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Statins have been reported to reduce cardiovascular events in patients with coronary artery disease (CAD). Percutaneous coronary intervention (PCI) is commonly used to relieve ischemic symptoms in patients with CAD. However, there is little information on the effect of statins on cardiovascular events after PCI, even in the era of coronary stent implantation.
Methods
A total of 1019 patients with acute or chronic CAD and modest total cholesterol levels (180–240 mg/dl) were enrolled and randomly assigned to treatment with or without statins. We evaluated the effect of any available statin on the incidence of cardiovascular events after PCI. The primary endpoint was a composite of cardiovascular death, nonfatal acute myocardial infarction (MI), recurrent angina pectoris requiring emergency rehospitalization (rAP), heart failure, and stroke.
Results
Indications for PCI were stable angina in 54%, ST-elevation MI in 41% and non-ST-elevation MI/unstable angina pectoris in 5%. After 2 years of statin treatment, low-density lipoprotein cholesterol (LDL-C) decreased from 133 to 96 mg/dl. Stents were implanted in 84% of all cases. The primary endpoint event rate was 9.5% in the statin group and 14.7% in the non-statin group (p = 0.0292). Of all primary endpoint events, only rAP was significantly suppressed by statins (p = 0.0027). In rAP patients, coronary angiography revealed that statins suppressed restenosis but not new lesions.
Conclusions
For Japanese CAD patients treated with PCI and stent implantation, statin therapy reduced the incidence of recurrent cardiovascular events, particularly rAP. Discretionary statin treatment to achieve LDL-C levels <100 mg/dl effectively reduced restenosis causing rAP.
Treatment of patients with coronary artery disease (CAD) with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been reported to decrease the incidence of cardiovascular events [
The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.
]. Furthermore, percutaneous coronary intervention (PCI) is commonly performed to relieve ischemic symptoms in patients with CAD. Recently, it has been reported that optimal medical therapy with or without PCI is equally effective in preventing cardiovascular events [
]. Optimal medical therapy includes aspirin, β-blockers, angiotensin-converting enzyme inhibitors, statins, and other agents. Thus, PCI may be less important than optimal medical therapy in reducing future cardiovascular events in patients with CAD. In fact, in the Lescol Intervention Prevention Study (LIPS), fluvastatin reduced the risk of major adverse cardiovascular events (MACE) significantly in patients undergoing their first successful PCI [
]. However, extrapolation of these results to Japanese patients who have undergone PCI is uncertain, because the Japanese population has a lower mortality from coronary artery disease compared with Western populations [
In the present multicenter, randomized, controlled trial, we investigated the effects of statins on cardiovascular events in Japanese patients with acute or chronic ischemic heart disease who underwent PCI with stents. In addition, we used coronary angiography (CAG) to precisely identify the culprit lesions in patients who required emergent rehospitalization for recurrent myocardial ischemia.
Methods
Study population
Between February 2002 and September 2004, 1019 consecutive patients were enrolled at 55 medical centers in 19 prefectures of Japan (see Appendix A). The patients had acute or chronic myocardial ischemia and serum total cholesterol levels ranging from 180 to 240 mg/dl on admission. All were to undergo emergent or elective (including ad hoc) PCI for their myocardial ischemia if CAG showed that their coronary lesions were suitable for PCI. Main exclusion criteria included <18 years of age, use of lipid-lowering agents within the previous 3 months, known familial dyslipidemia, severe renal failure, known hepatic disease, signs and symptoms of severe heart failure (New York Heart Association class III or IV), a scheduled coronary artery bypass grafting (CABG), previous PCI (within 6 months) or CABG (within 3 months), and the presence of malignant disease or allergy to statins. Patients with acute myocardial ischemia included in the present study comprised a large percentage of the population in the MUSASHI-AMI trial as described below [
Multicenter Study for Aggressive Lipid-Lowering Strategy by HMG-CoA Reductase Inhibitors in Patients With Acute Myocardial Infarction (MUSASHI-AMI) Investigators
Effects of early statin treatment on symptomatic heart failure and ischemic events after acute myocardial infarction in Japanese.
]. Patients without any reperfusion therapy and those treated with thrombolytics in the MUSASHI-AMI trial were excluded from the present study.
