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Original research
Difference in statin effects on neointimal coverage after implantation of drug-eluting stents Hiroyuki Yamamoto, Shinichiro Ikuta, Kazuhiro Kobuke, Masakazu Yasuda, Tomoyuki Ikeda, Kenji Yamaji, Masafumi Ueno, Yoshitaka Iwanaga and Shunichi Miyazaki Objective This study was carried out to examine the difference in effects between rosuvastatin and pravastatin on neointimal formation after the placement of a drug-eluting stent (DES). Materials and methods Forty patients who underwent placement of a DES in our hospital were prospectively randomized to receive rosuvastatin (n = 20) or pravastatin (n = 20), and analyzed by optical coherence tomography at the chronic stage. The main outcome measure was comparison of neointimal coverage analyzed at a strut level. Results A significant reduction in total cholesterol, low-density lipoprotein, and white blood cell count was observed during the study in the rosuvastatin group (total cholesterol, from 4.82±0.90 to 4.43±0.77 mmol/l, P = 0.038; low-density lipoprotein, from 2.85±0.76 to 2.34±0.57 mmol/l, P = 0.006; white blood cell count, from 5810±1399 to 5355±1257/ll, P = 0.048), but not in the pravastatin group. Although not statistically significant, C-reactive protein was lower in the rosuvastatin than in the pravastatin group at the chronic stage (1.14±1.21 vs. 7.67±13.67 mg/l, P = 0.051). Malapposed and uncovered struts were significantly less frequent in the rosuvastatin group than in the pravastatin group (malapposed, 0.06 vs. 0.60%, P < 0.001; uncovered, 6.49 vs. 11.29%, P < 0.001).
The difference in uncovered struts was maintained even when stent types were analyzed separately (everolimus-eluting stent, 4.81 vs. 6.21%, P = 0.007; sirolimus-eluting stent, 14.40 vs. 20.86%, P < 0.001). Comparison of neointimal thickness between the rosuvastatin and the pravastatin groups showed inconsistent results depending on the stent types analyzed. Conclusion Compared with pravastatin, the use of rosuvastatin resulted in lower frequency of uncovered and malapposed struts after the placement of a DES, which might be mediated through improved inflammatory and c 2014 Wolters lipid profiles. Coron Artery Dis 25:290–295 Kluwer Health | Lippincott Williams & Wilkins. Coronary Artery Disease 2014, 25:290–295 Keywords: neointima, optical coherence tomography, pravastatin, rosuvastatin, statins Department of Medicine, Division of Cardiology, Faculty of Medicine, Kinki University, Osaka, Japan Correspondence to Shunichi Miyazaki, MD, PhD, Department of Medicine, Division of Cardiology, Faculty of Medicine, Kinki University, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511, Japan Tel: + 81 72 366 0221; fax: + 81 72 368 2378; e-mail: [email protected] Received 19 December 2013 Revised 31 January 2014 Accepted 3 February 2014
Introduction
Materials and methods
A drug-eluting stent (DES) reduces restenosis and repeat revascularization rate after a coronary intervention compared with a bare metal stent (BMS) [1]. However, delayed vascular healing because of DES causes an increase in uncovered struts [2,3], which can lead to late stent thrombosis [4]. Strong statin therapy not only exerts a huge lipid-lowering effect but also shows pleiotropic effects such as improvement in endothelial function and reduction of restenosis after BMS implantation [5]. However, the effect of strong statin therapy is not clear at the chronic phase of neointimal stent coverage in DES. Recently, intracoronary optical coherence tomography (OCT) has emerged as a high-resolution imaging method for analysis of neointima that grows over the stent [6,7]. Here, we report the results of an OCT-based analysis on the effect of statin therapy on neointimal coverage after implantation of DES in our hospital.
Study design and population
c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-6928
This randomized, open-label, single-center study prospectively enrolled 40 patients who were implanted with DES for coronary artery disease and were eligible for statin therapy [low-density lipoprotein (LDL) was more than 2.59 mmol/l or any statin had already been in use]. The enrollment was performed consecutively between August 2009 and January 2012. The exclusion criteria were acute myocardial infarction, cardiopulmonary arrest, congestive heart failure in New York Heart Association functional class II–IV, left main coronary artery disease, bypass graft lesion and lesions unsuitable for OCT (e.g. ostium lesions), in-stent restenosis, medical condition that the physician in charge considered as unsuitable for OCT (impaired renal function, anemia, etc.), a history of poor compliance with medications, and unwillingness or inability to provide informed consent. Two stents with DOI: 10.1097/MCA.0000000000000102
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Statin effects on neointima of drug-eluting stents Yamamoto et al. 291
their edges overlapped were counted as a single stent, with its length and diameter substituted with the sum and the average of these two stents, respectively. Eligible patients provided written informed consent and were randomized 1 : 1 to receive rosuvastatin or pravastatin at stent implantation using a computer-generated random number table on the order of acquisition of informed consent. The dose of statin was titrated to achieve an LDL value of less than 2.59 mmol/l at the discretion of the physician in charge of each patient. All patients received dual antiplatelet therapy (oral aspirin 100 mg/ day and thienopyridine, either ticlopidine 200 mg/day or clopidogrel 75 mg/day) during the study period. This study was approved by our institutional ethics committee.
