Clinical Drug Investigation 2012

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ORIGINAL RESEARCH ARTICLE

Clin Drug Investig 2012; 32 (8): 513-521 1173-2563/12/0008-0513/$49.95/0 Adis ª 2012 Springer International Publishing AG. All rights reserved.

Predictive Value of the Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol Ratio for the Prevention of Stroke Recurrence in Japanese Patients Treated with Rosuvastatin

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. Michiya Igase,1 Katsuhiko Kohara,1 Ryosuke Katagi,2 Shiro Yamashita,2 Mutsuo Fujisawa2 and Tetsuro Miki3 1 Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan 2 Ryotenkai Katagi Neurosurgery, Ehime, Japan 3 Proteo Medicine Research Center, Ehime University Graduate School of Medicine, Ehime, Japan

Abstract

Background: HMG-CoA-reductase (statin) therapy to reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with coronary heart disease can substantially improve outcomes; however, the benefits of statins in stroke patients, particularly for secondary stroke prevention, remain poorly understood. Moreover, the degree of decrease in LDL-C that is required to prevent the recurrence of stroke is unknown. Objective: To determine whether the on-treatment LDL-C/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) is a predictive marker of stroke recurrence in patients with acute ischaemic stroke, and whether medical management of the LDL-C/HDL-C ratio would be of strategic significance for stroke prevention. Methods: A total of 137 dyslipidaemic patients who had suffered acute ischaemic stroke were enrolled and treated with rosuvastatin 2.5 mg within 24 hours of onset. Blood pressure and serum lipids were assessed at baseline and after 1 month of treatment with rosuvastatin. Fatal and non-fatal stroke events were recorded during a follow-up period of 36 months. We used univariate and multivariate analyses, as well as Kaplan-Meier analysis, to assess the predictive value of various parameters and to identify factors independently associated with stroke recurrence. Results: During a mean follow-up of 34.9 – 0.8 months, there were ten cases of stroke recurrence. Age, chronic kidney disease (CKD) at baseline, and an on-treatment LDL-C/HDL-C ratio >2 after 1 month of rosuvastatin treatment

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were predictors of stroke recurrence in univariate analyses. Stepwise regression analysis showed that CKD (standardized adjusted odds ratio [OR] 6.55; 95% confidence interval [CI] 1.12, 36.43; p = 0.030) and on-treatment LDL-C/HDL-C ratio >2 (standardized adjusted OR 9.70; 95% CI 1.70, 55.33; p = 0.011) were independent risk factors for stroke recurrence. Post hoc analysis indicated that more intensive lipid control, to an LDL-C/HDL-C ratio £1.5, may reduce the risk of stroke recurrence. Conclusion: These results suggest that the use of statin therapy to achieve an on-treatment LDL-C/HDL-C ratio £2 is a suitable treatment strategy in patients having suffered acute ischaemic stroke. Further studies are required to confirm the clinical benefits of reducing the on-treatment LDL-C/HDL-C ratio to £1.5.

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. Background

The primary characteristics of stroke, its high tendency to sequelae, requirements for long-term rehabilitation and care, and high medical costs, highlight the importance of preventing its recurrence. Although some studies have shown that intensive HMG-CoA-reductase (statin) therapy to reduce low-density lipoprotein cholesterol (LDL-C) levels below 100 mg/dL confers primary and secondary prevention against coronary heart disease,[1,2] the benefits of such therapies in stroke patients are unclear. Moreover, although primary prevention of stroke has been widely investigated,[3,4] its secondary prevention remains poorly understood. In particular, the degree of decrease in LDL-C that is required to prevent the recurrence of stroke is unknown.[5] In CHD patients, von Birgelen et al.[6] showed that an LDL-C value of 75 mg/dL was the cut-off level at which regression analysis predicted no average plaque increase. They also revealed an inverse relationship between the level of high-density lipoprotein cholesterol (HDL-C) and annual changes in plaque cross-sectional area, with an LDL-C/HDL-C ratio of 1.3 as the cutoff at which regression analysis predicted no average annual plaque increase. However, the association between on-treatment LDL-C/HDL-C ratio and the risk of recurrent stroke in patients with ischaemic stroke is unclear. In the present study, to determine whether medical management of the LDL-C/HDL-C ratio Adis ª 2012 Springer International Publishing AG. All rights reserved.