Study design
The Multicenter Study for Aggressive Lipid-Lowering Strategy by HMG-CoA Reductase Inhibitors in patients with CAD (MUSASHI) was a PROBE-design trial conducted in normocholesterolemic patients who were randomly assigned to receive any available statin or no statin. The MUSASHI study population consisted of MUSAHI-AMI (acute myocardial infarction) and MUSASHI-PCI (percutaneous coronary intervention) patients. The study was performed in accordance with the ethical principles of the Declaration of Helsinki and was approved by local ethics committees or institutional review boards. Written informed consent was obtained from all patients. The acute myocardial infarction (AMI) and unstable angina pectoris (uAP) patients who underwent PCI were randomly assigned within 96 h after symptom onset, and the stable angina patients were randomly assigned within 48 h after PCI with stratification by center using the envelope method to standard medical treatment with or without the addition of a statin.
The benefits of statin therapy were not well established at that time in Japan. The statin treatment was open label with any statin that was available in Japan during the recruitment period (pravastatin, atorvastatin, fluvastatin, simvastatin, or pitavastatin). Patients were monitored for a primary endpoint event every 30 days at each institutional outpatient clinic for up to 2 years. All patients received instruction and counseling to promote compliance with the Japan Atherosclerosis Society Guidelines for Diagnosis and Treatment of Atherosclerotic Cardiovascular Diseases Step I diet [
Treatment by changing the life-style. Japan Atherosclerosis Society guidelines for diagnosis and treatment of atherosclerotic cardiovascular diseases. Japan Atherosclerosis Society,
Tokyo2002
]. During follow-up, emergent CAG was performed in case of recurrent myocardial ischemia including AMI. Even if emergent CAG was not required, routine CAG was scheduled 3–6 months after enrollment regardless of ischemic symptoms to evaluate changes in the culprit lesion and lesions at other sites. According to the results of follow-up coronary angiography, CABG or PCI was performed for a new lesion or restenosis of a previous lesion, if necessary.
Endpoint events
The primary endpoint event was defined as a combination of cardiovascular death, nonfatal acute myocardial infarction (MI), emergent rehospitalization due to recurrent symptomatic myocardial ischemia with objective evidence [recurrent angina pectoris (rAP)], congestive heart failure (CHF) that required emergent rehospitalization, and nonfatal stroke. In cases of AMI and rAP, emergent or sub-emergent CAG was performed, and culprit lesions for acute myocardial ischemia were examined and treated by repeat PCI or coronary artery bypass grafting, if necessary. However, reintervention after routine CAG was not included as a primary endpoint event, and follow-up was terminated in patients that required this type of reintervention. Cardiovascular death was defined as that directly or indirectly related to AMI or ischemic heart disease. Definitions of AMI and heart failure were the same as previously reported [
Multicenter Study for Aggressive Lipid-Lowering Strategy by HMG-CoA Reductase Inhibitors in Patients With Acute Myocardial Infarction (MUSASHI-AMI) Investigators
Effects of early statin treatment on symptomatic heart failure and ischemic events after acute myocardial infarction in Japanese.
]. Stroke was diagnosed based on the presence of a neurologic deficit that was confirmed by computed tomography or magnetic resonance imaging.
Statistical analysis
Data are expressed as mean ± SD or median (range). Differences in patient characteristics between the 2 treatment groups were evaluated with Student's t test in the case of continuous variables and a chi-square test in the case of absolute categorical variables. Data that were not normally distributed were analyzed with a Wilcoxon's 2-sample test. Cumulative event curves of the study endpoint (the time from PCI to a specified event in each patient) were plotted with the Kaplan–Meier method and differences between event curves were compared with a log-rank test. Estimates of hazard ratios and associated 95% confidence intervals that compared the two groups were obtained with a Cox proportional hazards model. Interim statistical analyses of the study outcome were performed for independent data. A p-value <0.05 was considered statistically significant. All statistical analyses were conducted with SAS 8.2 (SAS Institute, Cary, NC, USA).
Results
Patients
Between February 2002 and September 2004, 1019 patients were enrolled; 504 were assigned to receive standard therapy with discretional statins, and 515 were assigned to receive standard therapy without statins. Patients with fatal complications of acute phase AMI, such as free wall rupture, and cases with study protocol violations were withdrawn. Patients who could not tolerate statin side effects were also excluded. The remaining 482 patients in the statin group and 497 patients in the non-statin group were followed up to 2 years. The baseline demographic characteristics of both groups were similar, except for a higher mean age in the non-statin group (64.8 vs. 66.4 years), more frequent administration of nitrates in the non-statin group (31% vs. 37%) and a higher mean total cholesterol level in the statin group (208 ± 17 vs. 206 ± 17 mg/dl) (Table 1). PCI for stable angina, ST-elevation MI, and non-ST-elevation MI/uAP was performed in 261 (54%), 193 (40%), and 28 (6%) patients in the statin group, and 269 (54%), 207 (42%), and 21 (4%) in the non-statin group, respectively. A coronary stent was implanted in 401 patients (83%) in the statin group and 425 (86%) in the non-statin group; conventional balloon angioplasty was performed in 81 (17%) in the statin group and 72 (14%) in the non-statin group. There were no significant differences in the indication and type of PCI between the two groups. Coronary stent implantation was performed in >80% of all patients. Bare metal stents were implanted rather than drug-eluting stents (DES), because the latter were not available at that time in Japan.