Fig. 1
Optical coherence tomographic image acquisition and analysis
OCT was performed B9 months after DES implantation. The time-domain OCT system (Model M2 Cardiology Imaging System; LightLab Imaging Inc., Westford, Massachusetts, USA) was used in the study. After the passage of a 0.014-inch coronary guidewire across the lesion, an occlusion balloon catheter (Helios; LightLab Imaging Inc.) was passed through the target stent and exchanged with an OCT image wire (Imaging Wire; LightLab Imaging Inc.). The occlusion balloon catheter was pulled back proximal to the target stent, where it was inflated, and lactated Ringer’s solution was flushed continuously through the lumen of the occlusion balloon catheter. Acquired OCT images were digitally stored. Quantitative assessment was performed using the OCT offline analysis software (LightLab Imaging Inc.). Cross-sectional OCT images were analyzed every 1 mm over the entire length of each stent. Uncovered struts were defined as stents that had no detectible covering tissue with OCT (Fig. 1). When neointimal coverage over a strut was observed, its thickness was measured from the neointimal surface to the center reflection of the strut. Malapposed struts were defined as struts whose center reflection was elevated from the vessel wall, that is, by more than the sum of actual strut thickness, polymer thickness, and the OCT resolution limit [81 + 8 + 20 mm in the everolimus-eluting stent (EES), 140 + 10 + 20 mm in the sirolimus-eluting stent (SES), 125 + 20 + 20 mm in the biolimus-eluting stent, and 130 + 14 + 20 mm in the paclitaxel-eluting stent] [8,9].
Blood pressure, and biochemical and hematological markers
As factors that may affect neointimal formation over stents, we evaluated blood pressure and biochemical or hematological markers as follows: total cholesterol, high-density lipoprotein, triglyceride, LDL, hemoglobin A1c, high-sensitive C-reactive protein (hs-CRP), creatinine, uric acid, and white blood cell (WBC) and platelet counts. They were measured before stent implantation and at the time of OCT analysis.
A representative optical coherence tomographic image of uncovered struts. The status of well apposed without neointimal coverage can be clearly observed (blue arrows).
Statistical analysis
Continuous variables were expressed as mean±SD or median [interquartile range (IQR), first quartile–third quartile], as indicated. Differences in categorical variables were assessed using Fisher’s exact test. Two-group comparisons were made using the unpaired or the paired t-test or the Mann–Whitney U-test, as appropriate. Data were analyzed using R version 3.0.1 (Free Software Foundation, Boston, Massachusetts, USA) [10]. A P value of less than 0.05 was considered statistically significant.
Results Patient, stent, and lesion characteristics
Forty patients were randomized to the rosuvastatin group [20 patients with 23 stents (SES, 3; EES, 18; others, 2)] and the pravastatin group [20 patients with 28 stents (SES, 8; EES, 16; others, 4)]. An average daily statin dose was 3.1±1.7 mg in the rosuvastatin group and 11.0±3.0 mg in the pravastatin group. Patient characteristics are summarized in Table 1. There was no significant difference in age, sex, and follow-up interval between the two groups. Stent types and lesion characteristics are summarized in Table 2. There was no significant difference in stent diameter, stent length, frequency of overlapping stents, target location, or frequency of type B2/C lesion between the two groups. The SES usage was less in the rosuvastatin group, but there was no significant difference. We performed intravascular ultrasound just after the placement of stents and confirmed no malapposition in any of the patients.
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292 Coronary Artery Disease 2014, Vol 25 No 4
Table 1
Clinical characteristics of the patients
Comparison of blood pressures, blood, and serum markers at baseline and at follow-up
Table 3
Rosuvastatin (n = 20) Pravastatin (n = 20) Age (years) Male Follow-up interval (days) BMI (kg/m2) Ejection fraction (%) Multivessel disease Diagnosis Hypertension Diabetes Smoking Acute coronary syndrome Drugs b-Blocker ACEI/ARB Calcium channel blocker Hypoglycemics
P
70.0±6.8 16 305.4±43.6 25.9±4.4 58.0±10.7 12
70.5±8.2 17 292.6±37.1 24.8±3.9 64.0±10.4 11
0.838 1.0 0.336 0.432 0.094 1.0
20 14 10 7
20 9 13 10
1.0 0.200 0.523 0.523
20 12 10 11
14 12 15 6
0.020 1.0 0.190 0.200
Continuous values were expressed as mean±SD. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
Table 2
Stent and stented-lesion characteristics Rosuvastatin (n = 23)
Type of stent EES SES Others Stent diameter (mm) Stent length (mm) Overlapping stents Target location LAD LCX RCA Type B2/C lesion
Pravastatin (n = 28)
P 0.274
18 3 2 (PES, 1; BES, 1) 2.95±0.41 23.0±10.8 4
16 8 4 (BES, 4) 2.99±0.70 25.1±17.9 4
5 6 12 15
8 9 11 19
0.840 0.517 1.0 0.630
1.0
Continuous values were expressed as mean±SD. BES, biolimus-eluting stent; EES, everolimus-eluting stent; LAD, left anterior descending; LCX, left circumflex; PES, paclitaxel-eluting stent; RCA, right coronary artery; SES, sirolimus-eluting stent.
