indicating decreased atherosclerosis. There was no differences among the low-fat, Mediterranean, or low-carbohydrate groups (−60.69, −37.69, and −84.33 mm3
, respectively; P
= 0.28) and mean change in intima-media thickness was −1.1% (P
= 0.18). Those participants who achieved greater weight loss exhibited greater decrease in carotid VWV regression (mean decrease, −128.0 mm3
; 95% CI −148.1 to −107.9 mm3
) than those who exhibited progression (mean increase, +89.6 mm3
; 95% CI +66.6 to +112.6 mm3
Nanomedical advances may have a role as approaches to reversing plaque formation.58
Nanotechnology has been primarily investigated as an enhancement of stent technology. Lobatto et al reviewed the anti-atherotic properties of liposomes, which are artificially prepared spherical self-closed structures formed by lipid bilayers that have an aqueous interior.59
Since their discovery in the 1960s, they have been extensively researched as drug carriers. Liposomes are currently being investigated for several therapeutic strategies such as plaque reversal and lipid-lowering, anti-inflammatory, and anti-restenotic therapies.59
Nanoparticles have been studied as potential anti-restenotic drug-delivery systems after angioplasty, with the target molecules being the extracellular matrix and collagen in the vascular basement membrane.60