Intensive-Dose Atorvastatin Regimen Halts Progression of Atherosclerotic Plaques in New-onset Unstable Angina With Borderline Vulnerable Plaque Lesions

Abstract

To compare the therapeutic effects of intensive versus moderate dosage of atorvastatin regimens in new-onset unstable angina with borderline lesions, 100 patients were randomized to receive either 80 mg/d or 20 mg/d atorvastatin for 9 months. Clinical symptoms, lipid profiles, and coronary stenosis (evaluated by coronary angiography and intravascular ultrasound) were compared to their corresponding baselines within each group and between the 2 groups after 9 months of treatment. The results showed that (1) when compared to their corresponding baselines, both groups exhibited improvement in clinical symptoms, a significant decrease in total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), and high-sensitivity C-reactive protein (hs-CRP; P < .01) and a significant increase in high-density lipoprotein cholesterol (HDL-C); (2) the improvement in clinical symptoms and the decrease in LDL-C and hs-CRP were significantly greater (P < .01) in the intensive-dose group than in the moderate-dose group; (3) the mean plaque volume did not progress in the intensive-dose group but increased significantly (P < .05) in the moderate-dose group. We conclude that compared to the moderate dose, the intensive-dose regimen significantly improves clinical symptoms, lowers LDL-C and hs-CRP, and halts the progression of borderline atherosclerotic plaques in patients with new-onset unstable angina.

Keywords

unstable angina atherosclerotic plaques atorvastatin coronary angiography and intravascular ultrasound.

Introduction

Patients with new-onset of unstable angina usually present up to 1-month history of present paroxysmal chest tightness and chest pain. At this stage, more than 50% of the patients show no signs of malignant arrhythmia, congestive heart failure, hemodynamic changes, increased cardiac enzyme profiles, or ST segment elevation on electrocardiogram (ECG). Stenosis resulting from culprit atheromatous plaques as evaluated by coronary angiography (CAG) is only 50% to 70%, which indicates an early stage of atherosclerosis. There has been no consensus on whether such patients should be routinely treated with percutaneous coronary intervention (PCI). Over the past decades, numerous clinical trials have shown that patients with acute coronary syndrome (ACS) achieve a significantly improved prognosis and decreased end-adverse events if treated earlier with statins. This benefit is attributed to statins’ pleiotropic effects that include inducing favorable lipid profile,¹ improving endothelial functions of diseased arteries,² dampening inflammatory reactions in the plaques,³ and increasing fibrous cap thickness and thereby stabilizing or regressing atherosclerotic plaques.^4

–8 Guidelines of the Chinese Society of Cardiology of Chinese Medical Association (CSCCMA) for diagnosis and treatment of patients with unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) state that patients with ACS should be given a lipid profiling within 24 hours upon admission and prescribed a long-term moderate-to-large dosage of statins as early as possible.⁹ Although previous trials have established the effectiveness of statins in treating ACS and preventing cardiovascular events, participants in most trials were patients with significantly higher fasting low-density lipoprotein cholesterol (LDL-C) and other concomitant risk factors for coronary artery diseases (CADs) such as diabetes, high blood pressure, and a prior history of myocardial infarctions (MI).^10,11 The potential therapeutic effects of statins on new-onset unstable angina with borderline lesions have not been explored. In this report, patients with new-onset unstable angina and borderline lesions were randomized to receive moderate (20 mg/day) or intensive (80 mg/d) atorvastatin for 9 months. Improvement in clinical symptoms, lipid profiles, and components of atherosclerotic plaque assessed by CAG and intravascular ultrasound (IVUS) were compared intragroup over their corresponding baselines and intergroup after the 9-month treatments.

Methods

The protocol employed in this study was reviewed and approved by the Ethics Committee of Shanghai Pudong Gongli Hospital, Shanghai, China. All patients were informed about the study and a written consent was obtained from each patient prior to enrollment.