Measured factors that may affect neointimal formation
Blood pressures, and biochemical and hematological markers that were measured at baseline and at follow-up are described in Table 3. Among lipid profiles, total cholesterol and LDL were significantly decreased and triglyceride was significantly increased during the study period in the rosuvastatin group (total cholesterol, from 4.82±0.90 to 4.43±0.77 mmol/l, P = 0.038; LDL, from 2.85±0.76 to 2.34± 0.57 mmol/l, P = 0.006; triglyceride, from 1.63±0.89 to 1.91±0.99 mmol/l, P = 0.037), but they were not altered in the pravastatin group. Among inflammatory parameters, the WBC count was significantly decreased in the rosuvastatin group (5810±1399 vs. 5355±1257/ml, P = 0.048), but not in the pravastatin group. Although it did not reach statistical significance, hs-CRP at follow-up was lower in the rosuvastatin group than in the pravastatin group (1.14±1.21 vs. 7.67±13.67 mg/l, P = 0.051). Quantitative optical coherence tomography analysis
Figure 2 shows the histographic distribution of neointimal thickness of all struts, with those of the rosuvastatin and
Rosuvastatin BP systole (mmHg) At baseline 124.3±14.8 At follow-up 126.0±16.2 Change (%) 2.6±16.5 BP diastole (mmHg) At baseline 68.4±9.8 At follow-up 66.6±9.5 Change (%) – 1.4±15.5 Total cholesterol (mmol/l) At baseline 4.82±0.90 At follow-up 4.43±0.77w Change (%) – 6.6±14.8 HDL (mmol/l) At baseline 1.19±0.23 At follow-up 1.21±0.25 Change (%) 2.5±15.7 Triglyceride (mmol/l) At baseline 1.63±0.89 At follow-up 1.91±0.99w Change (%) 23.7±38.8 LDL (mmol/l) At baseline 2.85±0.76 At follow-up 2.34±0.57z Change (%) – 13.9±22.0 HbA1c (%) At baseline 6.08±0.69 At follow-up 6.03±0.77 Change (%) – 0.8±5.9 hs-CRP (mg/l) At baseline 1.87±1.59 At follow-up 1.14±1.21 Change (%) 68.5±283.0 Creatinine (mmol/l) At baseline 75.8±18.9 At follow-up 75.5±23.7 Change (%) – 1.3±20.2 Uric acid (mmol/l) At baseline 353.9±63.0 At follow-up 349.5±56.8 Change (%) – 0.4±11.2 WBC (/ml) At baseline 5810±1399 At follow-up 5355±1257w Change (%) – 6.1±15.6 3 Platelet ( 10 /ml) At baseline 195.8±51.7 At follow-up 185.8±45.3 Change (%) – 3.7±15.4
Pravastatin
P
127.5±19.3 123.8±14.4 – 0.8±19.4
0.575 0.667 0.570
72.7±10.3 68.5±9.9 – 4.4±16.9
0.194 0.550 0.574
4.87±0.87 4.62±0.85 – 3.7±18.2
0.861 0.481 0.590
1.28±0.24 1.31±0.27 2.6±12.3
0.245 0.244 0.975
1.64±0.94 1.75±0.99 15.8±49.4
0.988 0.627 0.590
2.84±0.76 2.50±0.90 – 8.5±35.1
0.987 0.515 0.573
5.86±0.80 5.84±0.69 – 0.3±9.2
0.371 0.427 0.669
3.95±6.24 7.67±13.67 1470.6±5375.9
0.174 0.051 0.270
115.2±155.1 112.4±133.0 2.7±10.3
0.284 0.246 0.452
364.3±87.8 359.6±65.3 1.6±18.1
0.677 0.613 0.687
6120±2064 5770±1606 – 2.6±19.8
0.591 0.381 0.544
197.2±55.2 197.8±77.1 – 0.9±21.2
0.933 0.563 0.639
Continuous values were expressed as mean±SD. BP, blood pressure; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; hs-CRP, high-sensitive C-reactive protein; LDL, low-density lipoprotein; WBC, white blood cell. wP < 0.05 versus at baseline. zP < 0.01 versus at baseline.
the pravastatin groups summated separately and presented as an overlaid single graph. A bimodal distribution was obvious, where uncovered struts showed a single peak and the other peak showed a skewed distribution. Thus, we analyzed the uncovered and covered struts separately, comparing the former with the frequency and comparing the latter with the thickness of neointima between the rosuvastatin and the pravastatin groups. The uncovered struts were significantly less frequent in the rosuvastatin group than in the pravastatin group (6.49 vs. 11.29%, P < 0.001) (Table 4). Nonparametric comparison of the neointimal thickness of covered struts indicated a
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Statin effects on neointima of drug-eluting stents Yamamoto et al. 293
significant difference, where the rosuvastatin group more frequently had thinner neointima than the pravastatin group (Table 4 and Fig. 2). Among four types of stents used in our study, EES and SES constituted most part of the struts analyzed [EES, 7689 struts (70.0%); SES, 2233 struts (20.3%)]. When struts of EES and SES were analyzed individually, the same result was obtained for the ratio of uncovered struts: it was less frequent in the rosuvastatin group than in the pravastatin group in either stent (EES, 4.81 vs. 6.21%, P < 0.007; SES, 14.40 vs. 20.86%, P < 0.001) (Table 5 and Fig. 3). Although malapposed struts were observed only in SES, their ratio was significantly lower in the rosuvastatin group than in the pravastatin group when compared in the subgroups of SES (Table 5) as well as in all groups of stents (Table 4). In contrast, no consistent effect of statins was observed in neointimal thickness in the subgroup analysis with types of stents: the rosuvastatin group showed thinner and thicker neointima than the pravastatin group in EES
Fig. 2
12
Rosuvastatin
Ratio in each statin group (%)
10
Pravastatin
8
Overlap 6
4
2 0 0
200
400
600
800
Neointimal thickness (μm) Comparison of the histographic distribution of neointimal thickness in all stents. The rosuvastatin group and the pravastatin group are shown as blue and yellow bars, respectively, and their overlap is shown in French beige. The distribution was two-peaked, with the uncovered struts constituting a single peak. When neointimal thicknesses of covered struts were compared, they were significantly thicker in the pravastatin group than in the rosuvastatin group as shown by the Mann–Whitney U-test.
Table 4
[110 mm (IQR, 60–180 mm) vs. 120 mm (IQR, 70–190 mm), P < 0.001] and in SES [150 mm (IQR, 100–210 mm) vs. 110 mm (IQR, 80–160 mm), P < 0.01], respectively (Table 5 and Fig. 3).