Table 1Baseline characteristics of the patients.
Characteristic
Statin group (n = 504)
Non-statin group (n = 515)
p-Value
Age, mean (SD) (years)
64.8 (10.5)
66.4 (10.5)
0.0131
Male, n (%)
385 (76)
393 (76)
0.9766
BMI, mean (SD) (kg/m2)
24.2 (10.5)
24.1 (9.1)
0.9053
Hypertension, n (%)
326 (65)
311 (60)
0.2380
Current or ex smoker, n (%)
253 (50)
269 (52)
0.4953
Diabetes, n (%)
156 (31)
146 (28)
0.3732
Previous MI, n (%)
68(13)
71 (14)
0.8327
Previous stroke, n (%)
40 (8)
48 (9)
0.4317
Previous PCI, n (%)
77 (15)
72 (14)
0.5753
Concomitant medications, n (%)
Aspirin
485 (96)
481 (93)
0.0581
β-blockers
112 (22)
114 (22)
0.9736
Ca++ channel blockers
237 (47)
245 (48)
0.8607
Nitrates
154 (31)
192 (37)
0.0234
ACE inhibitors
175 (35)
154 (30)
0.1145
ARBs
179 (36)
190 (37)
0.6474
Lipids, mean (SD) (mg/dl)
Total cholesterol
208 (17)
206 (17)
0.0146
LDL-cholesterol
133 (22)
130 (20)
0.0768
HDL-cholesterol
47 (13)
47 (12)
0.2686
Triglycerides
144 (90)
142 (77)
0.7682
CRP, mean (SD) (mg/L)
4.5 (9.5)
5.5 (12.0)
0.5073
BMI, body mass index; MI, myocardial infarction; PCI, percutaneous coronary intervention; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blockers; LDL, low-density lipoprotein; HDL, high-density lipoprotein; CRP, C-reactive protein.
The fraction of each statin used in the present study and the mean daily dose were as follows: pravastatin (49.8%, 9.5 mg), atorvastatin (31.1%, 9.4 mg), fluvastatin (14.3%, 27.1 mg), simvastatin (4.6%, 5.4 mg), and pitavastatin (0.2%, 2.0 mg). As mentioned above, serum total cholesterol levels were higher in the statin group at baseline, whereas levels of low-density lipoprotein cholesterol (LDL-C) were equivalent in the two groups. After 2 years of treatment, LDL-C levels decreased 28% in the statin group and 7% in the non-statin group (p < 0.001 in both). There was a significant difference in the LDL-C levels between the two groups from 6 months after randomization to the end of the follow-up period (p < 0.0001). High-density lipoprotein cholesterol (HDL-C) levels were significantly increased from 47 mg/dl to 50 mg/dl in the statin group and 47 mg/dl to 48 mg/dl in the non-statin group (p < 0.01 in both) after 2 years. However, there was no significant difference between the two groups (Fig. 1).
Figure 1Serial changes in low-density lipoprotein cholesterol levels and high-density lipoprotein cholesterol levels in the statin and non-statin groups. *p < 0.001. LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.