Study Population

A total of 100 patients who were diagnosed with new-onset unstable angina with borderline lesions from August 2008 to August 2011 were randomly grouped to receive moderate-dose (20 mg/d, n = 50) or intensive-dose (80 mg/d, n = 50) atorvastatin (Pfizer Ireland Pharmaceuticals, Cork, Ireland) for 9 months. The enrolled patients met the following criteria: (1) at least 18 years old, (2) new-onset unstable angina, (3) a stenosis of 50% to 70%, (4) a lumenal area greater than 4 mm² (5) a plaque burden of 50% as measured by CAG and IVUS. A patient was excluded from the study if he or she presented 1 or more of the following criteria: prior history of ischemia-related congestive heart failure, malignant arrhythmia, increased cardiac enzyme profile, ST-segment elevation on ECG, prior history of statin treatments, uncontrolled high blood pressure, heart failure, renal dysfunction, and chronic hepatic diseases with either acute episodes or abnormal liver functions.

Study Design

This study was designed as an open-label, prospective, and randomized clinical trial. To ensure drug safety, patients in the intensive-dose group were monitored closely in the first 4 weeks during which the patients received a dosage regimen of 20 mg/d in the first week, 40 mg/d in the second week, 60 mg/d in the third week, and 80 mg/d in the fourth week. The dosage of 80 mg/d was continued thereafter to the end of the study. The patients in the moderate-dose group were given 20 mg/d for 9 months. A patient was removed from the study and treated accordingly if he or she experienced any adverse cardiovascular events, such as sudden cardiac death, acute MI, stroke, and documented unstable angina that required hospitalization, revascularization, or coronary artery bypass grafting (CABG) at least 30 days after enrollment. Diagnostic criteria for drug side effects were defined as any measurement showing greater than 3-fold deviation from the upper limits of the normal range. During the 9-month trial, all patients were given 100 mg aspirin daily. Any other lipid-lowering drugs were excluded during the trial.

Upon enrollment, all patients were given a standard lipid profile analysis. During the 9-month follow-up, changes in symptoms of angina and any drug side effects were evaluated and recorded weekly. Liver function panel and creatine kinase (CK) were examined and analyzed monthly. The patients who completed the 9-month trial were given another lipid profile analysis and CAG and IVUS on the target lesions.

The CAG and IVUS

Baseline and follow-up CAG and IVUS were performed on all patients upon enrollment and on those who completed the 9-month trial, respectively. The iLab Ultrasound Imaging system (Boston Scientific Corporation, Massachusetts) coupled with a coronary ultrasound imaging catheter size of 2.9 F and a center frequency of 40 MHz was employed in the study. Briefly, the 6F/7F IVUS catheter was advanced through the target coronary artery and sent to the position at least 10 mm to the distal end of the target lesion and then pulled back to the position at least 10 mm to the proximal end at a speed of 0.5 mm/s. At the beginning of pullback, the position of the catheter was recorded by angiography. All IVUS images were video-recorded for playback and quantitative analysis.

Off-line analysis of the recorded images was performed in a blinded fashion using Virtue Intravascular Imaging System (Beijing, China). Baseline and follow-up IVUS images were reviewed on a display. The start and end of the target lesions were marked for further evaluation. Identical cross-sectional image slices (1 mm apart) were identified by using reproducible axial landmarks such as side branches, aortoostial junction, calcium deposits, and a fixed pullback speed (0.5 mm/s).

Statistical Analysis

Statistical analysis was performed with SPSS18.0 (SPSS, Chicago, Illinios). Data were presented as mean ± standard deviation (SD) or frequency. Continuous variables were compared using student t tests. Categorical variables were compared using chi-square tests. A probability value <.05 (2-tailed) was considered significant.

Results

Patient Population

Baseline demographic characteristics and accompanying medical conditions were summarized in Table 1. There was no difference in the baseline demographic or clinical characteristics between the 2 groups.

Table 1.

Patient Characteristics.

Variables	Intensive-Dose Group, n = 50	Moderate-Dose Group, n = 50
Male, n (%)	31 (62)	29 (58)
Age, year (mean ± SD)	64.5 ± 13.8	65.5 ± 6.2
Hypertension, n (%)	29 (58.0)	28 (56.0)
Diabetes mellitus, n (%)	10 (20.0)	11 (22.0)
Current smoker, n (%)	19 (38.0)	18 (36.0)
Family history of CAD, n (%)	4 (8.0)	2 (4.0)
Descending anterior branch, n (%)	30 (60.0)	29 (58.0)
Right coronary artery, n (%)	20 (40.0)	21 (42.0)

Abbreviation: CAD, coronary artery disease.