Discussion Previous pathologic and OCT studies have shown that more frequent uncovered struts were observed after the placement of DES compared with BMS [11,12]. The larger number of uncovered struts is considered to be one of the causes for late stent thrombosis [4]. Therefore, it is important to quantitatively analyze neointimal strut coverage after DES implantation. OCT analysis of neointimal coverage of implanted DES during the follow-up period in this study showed that rosuvastatin treatment significantly reduced uncovered strut ratio, which was consistently observed in different types of stents. Pleiotropic effect of statins
The vascular healing process in the early phase after stent implantation consists of mural thrombus formation and of accumulation of inflammatory cells such as macrophages. Then, the proportion of smooth muscle cells is increased and re-endothelialization occurs. This vascular healing may be delayed by DES because of inhibition of the migration and proliferation of endothelial cell-like cells that originated from mononuclear cells [13]. Goto et al. [12] showed that an uncovered strut rate and hs-CRP were significantly higher in the SES than in the BMS. This led to the hypothesis that persistent inflammation is one of the causes of delayed vascular healing. Statin therapy has been shown to improve endothelial function, reduce hs-CRP, and suppress atherosclerosis [14–16]. Nissen et al. [17] showed that the reduced rate of progression of atherosclerosis with statin therapy was associated with a reduction in atherogenic lipoproteins and CRP. Although it did not reach statistical significance, hs-CRP was lower in the rosuvastatin group than in the pravastatin group at followup in our study. The paired t-test showed a significant reduction in WBC counts only in the rosuvastatin group. A lack of a significant reduction in hs-CRP may have been caused by a small number of patients included in our study. In addition to these pleiotropic effects, recent studies have shown that statin therapy improves vascular healing. Fukuda et al. [18] showed that fluvastatin accelerates re-endothelialization that was impaired by sirolimus treatment in the mouse femoral arteries. Wang
Comparison at the strut level in all stents
Malapposed struts Uncovered struts Neointimal thickness (mm)
Rosuvastatin (n = 5102) [n (%)]
Pravastatin (n = 5882) [n (%)]
P
3 (0.06) 331 (6.49) 110 (IQR, 60–180)
35 (0.60) 664 (11.29) 110 (IQR, 70–180)
< 0.001 < 0.001 0.002
Continuous values were expressed as median (IQR). IQR, interquartile range.
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Coronary Artery Disease 2014, Vol 25 No 4
Table 5
Comparison of stents and struts in subgroups of everolimus-eluting stent and sirolimus-eluting stent EES
Number of stents Stent diameter (mm) Stent length (mm) Overlapping stent Type B2/C lesion Number of struts Malapposed struts [n (%)] Uncovered struts [n (%)] Neointimal thickness (mm)
SES
Rosuvastatin
Pravastatin
P
18 2.97±0.42 22.4±10.8 3 11 4033 0 (0) 194 (4.81) 110 (IQR, 60–180)
16 3.04±0.85 25.8±20.5 3 11 3656 0 (0) 227 (6.21) 120 (IQR, 70–190)
0.793 0.574 1.0 0.728 1.0 0.007 < 0.001
Rosuvastatin
Pravastatin
3 2.71±0.21 29.0±11.8 1 3 771 3 (0.39) 111 (14.40) 150 (IQR, 100–210)
8 2.91±0.43 25.9±16.1 1 4 1462 35 (2.39) 305 (20.86) 110 (IQR, 80–160)
P 0.402 0.776 0.490 0.236 < 0.001 < 0.001 < 0.001
Continuous values were expressed as mean±SD or median (IQR) as appropriate. EES, everolimus-eluting stent; IQR, interquartile range; SES, sirolimus-eluting stent.
Fig. 3
(a)
(b)
8
20 Ratio in each statin group (%)
Rosuvastatin
Rosuvastatin
6 Pravastatin
Pravastatin
15
Overlap
4
Overlap 10
2
5
0
0 0
200
400
600
800
0
200
400
600
800
Neointimal thickness (μm)
Neointimal thickness (μm)
Comparison of the histographic distribution of neointimal thickness in everolimus-eluting stent (EES) (a) and sirolimus-eluting stent (SES) (b). The rosuvastatin group and the pravastatin group are shown as blue and yellow bars, respectively, and their overlap is shown in French beige. The distribution was two-peaked in either stent, with the uncovered struts constituting a single peak and more frequent in the pravastatin group. Neointimal thickness of covered struts was different between EES and SES: it was thicker in the pravastatin group in EES, whereas it was thicker in the rosuvastatin group in SES.
et al. [19] showed that atorvastatin accelerates both reendothelialization and neointimal coverage after SES implantation in porcine coronary artery. Differences in the effect on re-endothelialization between rosuvastatin and pravastatin would be an interesting topic that awaits further study.
LDL was detected in the paired t-test in the rosuvastatin group, but not in the pravastatin group, which could support an idea that the stronger lipid-lowering effect of rosuvastatin than pravastatin could have contributed toward less uncovered or malapposed struts.
Lipid-lowering effect of statins
Study limitation
It has been reported that rosuvastatin exerts a stronger effect of decreasing LDL cholesterol than pravastatin [20,21]. In the present study, no significant difference between the two groups was observed in LDL values at baseline and at followup, and in the rate of change in LDL, which may have been because of the small number of patients in our study. However, a significant reduction in total cholesterol and
First, the number of patients studied was small. Second, we randomized statins into two groups, but we did not randomize stent types. However, the number of struts analyzed was large enough to yield smoothness of distribution curves in Figs 2 and 3. Third, uncovered struts cannot be discriminated from struts that were covered by a single layer of endothelium or neointima of
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Statin effects on neointima of drug-eluting stents Yamamoto et al. 295
up to 20 mm thickness, either of which cannot be visualized even under resolution of OCT [6,7,22]. Conclusion
Rosuvastatin led to a lower frequency of uncovered and malapposed struts than pravastatin, which might lead to lower frequency of very late stent thrombosis. Rosuvastatin would be more effective in preventing very late stent thrombosis than pravastatin after DES placement.
Acknowledgements
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Conflicts of interest
S.M. has received unrestricted research grants from AstraZeneca Co. Ltd, Daiichi-Sankyo Pharmaceutical Co. Ltd, and Shionogi & Co. Ltd. For the remaining authors there are no conflicts of interest.