is of strategic significance for stroke prevention, we analysed the on-treatment LDL-C/HDL-C ratio cut-off value at which regression analysis predicted no recurrence of stroke. Patients and Methods Study Subjects

We prospectively enrolled consecutive patients with acute ischaemic stroke (lacunar, atherothrombotic and cardioembolic stroke) within 24 hours of onset between December 2005 and December 2006. Ischaemic stroke was defined as focal clinical signs of central nervous system dysfunction of vascular origin lasting >24 hours. Patients with a history of previous stroke or lipidlowering treatment were excluded. The present analysis was conducted in 137 patients for whom the serum lipid profile at baseline and after 1 month of treatment were available. Informed consent was obtained from all patients, and the study was conducted in accordance with the principles of the Declaration of Helsinki. All patients underwent brain magnetic resonance imaging (MRI). Age, sex and stroke type were recorded, and vascular risk factors of hypertension (defined as the use of antihypertensive agents, systolic blood pressure >140 mmHg, or diastolic blood pressure >90 mmHg before stroke onset), diabetes mellitus (defined as the use of oral hypoglycaemic agents or insulin, fasting blood glucose >126 mg/dL, or glycosylated haemoglobin Clin Drug Investig 2012; 32 (8)

LDL-C/HDL-C Ratio in Stroke Prevention

level >6.4%), and smoking status (smoking during the preceding 12 months) were evaluated. The estimated glomerular filtration rate (eGFR) was calculated using an equation from the Japanese Society of Nephrology.[7] Chronic kidney disease (CKD) was defined as an eGFR 120 mg/dL, HDL-C 150 mg/dL. A total of 137 patients with dyslipidaemia (76 men; mean age 69.7 years) who had not achieved the TC, LDL-C, HDL-C or HDL-C goals recommended by the Japan Atherosclerosis Society 2002 Guidelines[9] were enrolled. All subjects gave informed consent to receive single daily administration of rosuvastatin at 2.5 mg. Blood samples were collected at 1 month after starting rosuvastatin treatment (i.e. 1 month after stroke) to measure serum lipids. Baseline characteristics were collected from patient self-reports. Endpoint Assessment

Fatal and non-fatal stroke events within 36 months of baseline were recorded. Follow-up data were available for all 137 patients. Patients visited our hospital every month. At each visit, physical and laboratory examinations were performed as needed, and information on cerebrovascular endpoints was obtained in a standardized interview. Study endpoints reported by the patients were cross-checked against medical records, and all endpoints were independently adjudicated by two of the authors (M.I, R.K.). Statistical Analysis

Continuous values are expressed as means – SD. For baseline comparisons, dichotomous variables were compared between groups using the Adis ª 2012 Springer International Publishing AG. All rights reserved.

Results

Patient Characteristics

Brain MRI revealed ischaemic stroke in 137 patients. During a mean follow-up time of 34.9 – 0.8 months, we recorded ten cases of stroke recurrence, consisting of one cardioembolic, three lacunar and six atherothrombotic strokes. Table I summarizes the baseline characteristics of patients with respect to stroke recurrence. Blood Pressure and Heart Rate at Baseline and after 1 Month of Treatment

Blood pressure and heart rate measured at baseline and after 1 month of follow-up in patients with and without recurrence are summarized in table II. As shown in this table, there were no significant differences in these parameters between the two groups of patients. Low-Density Lipoprotein Cholesterol at Baseline and after 1 Month of Treatment

Lipid parameters during 1 month of treatment and at follow-up (i.e. 12 months) are shown in Clin Drug Investig 2012; 32 (8)

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Table I. Baseline clinical characteristics of subjects, categorized by recurrence of strokea p-Valueb

Characteristic

Total

Recurrence (+)

(-)

Patients, n (M/F)

137 (76/61)

10 (4/6)

127 (72/55)

Age, y

70 – 9

78 – 7

69 – 9

0.01

Stroke type, n (lacunar/atherothrombotic/cardioembolism)

68/51/18

3/6/1

65/45/17

0.30

0.24*

Hypertension, n (%)

125 (91)

10 (100)

115 (91)

0.60

Diabetes mellitus, n (%)

50 (37)

5 (50)

45 (35)

0.50*

Smoking, n (%)

51 (37)

2 (20)

49 (39)

0.32*

CKD, n (%)

50 (37)

8 (80)

42 (33)

2 had greater power (standardized adjusted odds ratio [OR] 7.54; 95% confidence interval [CI] 1.54, 37.05; p = 0.01) than on-treatment LDL-C Adis ª 2012 Springer International Publishing AG. All rights reserved.