Out of the 100 recruited patients, 62 patients completed both the baseline and the 9-month follow-up CAG and IVUS evaluations (Figure 1). A total of 38 patients were removed from the study for the following reasons. In all, 22 patients were removed because of their concern over a 2- to 3-fold increase in either liver alanine transaminase (ALT) or CK (18 from the intensive-dose group and 4 from the moderate-dose group). In the moderate-dose group, 13 patients voluntarily withdrew from the 9-month CAG and the IVUS. Another 3 patients in the moderate-dose group were removed because PCI treatment was employed to relieve adverse events.

Figure 1.

Flow of patients through the trial.

Intensive-Dose Atorvastatin Treatment Improved Clinical Symptoms

To evaluate the improvement in clinical symptoms, the following grading scale was used: (1) Excellent: free of chest pain; (2) Effective: decreased intensity or frequency of chest pain; (3) No changes: no changes in intensity or frequency of chest pain; and (4) Worse: increased frequency of chest pain or developed acute MI.

As shown in Table 2, in the intensive-dose group, 30 (60%) patients reported “excellent” and 15 (30%) patients reported “effective,” whereas in the moderate-dose group, 7 (14%) patients reported “excellent” and 9 (18%) patients reported “effective.” In all, 5 (10%) patients reported “no changes” and none reported “worse” in the intensive-dose group, whereas 31 (62%) patients reported “no changes” and 3 (6%) patients reported “worse” in the moderate-dose group and were admitted for PCI treatment.

Table 2.

Clinical Symptoms.

	Excellent n (%)	Effective n (%)	No Changes n (%)	Worse n (%)
Intensive-dose group	30 (60)	15 (30)	5 (10)	0 (0)
Moderate-dose group	7 (14)	9 (18)	31 (62)	3 (6)

Intensive-Dose Atorvastatin Treatment Decreases Both LDL-C and hs-CRP

As shown in Table 3, the baseline lipid profiles between the 2 groups were comparable with respect to their total cholesterol (TC), triglyceride (TG), LDL-C, HDL-C, and hs-CRP. Compared to their baseline values, TC, TG, LDL-C, and hs-CRP decreased and HDL-C increased significantly (P < .01) after the 9-month treatment in both the groups. Significantly, the mean levels of LDL-C after the 9-month treatment in the intensive- and moderate-dose groups were reduced to 62 and 80 mg/dL respectively. The decrease in LDL-C in the intensive-dose group (from 105.55 ± 22.65 to 62.37 ± 15.93 mg/dL) was significantly greater (P < .01) than in the moderate-dose group (from 106.13 ± 20.52 to 80.04 ± 17.77 mg/dL). Reduction of hs-CRP in the intensive-dose group was also significantly greater (P < .01) than that in the moderate-dose group after the 9-month follow-up. Levels of TC and TG were decreased in the intensive-dose group at the end of the follow-up; however, the decrease did not reach statistical significance. Similar to TC and TG, HDL-C was not significantly different between the 2 groups after the 9-month treatment.

Table 3.

Laboratory Results (n = 100).

	Baseline	At 9 Months	P Value Compared to Baseline
TC, mg/dL
Intensive-dose group	228.67 ± 15.49	149.19 ± 21.25	<.01
Moderate-dose group	221.61 ± 20.40	151.37 ± 22.07	<.01
P value between the groups	.13	.69
TG, mg/dL
Intensive-dose group	164.13 ± 56.01	133.65 ± 46.05	<.01
Moderate-dose group	162.26 ± 40.32	143.74 ± 42.80	<.01
P value between the groups	.88	.38
HDL-C, mg/dL
Intensive-dose group	51.45 ± 9.67	58.52 ± 8.87	<.01
Moderate-dose group	51.10 ± 9.52	56.64 ± 9.42	<.01
P value between the groups	.88	.42
LDL-C, mg/dL
Intensive-dose group	105.55 ± 22.65	62.37 ± 15.93	<.01
Moderate-dose group	106.13 ± 20.52	80.04 ± 17.77	<.01
P value between the groups	.92	<.01
hs-CRP, mg/L
Intensive-dose group	5.38 ± 1.48	1.81 ± 0.91	<.01
Moderate-dose group	5.40 ± 1.38	3.38 ± 1.28	<.01
P value between the groups	.87	<.01

Abbreviations: HDL-C, high-density lipoprotein cholestrol; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholestrol; TC, total cholesterol; TG, triglyceride.