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Original research
Difference in statin effects on neointimal coverage after implantation of drug-eluting stents Hiroyuki Yamamoto, Shinichiro Ikuta, Kazuhiro Kobuke, Masakazu Yasuda, Tomoyuki Ikeda, Kenji Yamaji, Masafumi Ueno, Yoshitaka Iwanaga and Shunichi Miyazaki Objective This study was carried out to examine the difference in effects between rosuvastatin and pravastatin on neointimal formation after the placement of a drug-eluting stent (DES). Materials and methods Forty patients who underwent placement of a DES in our hospital were prospectively randomized to receive rosuvastatin (n = 20) or pravastatin (n = 20), and analyzed by optical coherence tomography at the chronic stage. The main outcome measure was comparison of neointimal coverage analyzed at a strut level. Results A significant reduction in total cholesterol, low-density lipoprotein, and white blood cell count was observed during the study in the rosuvastatin group (total cholesterol, from 4.82±0.90 to 4.43±0.77 mmol/l, P = 0.038; low-density lipoprotein, from 2.85±0.76 to 2.34±0.57 mmol/l, P = 0.006; white blood cell count, from 5810±1399 to 5355±1257/ll, P = 0.048), but not in the pravastatin group. Although not statistically significant, C-reactive protein was lower in the rosuvastatin than in the pravastatin group at the chronic stage (1.14±1.21 vs. 7.67±13.67 mg/l, P = 0.051). Malapposed and uncovered struts were significantly less frequent in the rosuvastatin group than in the pravastatin group (malapposed, 0.06 vs. 0.60%, P < 0.001; uncovered, 6.49 vs. 11.29%, P < 0.001).
The difference in uncovered struts was maintained even when stent types were analyzed separately (everolimus-eluting stent, 4.81 vs. 6.21%, P = 0.007; sirolimus-eluting stent, 14.40 vs. 20.86%, P < 0.001). Comparison of neointimal thickness between the rosuvastatin and the pravastatin groups showed inconsistent results depending on the stent types analyzed. Conclusion Compared with pravastatin, the use of rosuvastatin resulted in lower frequency of uncovered and malapposed struts after the placement of a DES, which might be mediated through improved inflammatory and c 2014 Wolters lipid profiles. Coron Artery Dis 25:290–295 Kluwer Health | Lippincott Williams & Wilkins. Coronary Artery Disease 2014, 25:290–295 Keywords: neointima, optical coherence tomography, pravastatin, rosuvastatin, statins Department of Medicine, Division of Cardiology, Faculty of Medicine, Kinki University, Osaka, Japan Correspondence to Shunichi Miyazaki, MD, PhD, Department of Medicine, Division of Cardiology, Faculty of Medicine, Kinki University, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511, Japan Tel: + 81 72 366 0221; fax: + 81 72 368 2378; e-mail: [email protected] Received 19 December 2013 Revised 31 January 2014 Accepted 3 February 2014
Introduction
Materials and methods
A drug-eluting stent (DES) reduces restenosis and repeat revascularization rate after a coronary intervention compared with a bare metal stent (BMS) [1]. However, delayed vascular healing because of DES causes an increase in uncovered struts [2,3], which can lead to late stent thrombosis [4]. Strong statin therapy not only exerts a huge lipid-lowering effect but also shows pleiotropic effects such as improvement in endothelial function and reduction of restenosis after BMS implantation [5]. However, the effect of strong statin therapy is not clear at the chronic phase of neointimal stent coverage in DES. Recently, intracoronary optical coherence tomography (OCT) has emerged as a high-resolution imaging method for analysis of neointima that grows over the stent [6,7]. Here, we report the results of an OCT-based analysis on the effect of statin therapy on neointimal coverage after implantation of DES in our hospital.
Study design and population
c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-6928
This randomized, open-label, single-center study prospectively enrolled 40 patients who were implanted with DES for coronary artery disease and were eligible for statin therapy [low-density lipoprotein (LDL) was more than 2.59 mmol/l or any statin had already been in use]. The enrollment was performed consecutively between August 2009 and January 2012. The exclusion criteria were acute myocardial infarction, cardiopulmonary arrest, congestive heart failure in New York Heart Association functional class II–IV, left main coronary artery disease, bypass graft lesion and lesions unsuitable for OCT (e.g. ostium lesions), in-stent restenosis, medical condition that the physician in charge considered as unsuitable for OCT (impaired renal function, anemia, etc.), a history of poor compliance with medications, and unwillingness or inability to provide informed consent. Two stents with DOI: 10.1097/MCA.0000000000000102
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Statin effects on neointima of drug-eluting stents Yamamoto et al. 291
their edges overlapped were counted as a single stent, with its length and diameter substituted with the sum and the average of these two stents, respectively. Eligible patients provided written informed consent and were randomized 1 : 1 to receive rosuvastatin or pravastatin at stent implantation using a computer-generated random number table on the order of acquisition of informed consent. The dose of statin was titrated to achieve an LDL value of less than 2.59 mmol/l at the discretion of the physician in charge of each patient. All patients received dual antiplatelet therapy (oral aspirin 100 mg/ day and thienopyridine, either ticlopidine 200 mg/day or clopidogrel 75 mg/day) during the study period. This study was approved by our institutional ethics committee.
