Plasma lipids predict myocardial infarction, but not stroke, in patients with established cerebrovascular disease

Anushka Patel1,*, Mark Woodward1, Duncan J. Campbell2,3, David R. Sullivan4, Samuel Colman1, John Chalmers1, Bruce Neal1 and Stephen MacMahon1

1The George Institute for International Health, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW 2050, Australia
2St Vincent's Institute of Medical Research, Victoria, Australia
3Department of Medicine, University of Melbourne, Victoria, Australia
4Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney, Australia

Received 19 January 2005; revised 13 June 2005; accepted 16 June 2005; online publish-ahead-of-print 8 July 2005.

* Corresponding author. Tel: +61 2 9993 4564; fax: +61 2 9993 4502. E-mail address: apatel{at}thegeorgeinstitute.org

See page 1818 for the editorial comment on this article (doi:10.1093/eurheartj/ehi309)


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims To evaluate the role of plasma lipids in recurrent vascular events, including stroke, among individuals with established cerebrovascular disease.

Methods and results Plasma total cholesterol, HDL cholesterol, and triglycerides were measured at baseline among individuals participating in the Perindopril Protection Against Recurrent Stroke (PROGRESS) study, a randomized clinical trial of blood pressure lowering among patients with previous stroke or transient ischaemic attack. A series of nested case–control studies were used to investigate the association between each of these lipid variables and the risk of subsequent haemorrhagic stroke, ischaemic stroke, myocardial infarction (MI), and heart failure. A total of 895 patients were selected as cases (83 haemorrhagic stroke, 472 ischaemic stroke, 206 MI, and 258 heart failure) and each was matched with one to three controls. After adjustment for other major cardiovascular risk factors, none of the lipid variables was associated with the risk of either stroke subtype. There were significant positive and negative associations for total cholesterol and HDL, respectively, with the risk of MI; the odds ratio comparing the highest and lowest thirds of each of these lipid variables was 2.00 (95% CI: 1.30–3.09) for total cholesterol and 0.58 (95% CI: 0.37–0.90) for HDL. HDL was inversely associated with the risk of heart failure; however, this result was of borderline statistical significance (P=0.05).

Conclusion Lipid variables are associated with the risk of MI, but not recurrent stroke, in patients with established cerebrovascular disease.

Key Words: Nested case–control study • Ischaemic stroke • Haemorrhagic stroke • Myocardial infarction • Heart failure


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Individuals who experience a cerebrovascular event have a high prevalence of concomitant coronary heart disease and are at substantially increased risk of future acute coronary events and heart failure.1,2 Appropriately, therefore, much attention has been focused on preventive strategies to reduce these risks, including the use of lipid-lowering therapy. However, among individuals who survive a stroke or transient ischaemic attack (TIA), the risk of subsequent stroke is also high, with as many as one-third of survivors suffering another stroke within 5 years of the index event.3 Recurrent strokes are associated with a higher risk and a greater degree of disability;4,5 thus, the specific prevention of subsequent stroke in patients with cerebrovascular disease remains an important objective of treatment.

The recently published results of the Heart Protection Study (HPS) resolve much of the uncertainty relating to the role of lipid-lowering therapy using HMG-CoA reductase inhibitors (‘statins’) in preventing stroke among patients at high risk of vascular events.6 In the overall study population (selected on the basis of a history of cerebrovascular disease, coronary heart disease, other occlusive vascular disease, or diabetes), treatment with simvastatin was associated with a significant reduction in the risk of ischaemic stroke, without any apparent excess risk of haemorrhagic stroke. Treatment with simvastatin was also effective in reducing major vascular events (non-fatal MI, coronary death, stroke, or revascularization) among the subgroup of participants with established cerebrovascular disease, including those without known coronary heart disease at baseline. A clear reduction in the risk of recurrent stroke in these patients with prior cerebrovascular disease could not be demonstrated. Although when the outcome of ischaemic stroke was examined separately, a non-significant trend towards reduction in incidence with simvastatin, consistent with the overall results, was observed. Thus, the role of lipid lowering in specifically preventing recurrent stroke remains inconclusive.

Very few epidemiological data have examined the relative importance of plasma lipids in predicting the risk of stroke or other vascular events in patients with existing cerebrovascular disease. In this article, using a series of nested case–control studies within a large clinical trial, we investigate whether plasma total cholesterol, HDL cholesterol, and triglycerides are associated with the risks of vascular events, including subsequent stroke, among patients with established cerebrovascular disease.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
The design7 and principal results8 of the Perindopril pROtection AGainst REcurrent Stroke Study (PROGRESS) have been published previously. Briefly, PROGRESS was a double-blind placebo-controlled randomized trial of blood pressure-lowering therapy among 6105 hypertensive and non-hypertensive patients with a history of stroke or cerebral TIA within 5 years of enrolment. Participants were recruited between May 1995 and November 1997 from 172 centres in Asia, Australasia, and Europe. Active treatment comprised a flexible regimen based on perindopril (4 mg daily) with the addition of indapamide (2 mg in Japan, 2.5 mg elsewhere) in the absence of any specific contraindication to the use of this drug. The primary outcome was fatal or non-fatal stroke, and after an average of 3.9-year follow-up, active treatment was associated with a 28% (95% CI: 17–38%) reduction in the incidence of this endpoint.8