Kaplan–Meier cumulative event curves of the primary endpoint are shown in Fig. 2. A primary endpoint event occurred in 46 patients (9.5%) in the statin group and in 73 (14.7%) in the non-statin group during the follow-up period (p = 0.0292 by log-rank test). The relative risk of the primary endpoint was reduced by 34% with statin treatment during a mean follow-up of 416 ± 11 days. When individual events were considered separately, 2 (0.4%) patients in the statin group and 2 (0.4%) in the non-statin group died from cardiovascular causes; 7 (1.5%) in the statin group and 3 (0.6%) in the non-statin group had a nonfatal MI; 23 (4.7%) in the statin group and 51 (10.4%) in the non-statin group had rAP requiring emergent rehospitalization; 7 (1.5%) in the statin group and 12 (2.4%) in the non-statin group required emergent rehospitalization for CHF; 7 (1.5%) in the statin group and 5 (1.0%) in the non-statin group had a nonfatal stroke. In the subgroup of patients that had conventional balloon angioplasty, a primary endpoint event occurred in 8 patients (9.9%) in the statin group and in 15 (20.8%) in the non-statin group. In the stent subgroup, a primary endpoint event occurred in 38 patients (9.5%) in the statin group and 58 (13.6%) in the non-statin group. The relative risk reduction of the primary endpoint in the stent subgroup (30.1%) was significantly lower than that in the conventional balloon angioplasty subgroup (52.4%). When individual endpoints were analyzed separately, the statin group had a lower risk of rAP (4.8% vs. 10.4%, p = 0.0027), whereas the risk of the other endpoints was comparable between the two groups (Fig. 3). Angiographic analysis revealed that restenosis leading to rAP was suppressed by statin treatment (Fig. 4). Although de novo lesions (both target vessel and non-target vessel) responsible for rAP tended to be reduced by statin treatment (Table 2), there was no significant difference between the two groups (Fig. 5).
Figure 2Kaplan–Meier cumulative event curves of the primary endpoint.
Figure 4Hazard ratio according to the type of rAP lesion. CI, confidence interval; rAP, recurrent angina pectoris requiring emergency rehospitalization.
Figure 5Kaplan–Meier event curves for restenosis (upper panel) and new lesions (lower panel) in the rAP cases. rAP, recurrent angina pectoris requiring emergency rehospitalization.
The present study showed that discretional statin use decreases the incidence of cardiovascular events after PCI in Japanese patients with normal cholesterol levels. Patients at each center were treated with any available statin using modest doses. There was a 5.2% absolute and a 34% relative risk reduction in the primary combined endpoint. Although the rate of coronary stent implantation in our study was higher than that in the LIPS study, the effect of statins on cardiovascular events after PCI was similar comparing our results with the LIPS trial. Of all the primary endpoint events, the occurrence of rAP showed the most significant reduction in response to statins. In contrast, hard endpoint events, such as cardiovascular death and MI, were not influenced by statin treatment. These results are comparable with the results observed in the LIPS trial [
]. One reason why hard endpoint events such as cardiovascular death and non-fatal MI occurred equally in the two groups could depend on our manner of follow-up after PCI. Most Japanese patients undergo routine CAG 6–9 months after the indexed procedure regardless of the presence of ischemic symptoms. Since there is significant restenosis after implantation of bare metal stents [
], routine CAG followed by provisional repeat PCI might be effective in the prevention of future events in patients with silent but significant myocardial ischemia.
] reported that all-cause death but not cardiac death was reduced by statin therapy in PCI patients. However, the reported magnitude of reduction may have been overestimated as Zhang suggested [
]. Therefore, further studies are needed to elucidate the mortality benefit of statins in patients undergoing PCI.
In the present study, most of the culprit lesions responsible for rAP were identified by emergent CAG. This is the strength of our study as compared with other studies. CAG revealed that statin treatment significantly reduced restenosis of target lesions rather than the development of new lesions that caused rAP. Although Kaplan–Meier analysis of new lesions (including target vessel and non-target vessel) showed that the cumulative event curves seemed to separate gradually starting 3 moths after statin treatment, our study was not powered to detect significant differences in the location and type of lesion responsible for rAP. Recently, the PCI-PROVE IT study reported that intensive statin therapy reduced not only target vessel revascularization but also non-target vessel revascularization in patients treated with PCI for acute coronary syndrome (ACS) [
Effect of intensive statin therapy on clinical outcomes among patients undergoing percutaneous coronary intervention for acute coronary syndrome. PCI-PROVE IT: A PROVE IT-TIMI 22 (pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22) substudy.
]. That study enrolled almost 3 times more patients than our study, and the patients were randomly assigned to either intensive or modest statin therapy. The mean LDL-C levels with intensive statin therapy declined from 107 to 56.5 mg/dl at a mean follow-up of 24 months. If our statin group had a reduction in LDL-C levels that was similar to the reduction achieved by intensive statin therapy in PCI-PROVE IT, then it is possible that new lesions causing rAP might have been significantly reduced by statin treatment in our study.
In addition to the effects of statins on coronary spasm [
The Kuopio Atherosclerosis Prevention Study (KAPS): effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression.