Fig. 1
Optical coherence tomographic image acquisition and analysis
OCT was performed B9 months after DES implantation. The time-domain OCT system (Model M2 Cardiology Imaging System; LightLab Imaging Inc., Westford, Massachusetts, USA) was used in the study. After the passage of a 0.014-inch coronary guidewire across the lesion, an occlusion balloon catheter (Helios; LightLab Imaging Inc.) was passed through the target stent and exchanged with an OCT image wire (Imaging Wire; LightLab Imaging Inc.). The occlusion balloon catheter was pulled back proximal to the target stent, where it was inflated, and lactated Ringer’s solution was flushed continuously through the lumen of the occlusion balloon catheter. Acquired OCT images were digitally stored. Quantitative assessment was performed using the OCT offline analysis software (LightLab Imaging Inc.). Cross-sectional OCT images were analyzed every 1 mm over the entire length of each stent. Uncovered struts were defined as stents that had no detectible covering tissue with OCT (Fig. 1). When neointimal coverage over a strut was observed, its thickness was measured from the neointimal surface to the center reflection of the strut. Malapposed struts were defined as struts whose center reflection was elevated from the vessel wall, that is, by more than the sum of actual strut thickness, polymer thickness, and the OCT resolution limit [81 + 8 + 20 mm in the everolimus-eluting stent (EES), 140 + 10 + 20 mm in the sirolimus-eluting stent (SES), 125 + 20 + 20 mm in the biolimus-eluting stent, and 130 + 14 + 20 mm in the paclitaxel-eluting stent] [8,9].
Blood pressure, and biochemical and hematological markers
As factors that may affect neointimal formation over stents, we evaluated blood pressure and biochemical or hematological markers as follows: total cholesterol, high-density lipoprotein, triglyceride, LDL, hemoglobin A1c, high-sensitive C-reactive protein (hs-CRP), creatinine, uric acid, and white blood cell (WBC) and platelet counts. They were measured before stent implantation and at the time of OCT analysis.
A representative optical coherence tomographic image of uncovered struts. The status of well apposed without neointimal coverage can be clearly observed (blue arrows).
Statistical analysis
Continuous variables were expressed as mean±SD or median [interquartile range (IQR), first quartile–third quartile], as indicated. Differences in categorical variables were assessed using Fisher’s exact test. Two-group comparisons were made using the unpaired or the paired t-test or the Mann–Whitney U-test, as appropriate. Data were analyzed using R version 3.0.1 (Free Software Foundation, Boston, Massachusetts, USA) [10]. A P value of less than 0.05 was considered statistically significant.
Results Patient, stent, and lesion characteristics
Forty patients were randomized to the rosuvastatin group [20 patients with 23 stents (SES, 3; EES, 18; others, 2)] and the pravastatin group [20 patients with 28 stents (SES, 8; EES, 16; others, 4)]. An average daily statin dose was 3.1±1.7 mg in the rosuvastatin group and 11.0±3.0 mg in the pravastatin group. Patient characteristics are summarized in Table 1. There was no significant difference in age, sex, and follow-up interval between the two groups. Stent types and lesion characteristics are summarized in Table 2. There was no significant difference in stent diameter, stent length, frequency of overlapping stents, target location, or frequency of type B2/C lesion between the two groups. The SES usage was less in the rosuvastatin group, but there was no significant difference. We performed intravascular ultrasound just after the placement of stents and confirmed no malapposition in any of the patients.
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292 Coronary Artery Disease 2014, Vol 25 No 4
Table 1
Clinical characteristics of the patients
Comparison of blood pressures, blood, and serum markers at baseline and at follow-up
Table 3
Rosuvastatin (n = 20) Pravastatin (n = 20) Age (years) Male Follow-up interval (days) BMI (kg/m2) Ejection fraction (%) Multivessel disease Diagnosis Hypertension Diabetes Smoking Acute coronary syndrome Drugs b-Blocker ACEI/ARB Calcium channel blocker Hypoglycemics
P
70.0±6.8 16 305.4±43.6 25.9±4.4 58.0±10.7 12
70.5±8.2 17 292.6±37.1 24.8±3.9 64.0±10.4 11
0.838 1.0 0.336 0.432 0.094 1.0
20 14 10 7
20 9 13 10
1.0 0.200 0.523 0.523
20 12 10 11
14 12 15 6
0.020 1.0 0.190 0.200
Continuous values were expressed as mean±SD. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
Table 2
Stent and stented-lesion characteristics Rosuvastatin (n = 23)
Type of stent EES SES Others Stent diameter (mm) Stent length (mm) Overlapping stents Target location LAD LCX RCA Type B2/C lesion
Pravastatin (n = 28)
P 0.274
18 3 2 (PES, 1; BES, 1) 2.95±0.41 23.0±10.8 4
16 8 4 (BES, 4) 2.99±0.70 25.1±17.9 4
5 6 12 15
8 9 11 19
0.840 0.517 1.0 0.630
1.0
Continuous values were expressed as mean±SD. BES, biolimus-eluting stent; EES, everolimus-eluting stent; LAD, left anterior descending; LCX, left circumflex; PES, paclitaxel-eluting stent; RCA, right coronary artery; SES, sirolimus-eluting stent.
