Effect of Atorvastatin on Serial Changes in Coronary Physiology and Plaque Parameters

Background The effects of statin on coronary physiology have not been well evaluated. Objectives The authors performed this prospective study to investigate changes in coronary flow indexes and plaque parameters, and their associations with atorvastatin therapy in patients with coronary artery disease (CAD). Methods Ninety-five patients with intermediate CAD who received atorvastatin therapy underwent comprehensive physiological assessments with fractional flow reserve (FFR), coronary flow reserve, index of microcirculatory resistance, and intravascular ultrasound at the index procedure, and underwent the same evaluations at 12-month follow-up. Optimal low-density lipoprotein cholesterol (LDL-C) was defined as LDL-C <70 mg/dL or ≥50% reduction from the baseline. The primary endpoint was a change in the FFR. Results Baseline FFR, minimal lumen area, and percent atheroma volume (PAV) were 0.88 ± 0.05, 3.87 ± 1.28, 55.92 ± 7.30, respectively. During 12 months, the percent change in LDL-C was -33.2%, whereas FFR was unchanged (0.87 ± 0.06 at 12 months; P = 0.694). Vessel area, lumen area, and PAV were significantly decreased (all P values <0.05). The achieved LDL-C level and the change of PAV showed significant inverse correlations with the change in FFR. In patients with optimally modified LDL-C, the FFR had increased (0.87 ± 0.06 vs 0.89 ± 0.07; P = 0.014) and the PAV decreased (56.81 ± 6.44% vs 55.18 ± 8.19%; P = 0.031), whereas in all other patients, the FFR had decreased (0.88 ± 0.05 vs 0.86 ± 0.06; P = 0.025) and the PAV remained unchanged. Conclusions In patients with CAD, atorvastatin did not change FFR despite a decrease in the PAV. However, in patients who achieved the optimal LDL-C target level with atorvastatin, the FFR had significantly increased with decrease of the PAV. (Effect of Atorvastatin on Fractional Flow Reserve in Coronary Artery Disease [FORTE]; NCT01946815)

S tatins play major roles in treating patients with atherosclerotic cardiovascular disease by preventing the progression and stabilization of atherosclerosis. [1][2][3][4] The current guidelines recommend to achieve optimal low-density lipoprotein cholesterol (LDL-C) with a maximally tolerated statin-based intensive lipid-lowering therapy (LLT) in these patients. 5,6 The strong recommendations in the guidelines are supported by evidence from large randomized trials and meta-analyses that have a consistent relationship in reducing major adverse cardiovascular events. 2,7,8 In another aspect, several studies using serial intravascular imaging have also demonstrated the beneficial effects of statin on coronary atherosclerosis, which were summarized as stabilizing the plaque with a negative remodeling effect on the vessel, mainly through regression of plaque volume. 3,[9][10][11] However, the effects of  Table 1. After the diagnostic angiography, invasive physiological assessments for the target vessel and intravascular ultrasound (IVUS) were performed. All coronary physiological and imaging measurements were performed in an independent core laboratory.
During the follow-up, the recommended target goal with atorvastatin therapy was LDL-C <70 mg/dL or $50% LDL-C reduction compared with baseline. 12,13 The patients who achieved LDL-C target goal were defined as the optimal treatment group, and those who did not achieve the target goal as the suboptimal treatment group. Follow-up coronary angiography, FFR, coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) measurements, and IVUS were performed 12 months after the index procedure. Clinical follow-up and drug compliance were assessed at each visit after enrollment.
The primary efficacy parameter was the change in FFR between baseline and 12-month follow-up.
Secondary efficacy parameters were any changes in IVUS measurements, CFR, IMR, and any major cardiac adverse events, which were defined as a composite of death from any cause, any myocardial infarction, or target vessel repeat revascularization. The safety endpoint included the incidence of any adverse reactions caused by the study drug and the incidence of drug discontinuation. The institutional review boards of all participating centers approved the study protocol (NCT01946815), which was in accordance with the Declaration of Helsinki. All patients provided written informed consent.
CORONARY PHYSIOLOGICAL MEASUREMENTS. A 5-to 7-F guiding catheter without side holes was used to engage the coronary artery, and a pressuretemperature sensor-tipped guidewire was used with a 0.014-inch pressure guidewire (St Jude Medical) to measure the pressure. The FFR was calculated as the ratio between the mean distal coronary pressure (Pd) and mean proximal aortic pressure (Pa) at maximal hyperemia. Hyperemia was induced with an intravenous continuous infusion of adenosine (140 mg/kg/min). The pressure sensor was positioned at the distal segment of a target vessel, and intracoronary nitrate (200 mg) was administered before each measurement. To derive the resting mean transit time (T mn ), a thermodilution curve was obtained by using 3 injections of 4 mL of room temperature saline, and hyperemic Pa, Pd, and T mn were measured during sustained hyperemia. The CFR was calculated as the ratio of resting T mn /hyperemic T mn .
The IMR was calculated using Pd Â T mn during hyperemia. The evaluation of FFR was measured that the sensor of the FFR wire was placed the distal 1/3 of the target vessel or at least 20 mm below the target lesion. In addition, in follow-up FFR evaluation, fluoroscopic image capture was used as a reference during the index procedure to match the FFR measured position between the index procedure and follow-up.  Table 1 for model 1 and the added change of parameters in    Table 1. At 12 months, mean atorvastatin dose was 42.7 mg and the percent change in LDL-C was -33.2% (baseline vs 12 months, 119.9 AE 37.0 vs 80.1 AE 23.0; P < 0.001) ( Table 2). Thirty-three patients (34.7%) had an LDL-C <70 mg/dL, and 19 patients (20.0%) had a $50% LDL-C level reduction from baseline.
Supplemental Figure 1 shows the distribution of the coronary angiographic, physiological, and IVUS measurements.   Table 2).  Values are mean AE SD or n (%).
Lee et al  Figures 4C and 4D). Analysis of coronary physiological and plaque parameters according to atorvastatin intensity is shown in Supplemental Table 3.   Values are n (%). a Intravascular ultrasound images were assessed at the minimal lumen site. b Differences between baseline and 12-mo follow-up data were compared using the paired t test. c Differences between baseline and 12-mo follow-up data were compared using the Wilcoxon signed rank-sum test.