(table IV). This association was not attenuated after adjustment for age, sex or CKD status (standardized adjusted OR 9.70; 95% CI 1.70, 55.33; p = 0.01) [table V]. As shown in table IV, other general characteristics, such as sex, blood pressure, heart rate, presence of diabetes and smoking were not significantly associated with the recurrence of stroke. Table II. Blood pressure and heart rate at baseline and after 1 month of follow-up, categorized by recurrence of strokea Variable

Total

Recurrence

(+)

p-Value

(–)

SBP, mmHg Baseline

146 – 14

147 – 10

146 – 14

0.89

At 1 month

131 – 15

128 – 13

132 – 15

0.39

DBP, mmHg Baseline

79 – 13

74 – 15

79 – 13

0.27

At 1 month

74 – 8

75 – 8

74 – 8

0.94

HR, beats/min

a

Baseline

68 – 9

65 – 6

68 – 9

0.12

At 1 month

67 – 9

69 – 10

66 – 9

0.95

Values are mean – SD.

DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure; SD = standard deviation.

Clin Drug Investig 2012; 32 (8)


517

Table III. Lipid profile during 1 month of treatment and at follow-up (at 12 months), categorized by recurrence of strokea Variable

Recurrence (+)

Recurrence (-)

p-Value

During treatment

184 – 31

171 – 29

0.15

At follow-up

176 – 34

165 – 29

0.20

During treatment

120 – 62

132 – 67

0.59

At follow-up

116 – 53

125 – 54

0.61

During treatment

49 – 14

50 – 11

0.89

At follow-up

50 – 10

51 – 11

0.80

During treatment

115 – 23

96 – 24

0.02

At follow-up

104 – 24

90 – 26

0.08

During treatment

2.5 – 0.5

2.0 – 0.7

0.03

At follow-up

2.1 – 0.4

1.9 – 0.7

0.09

During treatment

135 – 21

121 – 29

0.13

At follow-up

135 – 21

121 – 29

0.13

TC, mg/dL

TG, mg/dL

other group with an on-treatment LDL-C/HDL-C ratio £2. We constructed Kaplan-Meier survival curves and compared these two groups using the log rank test to assess the significance of differences. The Kaplan-Meier curves for recurrence shown in figure 2 show that the incidence of recurrent stroke in patients with on-treatment LDL-C/HDL-C ratio >2 was significantly higher than that in patients with on-treatment LDL-C/ HDL-C ratio £2 (p = 0.0322). We also reanalysed the results in the context of a number of studies on secondary prevention of coronary artery disease, including the work of Matsumoto et al.[10] in post-percutaneous coronary intervention patients, which targeted a LDL-C/HDL-C ratio of 1.5. When the findings from our study were divided into three groups with cutoff points of >2.0, £2.0 to >1.5, and £1.5, the rate of stroke recurrence was significantly lower in the £1.5 group than in the >2.0 group (p = 0.0383; there was no stroke recurrence within the £1.5 group, figure 3). There was no incidence of haemorrhagic stroke in this study.

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. HDL-C, mg/dL

LDL-C, mg/dL

LDL-C/HDL-C

Non-HDL-C

a

Values are mean – SD.

HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; SD = standard deviation; TC = total cholesterol; TG = triglycerides.

Predictive values for LDL-C/HDL-C ratios Line of no discrimination Point of optimal predictive value

Impact of Baseline Chronic Kidney Disease on the Recurrence of Cerebrovascular Events

0.75

Sensitivity

As shown in table IV, CKD significantly predicted stroke recurrence in our cohort of ischaemic stroke patients on univariate analysis (standardized adjusted OR 8.01; 95% CI 1.65, 39.78; p = 0.01). This association between CKD and recurrence was not significantly attenuated by adjustment for age, sex or on-treatment LDL-C/HDL-C ratio (standardized adjusted OR 9.70; 95% CI 1.70, 55.33; p = 0.01) [table V].

1.00

LDL-C/HDL-C 2.04

0.50

0.25

Kaplan-Meier Analysis

To determine the time-dependent effects of the on-treatment LDL-C/HDL-C ratio, we performed a Kaplan-Meier analysis according to the ontreatment LDL-C/HDL-C ratio. Patients were subdivided into two groups: one group with an on-treatment LDL-C/HDL-C ratio >2 and the Adis ª 2012 Springer International Publishing AG. All rights reserved.