Measured factors that may affect neointimal formation
Blood pressures, and biochemical and hematological markers that were measured at baseline and at follow-up are described in Table 3. Among lipid profiles, total cholesterol and LDL were significantly decreased and triglyceride was significantly increased during the study period in the rosuvastatin group (total cholesterol, from 4.82±0.90 to 4.43±0.77 mmol/l, P = 0.038; LDL, from 2.85±0.76 to 2.34± 0.57 mmol/l, P = 0.006; triglyceride, from 1.63±0.89 to 1.91±0.99 mmol/l, P = 0.037), but they were not altered in the pravastatin group. Among inflammatory parameters, the WBC count was significantly decreased in the rosuvastatin group (5810±1399 vs. 5355±1257/ml, P = 0.048), but not in the pravastatin group. Although it did not reach statistical significance, hs-CRP at follow-up was lower in the rosuvastatin group than in the pravastatin group (1.14±1.21 vs. 7.67±13.67 mg/l, P = 0.051). Quantitative optical coherence tomography analysis
Figure 2 shows the histographic distribution of neointimal thickness of all struts, with those of the rosuvastatin and
Rosuvastatin BP systole (mmHg) At baseline 124.3±14.8 At follow-up 126.0±16.2 Change (%) 2.6±16.5 BP diastole (mmHg) At baseline 68.4±9.8 At follow-up 66.6±9.5 Change (%) – 1.4±15.5 Total cholesterol (mmol/l) At baseline 4.82±0.90 At follow-up 4.43±0.77w Change (%) – 6.6±14.8 HDL (mmol/l) At baseline 1.19±0.23 At follow-up 1.21±0.25 Change (%) 2.5±15.7 Triglyceride (mmol/l) At baseline 1.63±0.89 At follow-up 1.91±0.99w Change (%) 23.7±38.8 LDL (mmol/l) At baseline 2.85±0.76 At follow-up 2.34±0.57z Change (%) – 13.9±22.0 HbA1c (%) At baseline 6.08±0.69 At follow-up 6.03±0.77 Change (%) – 0.8±5.9 hs-CRP (mg/l) At baseline 1.87±1.59 At follow-up 1.14±1.21 Change (%) 68.5±283.0 Creatinine (mmol/l) At baseline 75.8±18.9 At follow-up 75.5±23.7 Change (%) – 1.3±20.2 Uric acid (mmol/l) At baseline 353.9±63.0 At follow-up 349.5±56.8 Change (%) – 0.4±11.2 WBC (/ml) At baseline 5810±1399 At follow-up 5355±1257w Change (%) – 6.1±15.6 3 Platelet ( 10 /ml) At baseline 195.8±51.7 At follow-up 185.8±45.3 Change (%) – 3.7±15.4
Pravastatin
P
127.5±19.3 123.8±14.4 – 0.8±19.4
0.575 0.667 0.570
72.7±10.3 68.5±9.9 – 4.4±16.9
0.194 0.550 0.574
4.87±0.87 4.62±0.85 – 3.7±18.2
0.861 0.481 0.590
1.28±0.24 1.31±0.27 2.6±12.3
0.245 0.244 0.975
1.64±0.94 1.75±0.99 15.8±49.4
0.988 0.627 0.590
2.84±0.76 2.50±0.90 – 8.5±35.1
0.987 0.515 0.573
5.86±0.80 5.84±0.69 – 0.3±9.2
0.371 0.427 0.669
3.95±6.24 7.67±13.67 1470.6±5375.9
0.174 0.051 0.270
115.2±155.1 112.4±133.0 2.7±10.3
0.284 0.246 0.452
364.3±87.8 359.6±65.3 1.6±18.1
0.677 0.613 0.687
6120±2064 5770±1606 – 2.6±19.8
0.591 0.381 0.544
197.2±55.2 197.8±77.1 – 0.9±21.2
0.933 0.563 0.639
Continuous values were expressed as mean±SD. BP, blood pressure; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; hs-CRP, high-sensitive C-reactive protein; LDL, low-density lipoprotein; WBC, white blood cell. wP < 0.05 versus at baseline. zP < 0.01 versus at baseline.
the pravastatin groups summated separately and presented as an overlaid single graph. A bimodal distribution was obvious, where uncovered struts showed a single peak and the other peak showed a skewed distribution. Thus, we analyzed the uncovered and covered struts separately, comparing the former with the frequency and comparing the latter with the thickness of neointima between the rosuvastatin and the pravastatin groups. The uncovered struts were significantly less frequent in the rosuvastatin group than in the pravastatin group (6.49 vs. 11.29%, P < 0.001) (Table 4). Nonparametric comparison of the neointimal thickness of covered struts indicated a
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Statin effects on neointima of drug-eluting stents Yamamoto et al. 293
significant difference, where the rosuvastatin group more frequently had thinner neointima than the pravastatin group (Table 4 and Fig. 2). Among four types of stents used in our study, EES and SES constituted most part of the struts analyzed [EES, 7689 struts (70.0%); SES, 2233 struts (20.3%)]. When struts of EES and SES were analyzed individually, the same result was obtained for the ratio of uncovered struts: it was less frequent in the rosuvastatin group than in the pravastatin group in either stent (EES, 4.81 vs. 6.21%, P < 0.007; SES, 14.40 vs. 20.86%, P < 0.001) (Table 5 and Fig. 3). Although malapposed struts were observed only in SES, their ratio was significantly lower in the rosuvastatin group than in the pravastatin group when compared in the subgroups of SES (Table 5) as well as in all groups of stents (Table 4). In contrast, no consistent effect of statins was observed in neointimal thickness in the subgroup analysis with types of stents: the rosuvastatin group showed thinner and thicker neointima than the pravastatin group in EES
Fig. 2
12
Rosuvastatin
Ratio in each statin group (%)
10
Pravastatin
8
Overlap 6
4
2 0 0
200
400
600
800
Neointimal thickness (μm) Comparison of the histographic distribution of neointimal thickness in all stents. The rosuvastatin group and the pravastatin group are shown as blue and yellow bars, respectively, and their overlap is shown in French beige. The distribution was two-peaked, with the uncovered struts constituting a single peak. When neointimal thicknesses of covered struts were compared, they were significantly thicker in the pravastatin group than in the rosuvastatin group as shown by the Mann–Whitney U-test.
Table 4
[110 mm (IQR, 60–180 mm) vs. 120 mm (IQR, 70–190 mm), P < 0.001] and in SES [150 mm (IQR, 100–210 mm) vs. 110 mm (IQR, 80–160 mm), P < 0.01], respectively (Table 5 and Fig. 3).