Intensive-Dose Atorvastatin Treatment Halts the Progression of Atherosclerotic Plaques

As shown in Table 4, upon enrollment, patients from the 2 treatment groups were comparable in terms of the mean vessel volume, mean lumen volume, and mean plaque volume of the target lesions. After the 9-month treatment, the moderate-dose group showed significantly increased mean vessel volume (P < .05), increased mean plaque volume (P < .05), and decreased mean lumen volume (P < .05) over their baselines, whereas this set of parameters showed no progression over their baselines in the intensive-dose group. When intergroup differences were compared after the 9-month treatment, the mean plaque volume was significantly smaller (P < .01) and mean lumen volume was significantly larger (P < .05) in the intensive-dose group, whereas there was no significant difference in the mean vessel volume between the 2 groups.

Table 4.

Volume Parameters Derived From Intravascular Ultrasound Measurements.

	Baseline	At 9 Months	P Value Compared to Baseline
Vessel volume, mm³
Intensive-dose group	144.97 ± 12.74	145.33 ± 12.74	.68
Moderate-dose group	141.78 ± 10.54	144.67 ± 9.63	<.05
P value between the groups	.29	.84
Lumen volume, mm³
Intensive-dose group	101.71 ± 11.21	103.63 ± 06.50	.07
Moderate-dose group	99.46 ± 7.80	93.89 ± 8.39	<.05
P value between the groups	.36	<.05
Plaque volume, mm³
Intensive-dose group	43.20 ± 6.33	41.70 ± 4.60	.06
Moderate-dose group	42.32 ± 9.33	50.68 ± 9.78	<.05
P value between the groups	.67	<.01

Drug Tolerance and Safety

Neither rhabdomyolysis nor proteinuria was observed in either of the group. In all, 13 patients in the intensive-dose group experienced an increase in ALT, whereas 4 patients in the moderate-dose group exhibited an increase in ALT. Two patients experienced an increase in CK in the intensive-dose group, whereas none in the moderate-dose group exhibited such an increase. According to the international standards, the increase in ALT and CK was not considered as drug side effects because they were less than 3 times the upper limits of normal ranges. Although we recommended continuation of the treatment with close monitoring of patients with increased ALT or CK, unfortunately they chose to stop atorvastatin and withdrew from the trial because of personal concerns.

Discussion

Currently, there is no consensus on the best treatment strategy for patients who present with borderline coronary artery stenosis without clinical signs of ischemia-related congestive heart failure, malignant arrhythmia, hemodynamic changes, increased cardiac enzyme profiles, or ST-segment elevation on ECG. More than a dozen clinical trials have demonstrated that statins, especially atorvastatin, prevent cardiovascular events¹⁰ ^,12,13 and improve survival in patients with prior cardiovascular events or high risk. The statins’ benefits are attributed mostly to their multifaceted functions including inhibition of cholesterol synthesis,¹⁴ ^,15 modulation of immune/inflammatory system,³ ^,16 improved functions of endothelial and vascular smooth muscle cells,¹⁷ reduced thrombus formation, and stabilization or regression of atherosclerotic plaques.⁴ ^,18,19

The CAG provides information on the pathology of atherosclerotic plaques and the severity of luminal stenosis and has been the “golden standard” for diagnosis of CAD. The advent of IVUS provides cardiologists an aided eye to examine the morphology of artery walls including wall structure, luminal dimension, the extent of the lipid-rich atheroma, and calcification and texture of the fibrous cap.¹ ^{-8,11,14,15,18

–22}

In this prospective study, patients with newly diagnosed new-onset unstable angina with borderline lesions were randomly grouped into either moderate-dose (20 mg/d) or intensive-dose (80 mg/d) atorvastatin and treated for 9 months. The therapeutic effects were evaluated in terms of improvement in clinical symptoms, favorable changes in lipid profile, and dampening of the systemic inflammation. Furthermore, the morphological changes of diseased arteries were evaluated using CAD combined with IVUS. We report that although both treatment dosages significantly decreased TC, TG, LDL-C, and hs-CRP and concomitantly increased HDL-C, only intensive-dose treatment reduced LDL-C to a significantly greater extent and halted the progression of atherosclerotic plaques after a 9-month treatment.