] may have played an important role in the prevention of rAP. Moreover, we previously reported that pravastatin increased plasma levels of adiponectin and had anti-diabetic effects in patients with CAD [
Kumamoto Joint Research on Hypercholesterolemia Investigators
The effect of 6 months of treatment with pravastatin on serum adiponectin concentrations in Japanese patients with coronary artery disease and hypercholesterolemia: a pilot study.
Pravastatin improved glucose metabolism associated with increasing plasma adiponectin in patients with impaired glucose tolerance and coronary artery disease.
], similar to the results of the present study. However, cases with PCI were excluded in the MIRACL study, and this is not consistent with clinical practice and most current guidelines. The results of the present study clearly demonstrated that statins reduced the incidence of rAP during 2 years of follow-up, even after successful PCI. Furthermore, unlike the MIRACL study, CAG was performed in our study to elucidate the precise mechanism responsible for rAP. Kaplan–Meier analysis of rAP in the present study revealed that the cumulative event curves began to separate 3 months after the initiation of statin therapy. This is somewhat similar to the results of the MIRACL study, in which a significant difference in rAP was observed after 16 weeks of statin treatment. When the patients in the present study were stratified according to the culprit lesion responsible for rAP, it appeared that both new lesions and restenosis contributed equally to the number of rAP events, although there was no significant difference in number of patients with new lesions causing rAP. The new lesions emerged from the beginning of follow-up, whereas restenosis occurred mainly 6 months after PCI. Based on these results, we suggest that statin treatment following PCI acts to prevent rAP by attenuating new lesions that develop during early follow-up, as well as by attenuating late restenosis.
Japanese Stable Angina Pectoris Study Investigators
Percutaneous coronary intervention plus medical therapy reduces the incidence of acute coronary syndrome more effectively than initial medical therapy only among patients with low-risk coronary artery disease: a randomized, comparative, multicenter study.
] reported that PCI with medical therapy reduced deaths and ACS events in Japanese patients with stable, low-risk CAD. However, statins were used in only half of their study patients, and the mean LDL-C level was >100 mg/dl. More extensive use of statins after PCI may contribute to the prevention of recurrent symptomatic myocardial ischemia requiring emergent rehospitalization.
With the introduction of DES, the rates of restenosis and target-vessel revascularization have dropped below 10%. However, angioscopy showed that the restenosis site in patients treated with DES looked like vulnerable plaque [
]. Therefore, statins could still be useful after PCI even in patients treated with DES.
Study limitations
Our study has several limitations. The most important limitation was the heterogeneity of the study population since it included ST-elevation MI, non-ST-elevation MI/uAP, and stable angina patients; and all patients were treated by either conventional balloon angioplasty or stenting. The effect of statins would be different between acute and chronic CAD or between stent implantation and conventional balloon angioplasty. However, we could not compare the differences in the effect of statins among subgroups because of the small number of patients in this study, especially patients treated by conventional balloon angioplasty. Second, although statins reduced only restenosis causing rAP, we could not precisely assess the mechanisms responsible for this effect.
Conclusions
Discretional statin treatment with relatively low doses reduces the incidence of cardiovascular events after PCI in Japanese patients with normal cholesterol levels. The reduction in events appears to be mainly due to a reduction in the incidence of rAP that is caused by restenosis of the target lesion.
Acknowledgment
This study was presented in part at the Scientific Sessions 2008 of the American Heart Association held in New Orleans in November 2008. The authors also thank Ms Yuko Kuratsu for her secretarial assistance.
Appendix A.
The MUSASHI investigators are listed below in alphabetical order by center.