FIGURE 2 Changes in Coronary Flow and Plaque Parameters After Atorvastatin Therapy
The changes in physiological (A) and intravascular imaging (B) parameters during the 12-mo atorvastatin therapy are shown. CFR ¼ coronary flow reserve; IMR ¼ index of microcirculatory resistance; Pa ¼ proximal aortic pressure; PAV ¼ percent atheroma volume; Pd ¼ distal coronary pressure; TAV ¼ total atheroma volume; other abbreviations as in Figure 1. In previous studies using serial intravascular imaging to demonstrate plaque changes, highintensity atorvastatin or rosuvastatin therapy negatively remodeled the vessel mainly by decreasing the TAV and PAV while increasing or decreasing the lumen size in some cases. 3,10,11,21 Similarly, the TAV and PAV significantly decreased in this study, and negative remodeling of the vessel including the lumen area was observed after the 12-   Figure 2), and similar trends were observed in another study. 27 Another interesting finding was that the physiological coronary vascular response was bidirectional, ie, the FFR was decreased or increased, according to whether the LDL-C target had been achieved after the atorvastatin therapy. However, the anatomic coronary vascular response based on IVUS parameters was unidirectional, ie, the target achievement was reflected in the degree of decrease. Therefore, as a surrogate marker for assessing the vascular response to a certain therapy, the coronary physiological parameter can be useful in addition to traditional anatomical parameters.
Furthermore, changes in FFR had a significant inverse correlation with changes in PAV and achieved LDL-C levels (Figure 3), confirming that coronary anatomical and physiological responses were highly correlated after atorvastatin therapy.
Although the updated lipid guidelines recommend a more powerful LDL-C modification therapy, especially in very high-risk patients, 5,6 the number of patients that fail to reach the optimal LDL-C target is not small in real-world practice. 28   In the patients who achieved the optimal LDL-C target by atorvastatin therapy, the lumen area was well preserved due to a significant decrease in plaque volume despite negative remodeling of the vessel and increased FFR with improving trend of microvascular function, whereas this was not the case in patients who failed to reach the target level.