At recruitment, baseline data were collected on medical history, current medication, and several risk factors, including blood pressure, body mass index, diabetes, atrial fibrillation (AF), and smoking. In addition, each participant consented to the withdrawal of a 20 mL blood sample, with 10 mL collected into EDTA and 10 mL collected into lithium heparin. Blood sampling was performed during either fasted state or unfasted state. Blood samples were centrifuged at 2000 g for 10 min at 4°C and separated. Plasma samples were stored at –80°C and subsequently shipped to a central storage facility, where they remained in deep-frozen storage.

The base population for case–control studies of lipid variables was taken as all those who had blood samples taken at entry into PROGRESS. From this base population, four nested case–control samples for ischaemic stroke, haemorrhagic stroke, MI, and heart failure were selected. For the stroke studies, only participants with plasma frozen within 48 h of venepuncture and whose most recent qualifying event (stroke or TIA) for the clinical trial occurred more than 1 month prior to study entry were included. These restrictions give protection against deterioration of the blood samples and confounding due to acute-phase reactant increases in plasma variables as a result of the incident stroke or its acute complications. No such restrictions were used for the MI or heart failure studies; however, very few patients included in these studies experienced their qualifying events less than 1 month prior to enrolment. Overall, in PROGRESS, the median time between qualifying event and entry was 8 months; in the nested MI and heart failure case–control studies, 23 and 28% of index cerebrovascular events occurred within 3 months of blood sampling, respectively.

Cases were study participants who had a relevant event during the follow-up period. All deaths, strokes, and MIs that occurred during the follow-up phase of PROGRESS were adjudicated by an independent endpoint committee, blind to treatment allocation. Ischaemic stroke was defined as definite stroke with CT scan (performed within 3 weeks) that was either normal or showed infarction in the clinically expected area, or with autopsy evidence of cerebral infarction. Expert members of the adjudication committee further classified ischaemic strokes as cardioembolic, lacunar, large artery, or unclassified type. Haemorrhagic stroke was defined as a definite stroke with CT or autopsy evidence of cerebral haemorrhage, not including haemorrhage secondary to cerebral infarction. The diagnosis of MI was based on the combination of an appropriate clinical history supported by electrocardiographic changes and/or an elevation of biomarkers of myocardial injury. Unless this was the underlying cause of death, heart failure was not independently adjudicated; to minimize the risk of misclassification, only reported cases of heart failure resulting in death, hospitalization, or discontinuation of randomized therapy were included.

Using standard methodology for nested case–control studies,9 in the MI study, each case was randomly matched to between one and three controls selected from all those without MI at the time of that case's diagnosis of MI. Under this sampling scheme, any case may be selected as a control for other cases whose diagnosis of MI pre-dates their own, although cases may have common controls. Similar sampling schemes were used for the other three studies. Matching variables were age (within 5 years), sex, treatment allocated (active/placebo), therapy (mono/dual), region (Australia or New Zealand/China/Japan/France or Belgium/Italy/Sweden/UK or Ireland), and most recent qualifying event (ischaemic stroke or TIA/haemorrhagic stroke/stroke of unknown type) at the trial baseline.

Frozen plasma samples for selected cases and controls were retrieved from the central storage facility. Total cholesterol, HDL cholesterol, and triglycerides were measured on the first thaw EDTA plasma by automated direct-measurement assay (Olympus AU2700, Olympus America Inc., Melville, NY, USA). LDL cholesterol was calculated for those with triglycerides ≤4.4 mmol/L using Friedewald's equation.10 Blood pressure recorded was the average of two measurements made at baseline in the clinical trial, using a mercury sphygmomanometer.

Statistical analysis
Baseline values for unique cases and controls (after removing the duplication inherent to the study design) were compared using unpaired t-tests and {chi}2 tests, as appropriate. The linearity assumption for continuous variables included in the models was assessed through descriptive statistics. Conditional logistic regression models were used to estimate odds ratios.9 In addition to unadjusted analyses (allowing only for the confounding effects of the matched variables by design), additional adjustments through the regression model were made for the baseline values of the following potentially confounding variables: systolic blood pressure (SBP), smoking (current/not), diabetes, previous coronary heart disease, AF, valvular heart disease, left ventricular hypertrophy, and cholesterol-lowering drugs at baseline. Odds ratios were calculated according to equal thirds of the distribution of each risk factor in the total sample (cases and controls together), and the P-value for a linear trend across these thirds was computed.