Descriptive studies have repeatedly shown that levels of blood cholesterol are strongly correlated with coronary mortality,²³ so lowering LDL-C is one of the most important criteria in selecting drugs for CAD. Although there is no defined safe LDL-C level to achieve, the guidelines recommend targeting the LDL-C level to less than 100 mg/dL to prevent coronary events for treatment of patients with established CAD and patients with acute coronary syndromes and no persistent ST-segment elevation.²² ^,24
–26 In the PROVE IT trial, further coronary event rate reduction was observed by reducing the LDL-C levels to 70 mg/dL.¹⁰ In the ASTEROID trial, the levels of LDL-C achieved were 61 mg/dL with rosuvastatin 40 mg daily, which resulted in highly significant regression of coronary atherosclerosis²⁷ without increased side effects or adverse events. They recommend that the optimal strategy for lipid lowering in patients with CAD was to achieve the lowest possible LDL-C level without causing any adverse effects. In the present study, both dosages reduced LDL-C level to less than 100 mg/dL. It is plausible that intensive dosage improves clinical symptoms and therapy response (60% = excellent, 30% = effective, and none reported = worse) via reducing LDL-C level to below 70 mg/dL. In contrast, the moderate-dose group reports an inferior response (14% = excellent, 18% = effective, and 6% = Worse).

Until now, most large atorvastatin clinical trials have been conducted in the Western population, which showed that intensive dosage of atorvastatin greatly decreased the levels of LDL-C and atheroma volume when compared to other statins of equivalent dosages or moderate dosage of atorvastatin.²⁸ In the ESTABLISH trial conducted in Japan, patients with ACS were treated with atorvastatin 20 mg daily for 6 months and showed a reduction of 13.1% in plaque volume versus an 8.7% increase in the control group.¹⁵ Although we demonstrated a significant decrease in the TC, hs-CRP, and LDL-C and a significant increase in HDL-C over their corresponding baselines, the mean plaque volume was significantly increased (P < .05) as measured by IVUS in our 20 mg daily treatment. In contrast, our 9-month 80 mg atorvastatin daily treatment not only substantially reduced the levels of LDL-C and hs-CRP but also stabilized the target atherosclerotic plaques.

Although intensive-dose atorvastatin regimens are statistically associated with an increased risk of myopathy, elevated transamineases, and other statin-related side effects,²³ the ASAP trial¹⁹ and the ARBITER trial²⁹ reported that atorvastatin at 80 mg/d was well tolerated and no patients had any drug-related side effects.

In our 80 mg/d treatment group, 13 patients had increased ALT and 2 patients had increased CK. However, the increase was lower than 3 times the upper limits of normal range that was defined as drug side effects. We also noticed that the percentage of patient withdrawals because of increased liver enzymes was higher than that in other similar trials, suggesting an intolerance of 80 mg/d dosage in Chinese population. This discrepancy might be attributed to the difference in drug metabolism/excretion between the Chinese and the Western populations and the higher per body weight dosage of atorvastatin used in this trial. Our findings warrant further dosage adjustment to improve therapeutic potentials of atorvastatin.

Conclusion

Intensive atorvastatin treatment for 9 months can significantly lower LDL-C and hs-CRP and stabilize or regress the progression of minimally obstructive atherosclerotic plaques in patients with new-onset unstable angina.

Footnotes

Authors’ Note

This study was registered and the trial identification number was ChiCTR-ONRC-12002035 (). Xin Zhang and Hairong Wang contributed equally to this work.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by a leadership award to H.W. (PWRd2011-04) and by the key discipline construction funding (PWZxk201005) from the Pudong New Area Health Bureau, Shanghai, China.

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