0 0

0.25

0.50 1 − Specificity

0.75

1.00

Fig. 1. Receiver operating curve analysis showing the performance characteristics of the LDL-C/HDL-C ratio for predicting recurrence of stroke within 3 years. HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.


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Table IV. Univariate analysis for recurrence of stroke Variable

Odds ratio

95% CI

p-Value

Age

1.12

1.04, 1.22

0.005

Sex, male

0.51

0.14, 1.89

0.314

SBP

1.00

0.96, 1.05

0.890

DBP

0.97

0.92, 1.02

0.970

HR

0.95

0.88, 1.03

0.186

Diabetes mellitus

0.55

0.15, 2.00

0.363

Smoking

2.51

0.51, 12.32

0.256

CKD

8.01

1.65, 39.78

0.010

LDL-C

1.03

1.01, 1.06

0.021

HDL-C

1.00

0.94, 1.06

0.885

LDL-C/HDL-C

2.25

0.93, 5.47

0.073

LDL-C/HDL-C >2

7.54

1.54, 37.05

0.013

currently recommended LDL-C values are not sufficiently low to prevent the recurrence of stroke. Second, the on-treatment LDL-C/HDL-C ratio was significantly higher in patients with recurrent stroke than in patients without recurrence. In addition, an on-treatment LDL-C/HDL-C ratio >2.0 after 1 month of treatment was a positive predictor of recurrent stroke. Notably, blood pressure and heart rate were not significantly different between patients with and without recurrence, suggesting LDL-C is a more important treatment target than abnormal blood pressure in reducing the risk of stroke recurrence. These results have encouraged us to implement intensive lipid-lowering treatment for the prevention of recurrence. Further analysis showed that, after stratifying LDL-C/HDL-C ratio, stroke recurrence was significantly lower in the £1.5 group than in the >2.0 group, with no stroke recurrence in the £1.5 group and no increase in side effects. These findings suggest that an LDL-C/HDL-C ratio £1.5 may prove to be an even more desirable goal for lipid management in protecting against stroke recurrence. However, an LDL-C/HDL-C ratio £1.5 was achieved in only 23.3% of subjects in this study. Appropriate increases in the statin dose may be required to achieve this ratio in a higher proportion of patients. Additional studies will be needed to confirm these findings. Decades of research have shown that lower LDL-C levels provide better stroke prevention than higher levels. Recent statin trials, most of which used LDL-C levels in their criteria for

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. CI = confidence interval; CKD = chronic kidney disease; DBP = diastolic blood pressure; HDL-C = high-density lipoprotein cholesterol; HR = heart rate; LDL-C = low-density lipoprotein cholesterol; SBP = systolic blood pressure.

Discussion

There are several key findings in this study. First, we used rosuvastatin 2.5 mg to reduce LDL-C below the level recommended by the Japan Atherosclerosis Society (JAS) Guidelines (2007)[11] of 120 mg/dL. However, we noted stroke recurrence even though the mean LDL-C value was successfully reduced after 1 month of treatment. The mean LDL-C in patients with recurrence was 115 – 23 mg/dL, 23% lower than baseline. Patients with recurrence continued to have higher, albeit not significantly, LDL-C levels and LDL-C/HDL-C ratio compared with patients without recurrence at the 1-year follow-up. This suggests that the

Table V. Multiple logistic regression analysis for recurrence of strokea Variable

Model 1

Model 2

Model 3

OR (95% CI)

OR (95% CI)

OR (95% CI)

Age

1.10 (1.01, 1.19)

1.13 (1.00, 1.20)*

1.10 (1.01, 1.21)*

Sex

0.81 (0.20, 3.36)

0.71 (0.17, 2.02)

CKD

5.20 (1.00, 27.02)*

LDL-C/HDL-C >2 a

0.85 (0.19, 3.86) 6.55 (1.18, 36.43)*

7.95 (1.49, 42.40)*

9.70 (1.70, 55.33)*

Model 1: corrected for age, sex, CKD Model 2: corrected for age, sex, LDL-C/HDL-C >2 Model 3: corrected for age, sex, CKD and LDL-C/HDL-C >2.

CI = confidence interval; CKD = chronic kidney disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; OR = odds ratio. * p < 0.05.