Amakusa Medical Center: Naritsugu Sakaino, Shota Nakamura, Shinichi Nakamura; Arao City Hospital: Ikuo Misumi; Asahikawa Medical College Hospital: Naoyuki Hasebe, Masaru Yamaki, Kenjiro Kikuchi; Chikamori Hospital: Naohisa Hamashige; Dokkyo University Koshigaya Hospital: Toshihiko Uchida, Hiroshi Takayanagi; Fukuoka Tokushukai Medical Center: Hideki Shimomura, Kenichi Tsujita, Takuro Yamashita; Fukuoka University Hospital: Keijiro Saku; Gunma Prefectural Cardiovascular Center: Shigeru Ohshima; Health Insurance Hitoyoshi General Hospital: Kenji Obata, Hideki Oka; Hirosaki University Hospital: Ken Okumura, Toshiro Matsunaga; Hiroshima City Hospital: Masaharu Ishihara; Izumi City Hospital: Shigenobu Tateishi; Japanese Red Cross Kumamoto Hospital: Hitoshi Sumida, Ryusuke Tsunoda, Yasuhiro Ogata; Kagoshima City Hospital: Hitoshi Toda; Kagoshima Medical Association Hospital: Hiroyuki Torii; Kagoshima University Hospital: Chuwa Tei; Karatsu Red Cross Hospital: Takanobu Nii; Kihara Cardiovascular Clinic: Hajime Kihara; Kitasato University Hospital: Naoto Fukuda, Tohru Izumi; Kohseikai Hospital: Yoshihiro Iwasaki; Kumamoto Central Hospital: Shuichi Oshima; Kumamoto City Hospital: Yoshihiro Kimura; Kumamoto Kinoh Hospital: Yuji Mizuno; Kumamoto Regional Medical Center: Nobutaka Hirai; Kumamoto Rosai Hospital: Toshiyuki Matsumura, Hideki Doi; Kumamoto University Hospital: Hisao Ogawa, Tomohiro Sakamoto, Sunao Kojima, Koichi Kaikita; Mie University Hospital: Takeshi Nakano, Naoki Isaka; Minamata City General Hospital and Medical Center: Hideki Maruyama; Miyazaki Medical Association Hospital: Yoshisato Shibata; Miyazaki University Hospital: Takuro Imamura, Tanenao Eto; Miyazaki Prefectural Nobeoka Hospital: Yasushi Moriyama, Nobuyasu Yamamoto; Nagasaki Municipal Medical Center: Kazuaki Yakabe; Nagasaki University Hospital 2nd Internal Medicine: Yoshiyuki Miyahara, Shigeru Kohno; Nagasaki University Hospital 3rd Internal Medicine: Katsusuke Yano, Yuji Koide; Nara Medical University Hospital: Yoshihiko Saito, Shiro Uemura; National Hospital Organization Kumamoto Medical Center: Kazuteru Fujimoto, Yuji Miyao; National Hospital Organization Kyushu Cardiovascular Center: Tatsuru Matsuoka; National Hospital Organization Oita Medical Center: Tatsuhiko Ooie; Oji General Hospital: Hitoshi Ooiwa; Okitama Public General Hospital: Motoyuki Matsui; Saiseikai Kumamoto Hospital: Takashi Honda, Koichi Nakao; Saitama Medical Center: Nobuo Yoshimoto; Sapporo Medical University Hospital: Kazufumi Tsuchihashi, Kazuaki Shimamoto; Sasebo City General Hospital: Toshihiko Yamasa; Shinbeppu Hospital: Natsuki Nakamura; Social Insurance Ohmuta-Tenryoh Hospital: Kohshi Matsuyama; Social Insurance Yatsushiro General Hospital: Toshifumi Tabuchi; Tamana Chuo Municipal Hospital: Toru Takahashi; Tenyoukai Chuo Hospital: Akihiro Miyamura; University of the Ryukyus Hospital: Michio Shimabukuro; Urasoe General Hospital: Toru Higa; Yamagata University Hospital: Isao Kubota; Yokohama City Medical Center: Kiyoshi Hibi, Masami Kosuge, Kazuo Kimura.
References
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The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.
Multicenter Study for Aggressive Lipid-Lowering Strategy by HMG-CoA Reductase Inhibitors in Patients With Acute Myocardial Infarction (MUSASHI-AMI) Investigators
Effects of early statin treatment on symptomatic heart failure and ischemic events after acute myocardial infarction in Japanese.
Treatment by changing the life-style. Japan Atherosclerosis Society guidelines for diagnosis and treatment of atherosclerotic cardiovascular diseases. Japan Atherosclerosis Society,
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Effect of intensive statin therapy on clinical outcomes among patients undergoing percutaneous coronary intervention for acute coronary syndrome. PCI-PROVE IT: A PROVE IT-TIMI 22 (pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22) substudy.
The Kuopio Atherosclerosis Prevention Study (KAPS): effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression.
Kumamoto Joint Research on Hypercholesterolemia Investigators
The effect of 6 months of treatment with pravastatin on serum adiponectin concentrations in Japanese patients with coronary artery disease and hypercholesterolemia: a pilot study.
Pravastatin improved glucose metabolism associated with increasing plasma adiponectin in patients with impaired glucose tolerance and coronary artery disease.
Japanese Stable Angina Pectoris Study Investigators
Percutaneous coronary intervention plus medical therapy reduces the incidence of acute coronary syndrome more effectively than initial medical therapy only among patients with low-risk coronary artery disease: a randomized, comparative, multicenter study.
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