Discussion Previous pathologic and OCT studies have shown that more frequent uncovered struts were observed after the placement of DES compared with BMS [11,12]. The larger number of uncovered struts is considered to be one of the causes for late stent thrombosis [4]. Therefore, it is important to quantitatively analyze neointimal strut coverage after DES implantation. OCT analysis of neointimal coverage of implanted DES during the follow-up period in this study showed that rosuvastatin treatment significantly reduced uncovered strut ratio, which was consistently observed in different types of stents. Pleiotropic effect of statins
The vascular healing process in the early phase after stent implantation consists of mural thrombus formation and of accumulation of inflammatory cells such as macrophages. Then, the proportion of smooth muscle cells is increased and re-endothelialization occurs. This vascular healing may be delayed by DES because of inhibition of the migration and proliferation of endothelial cell-like cells that originated from mononuclear cells [13]. Goto et al. [12] showed that an uncovered strut rate and hs-CRP were significantly higher in the SES than in the BMS. This led to the hypothesis that persistent inflammation is one of the causes of delayed vascular healing. Statin therapy has been shown to improve endothelial function, reduce hs-CRP, and suppress atherosclerosis [14–16]. Nissen et al. [17] showed that the reduced rate of progression of atherosclerosis with statin therapy was associated with a reduction in atherogenic lipoproteins and CRP. Although it did not reach statistical significance, hs-CRP was lower in the rosuvastatin group than in the pravastatin group at followup in our study. The paired t-test showed a significant reduction in WBC counts only in the rosuvastatin group. A lack of a significant reduction in hs-CRP may have been caused by a small number of patients included in our study. In addition to these pleiotropic effects, recent studies have shown that statin therapy improves vascular healing. Fukuda et al. [18] showed that fluvastatin accelerates re-endothelialization that was impaired by sirolimus treatment in the mouse femoral arteries. Wang
Comparison at the strut level in all stents
Malapposed struts Uncovered struts Neointimal thickness (mm)
Rosuvastatin (n = 5102) [n (%)]
Pravastatin (n = 5882) [n (%)]
P
3 (0.06) 331 (6.49) 110 (IQR, 60–180)
35 (0.60) 664 (11.29) 110 (IQR, 70–180)
< 0.001 < 0.001 0.002
Continuous values were expressed as median (IQR). IQR, interquartile range.
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Coronary Artery Disease 2014, Vol 25 No 4
Table 5
Comparison of stents and struts in subgroups of everolimus-eluting stent and sirolimus-eluting stent EES
Number of stents Stent diameter (mm) Stent length (mm) Overlapping stent Type B2/C lesion Number of struts Malapposed struts [n (%)] Uncovered struts [n (%)] Neointimal thickness (mm)
SES
Rosuvastatin
Pravastatin
P
18 2.97±0.42 22.4±10.8 3 11 4033 0 (0) 194 (4.81) 110 (IQR, 60–180)
16 3.04±0.85 25.8±20.5 3 11 3656 0 (0) 227 (6.21) 120 (IQR, 70–190)
0.793 0.574 1.0 0.728 1.0 0.007 < 0.001
Rosuvastatin
Pravastatin
3 2.71±0.21 29.0±11.8 1 3 771 3 (0.39) 111 (14.40) 150 (IQR, 100–210)
8 2.91±0.43 25.9±16.1 1 4 1462 35 (2.39) 305 (20.86) 110 (IQR, 80–160)
P 0.402 0.776 0.490 0.236 < 0.001 < 0.001 < 0.001
Continuous values were expressed as mean±SD or median (IQR) as appropriate. EES, everolimus-eluting stent; IQR, interquartile range; SES, sirolimus-eluting stent.
Fig. 3
(a)
(b)
8
20 Ratio in each statin group (%)
Rosuvastatin
Rosuvastatin
6 Pravastatin
Pravastatin
15
Overlap
4
Overlap 10
2
5
0
0 0
200
400
600
800
0
200
400
600
800
Neointimal thickness (μm)
Neointimal thickness (μm)
Comparison of the histographic distribution of neointimal thickness in everolimus-eluting stent (EES) (a) and sirolimus-eluting stent (SES) (b). The rosuvastatin group and the pravastatin group are shown as blue and yellow bars, respectively, and their overlap is shown in French beige. The distribution was two-peaked in either stent, with the uncovered struts constituting a single peak and more frequent in the pravastatin group. Neointimal thickness of covered struts was different between EES and SES: it was thicker in the pravastatin group in EES, whereas it was thicker in the rosuvastatin group in SES.
et al. [19] showed that atorvastatin accelerates both reendothelialization and neointimal coverage after SES implantation in porcine coronary artery. Differences in the effect on re-endothelialization between rosuvastatin and pravastatin would be an interesting topic that awaits further study.
LDL was detected in the paired t-test in the rosuvastatin group, but not in the pravastatin group, which could support an idea that the stronger lipid-lowering effect of rosuvastatin than pravastatin could have contributed toward less uncovered or malapposed struts.
Lipid-lowering effect of statins
Study limitation
It has been reported that rosuvastatin exerts a stronger effect of decreasing LDL cholesterol than pravastatin [20,21]. In the present study, no significant difference between the two groups was observed in LDL values at baseline and at followup, and in the rate of change in LDL, which may have been because of the small number of patients in our study. However, a significant reduction in total cholesterol and
First, the number of patients studied was small. Second, we randomized statins into two groups, but we did not randomize stent types. However, the number of struts analyzed was large enough to yield smoothness of distribution curves in Figs 2 and 3. Third, uncovered struts cannot be discriminated from struts that were covered by a single layer of endothelium or neointima of
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Statin effects on neointima of drug-eluting stents Yamamoto et al. 295
up to 20 mm thickness, either of which cannot be visualized even under resolution of OCT [6,7,22]. Conclusion
Rosuvastatin led to a lower frequency of uncovered and malapposed struts than pravastatin, which might lead to lower frequency of very late stent thrombosis. Rosuvastatin would be more effective in preventing very late stent thrombosis than pravastatin after DES placement.
Acknowledgements
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Conflicts of interest
S.M. has received unrestricted research grants from AstraZeneca Co. Ltd, Daiichi-Sankyo Pharmaceutical Co. Ltd, and Shionogi & Co. Ltd. For the remaining authors there are no conflicts of interest.
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