Adis ª 2012 Springer International Publishing AG. All rights reserved.


Recurrence of stroke (%)


519

LDL-C/HDL-C >2.0 (n = 65) LDL-C/HDL-C ≤2.0 (n = 72)

20 15 10

p = 0.0322 (Log-rank)

5 0

These results indicate that intensive statin treatment does not substantially increase the risk of haemorrhagic stroke in patients with ischaemic stroke. Most recently, the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) study showed that the mean on-treatment LDL-C level (55 mg/dL) in patients treated with rosuvastatin was not associated with an increased risk of cerebral haemorrhage compared with that in patients treated with placebo (although the median followup of subjects was only 1.9 years).[18] The mean on-treatment LDL-C level (97 mg/dL) at 2-year follow-up was not associated with cerebral haemorrhage. The first detailed description of the association between stroke and HDL-C in the Framingham Heart Study documented an inverse relationship between HDL-C and the incidence of atherothrombotic brain infarction.[19] However, in a Japanese population, lower HDL-C levels were significantly and independently related to an increased risk of ischaemic stroke.[20] Phan et al.[21] showed that MRI-estimated carotid plaque volume or atherosclerotic burden was significantly associated with total HDL-C levels (r = –0.39; p = 0.02). Patients with low HDL levels (£35 mg/dL) had greater carotid plaque volumes than those with HDL levels >35 mg/dL. In addition, among coronary artery disease patients, low HDL-C levels were significantly associated with increased carotid atherosclerotic plaque burden.

4

8

12 16 20 24 Months elapsed

28

32

36

Fig. 2. Kaplan-Meier analysis of the on-treatment LDL-C/HDL-C ratio and recurrence of stroke. HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.

enrollment, have generally reported a 20% decrease in vascular risk for each 1 mmol/L (38.7 mg/dL) absolute reduction in LDL-C level.[12,13] These findings reinforce the need to consider statin treatment to achieve substantial LDL-C reductions in all patients at high risk for any type of major vascular event. Nevertheless, with the notable exception of the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study, there has been little substantial evidence to suggest that dyslipidaemia treatment plays a role in the secondary prevention of stroke; as a result, most specialist physicians fail to consider lipid control in stroke patients.[14] In addition, although the SPARCL study showed a decrease in the occurrence of both fatal and non-fatal stroke, the beneficial effects of treatment were likely diminished by an increased risk of haemorrhagic stroke during the 5-year observation period.[15] Moreover, Bang et al.[16] also demonstrated that low LDL-C was independently associated with haemorrhagic stroke after recanalization therapy for ischaemic stroke. However, in a follow-up review, post hoc analyses of results from the SPARCL trial showing that patients receiving statin treatment had a higher incidence of haemorrhagic stroke revealed that this increased risk primarily affected elderly men with a history of haemorrhagic stroke. In addition, no relationship was noted between baseline or on-treatment LDL-C levels and the incidence of haemorrhagic stroke.[17] Adis ª 2012 Springer International Publishing AG. All rights reserved.

Recurrence of stroke (%)

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. 0

LDL-C/HDL-C >2.0 (n = 65) 1.5 < LDL-C/HDL-C ≤2.0 (n = 40) LDL-C/HDL-C ≤1.5 (n = 32)

20 15 10

NS

5

p = 0.0383 (Log-rank)

NS 0 0

4

8

12 16 20 24 28 32 36 Months elapsed

Fig. 3. Kaplan-Meier analysis of the on-treatment LDL-C/HDL-C ratio and recurrence of stroke (post hoc reanalysis of data). HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; NS = not significant.


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The results of this study should be interpreted taking into account some limitations. First, the incidence of stroke recurrence was quite low, occurring in 10/137 patients over a mean follow-up of approximately 36 months. This low rate in a small sample possibly introduced some bias into the results, reducing the strength of associations among some factors with the risk of stroke recurrence. Second, although patients were prescribed rosuvastatin, it is quite likely that they received additional drugs during the follow-up that could also influence the risk of stroke recurrence, such as fibrates and antihypertensive drugs. Unfortunately, we could not take this into account in univariate analyses. Finally, patients were treated in order to reach lipid targets established for Japanese patients. These targets may not be appropriate for other populations, and it seems likely that tighter LDL-C targets may be required. In the present study, although on-treatment HDL-C was lower in the stroke recurrence group than in the no recurrence group, the difference was not statistically significant. Moreover, ontreatment HDL-C was not significantly increased. These findings fail to conclusively indicate an inverse relationship between HDL-C and the risk of stroke recurrence.

215-22). The publishers of Therapeutic Research have given permission for publication of this article in English.

References 1. Rosenson RS. Statins: can the new generation make an impression? Expert Opin Emerg Drugs 2004 Nov; 9 (2): 269-79 2. La Rosa JC, Grundy SM, Walters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005 Apr; 352: 1425-35 3. Sever PS, Dahlo¨f B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003 Apr; 361 (9364): 1149-58 4. Collins R, Armitage J, Parish S, et al. Effects of cholesterollowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004 Mar; 363 (9411): 757-67 5. Crouse 3rd JR, Byington RP, Hoen HM, et al. Reductase inhibitor monotherapy and stroke prevention. Arch Intern Med 1997 Jun; 157 (12): 1305-10 6. von Birgelen C, Hartmann M, Mintz GS, et al. Relation between progression and regression of atherosclerotic left main coronary artery disease and serum cholesterol levels as assessed with serial long-term (> or = 12 months) followup intravascular ultrasound. Circulation 2003 Dec; 108 (22): 2757-62 7. Ando Y, Ito S, Uemura O, et al. CKD Clinical Practice Guidebook. The essence of treatment for CKD patients. Clin Exp Nephrol 2009 Jun; 13 (3): 191-248 8. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972 Jun; 18 (6): 499-502 9. Japan Atherosclerosis Society Guidelines for Diagnosis and Treatment of Atherosclerotic Cardiovascular Diseases [in Japanese]. Tokyo: Japan Atherosclerosis Society, 2002 10. Matsumoto I, Miyake Y, Mizukawa M, et al. Usefulness of aggressive lipid management for prevention of recurrence subsequent to PCI [in Japanese]. Pharma Medica 2009; 27 (11): 93-9 11. Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases [in Japanese]. Tokyo: Japan Atherosclerosis Society, 2007 12. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective metaanalysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005 Oct; 366 (9493): 1267-78 13. Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006 Aug; 48 (3): 438-45 14. Amarenco P, Goldstein LB, Szarek M, et al. Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke 2007 Dec; 38 (12): 3198-204

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. Conclusion

Our results suggest that treatment with rosuvastatin to achieve an on-treatment LDL-C/HDL-C ratio £2 may represent a viable treatment strategy to prevent recurrence in patients with acute ischaemic stroke. Long-term prospective studies are needed to confirm these findings, in which the lipid-lowering treatment is titrated to achieve and maintain this target. It would also be important to determine whether further reductions in the on-treatment LDL-C/HDL-C ratio to £1.5 have any additional clinical benefits. Acknowledgements

The authors have no conflicts of interest to declare. No funding was received for the research reported in the article. A version of this manuscript was previously published in Japanese in the journal Therapeutic Research (2011; 32 (2):




15. Vergouwen MD, de Haan RJ, Vermeulen M, et al. Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke 2008 Feb; 39 (2): 497-502 16. Bang OY, Saver JL, Liebeskind DS, et al. Cholesterol level and symptomatic hemorrhagic transformation after ischemic stroke thrombolysis. Neurology 2007 Mar; 68 (10): 737-42 17. Athyros VG, Tziomalos K, Karagiannis A, et al. Aggressive statin treatment, very low serum cholesterol levels and haemorrhagic stroke: is there an association? Curr Opin Cardiol 2010 Jul; 25 (4): 406-10 18. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008 Nov; 359: 2195-207

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19. Gordon T, Kannel WB, Castelli WP, et al. Lipoproteins, cardiovascular disease, and death. The Framingham study. Arch Intern Med 1981 Aug; 141 (9): 1128-31 20. Soyama Y, Miura K, Morikawa Y, et al. High-density lipoprotein cholesterol and risk of stroke in Japanese men and women: the Oyabe Study. Stroke 2003 Apr; 34 (4): 863-8 21. Phan BA, Chu B, Polissar N, et al. Association of highdensity lipoprotein levels and carotid atherosclerotic plaque characteristics by magnetic resonance imaging. Int J Cardiovasc Imaging 2007 Jun; 23 (3): 337-42

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Correspondence: Dr Michiya Igase, Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan. E-mail: [email protected]