In addition, the associations were expressed as the odds ratio associated with a 1 mmol/L increase in the ‘usual’ level of the plasma lipid parameters. Analyses based on a single baseline measure of a risk factor are likely to underestimate true associations, particularly for those variables (e.g. plasma triglycerides) that exhibit a relatively high degree of intra-individual variability.11,12 These estimates, therefore, were adjusted for regression dilution bias using repeat lipid measurements performed on plasma collected from a 10% random sample of PROGRESS participants 12 months after randomization. For each lipid variable, repeat values were regressed on baseline values, and a regression dilution coefficient was derived as the inverse of the regression slope. Only patients assigned placebo, who were not a case, were used to derive regression dilution coefficients. The log odds ratios and standard errors for each of the associations were adjusted by coefficients derived using this method (1.38 for total cholesterol, 1.13 for HDL cholesterol, and 1.53 for triglycerides).9 All statistical tests were two-sided with {alpha}=0.05, and no adjustments were made for multiple testing.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
A total of 895 patients were selected as cases (83 haemorrhagic stroke, 472 ischaemic stroke, 206 MI, and 258 heart failure; some patients were cases for more than one study). Of the ischaemic strokes selected as cases, 6, 24, 14, and 56% were cardioembolic, lacunar, large vessel, and unclassified, respectively. Overall, controls satisfying all matching criteria were found for 97% of cases.

Participants who experienced an ischaemic stroke during follow-up were significantly more likely to have a higher SBP, diabetes, and AF and be current smokers when compared with controls (Table 1). Higher SBP and previous history of coronary heart disease were associated with the risk of MI and of developing heart failure during follow-up (Table 2). Body mass index, diabetes, and AF at baseline were also associated with a subsequent diagnosis of heart failure. Approximately 14% of participants used cholesterol-lowering drugs at baseline in each of the studies (about one-half were statins); however, there were no significant differences in the use of these drugs between cases and controls for any of the outcomes studied.


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Table 1 Characteristics of study participants: stroke
 

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Table 2 Characteristics of study participants: MI and heart failure
 
None of the lipid variables showed any association with either haemorrhagic stroke or overall ischaemic stroke (Table 3). After subclassification of ischaemic stroke, however, a significant association was observed between HDL cholesterol and lacunar stroke; the odds ratio (95% CI) for the highest vs. lowest third of HDL cholesterol was 0.54 (0.30–0.96). Each 1 mmol/L higher level of HDL cholesterol was associated with a 27% (95% CI: 2–46) lower risk of lacunar stroke. The risk of MI was positively associated with total cholesterol and negatively associated with HDL cholesterol. The latter was also significantly and inversely associated with the risk of heart failure on univariate analysis [odds ratio (95% CI) for highest vs. lowest third of HDL cholesterol, 0.58 (0.39–0.87)]. However, after further adjustment for diabetes and history of coronary heart disease, this association was substantially attenuated and was of borderline statistical significance. Each 1 mmol/L higher level of usual total cholesterol and each 1 mmol/L lower level of usual HDL were associated with a 44 (95% CI: 15–81) and 49% (95% CI: 5–72) higher risk of MI, respectively (Figure 1).


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Table 3 Adjusteda odds ratio (95% CI) for each outcome
 


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Figure 1 Adjusted odds ratios (and 95% CI) associated with a 1 mmol/L higher usual level of total cholesterol, HDL cholesterol, and triglycerides, for each of the outcomes: ischaemic stroke, haemorrhagic stroke, MI, and heart failure. Analyses are adjusted for regression dilution and for other covariates as in Table 3. The horizontal lines are 95% confidence limits; the boxes are drawn in proportion to the number of events.

 
The analyses for calculated LDL cholesterol were based on 96% of the study participants, and the results were very similar to those observed for total cholesterol. No association was observed between LDL cholesterol and haemorrhagic stroke, ischaemic stroke (including specific subtypes), or heart failure. LDL cholesterol was associated with the risk of MI; the adjusted odds ratio (95% CI) comparing individuals grouped in the highest to lowest third of LDL cholesterol levels was 1.98 (1.29–3.01). After adjustment, each 1 mmol/L higher level of LDL cholesterol was associated with a 40% (95% CI: 16–70%) increased risk of MI. The results for LDL/HDL ratio were similar to those observed separately for LDL and HDL cholesterol. The ratio was strongly associated with the risk of MI, but no association was observed for any stroke outcome. As with HDL cholesterol, the LDL/HDL ratio was also inversely associated with the risk of heart failure; the adjusted odds ratio (95% CI) comparing individuals grouped in the highest to lowest LDL/HDL ratio was 1.65 (1.12–2.43).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
In this series of nested case–control studies among patients with established cerebrovascular disease, plasma total cholesterol, LDL cholesterol, and HDL cholesterol levels were found to be associated with the risk of MI. We were unable to detect an association between total cholesterol or LDL cholesterol and the risk of ischaemic stroke. An isolated finding of an association between HDL cholesterol and lacunar stroke is an interesting but unexpected finding. This may be a chance for observation, given the lack of association with total or LDL cholesterol and the absence of any relationship between lipid variables and the risk of large artery ischaemic stroke. High HDL levels were also found to be protective against the development of heart failure among these patients; however, this relationship was confounded by presence of a history of coronary heart disease or diabetes at baseline.

Epidemiological data relating to cholesterol and the risk of a first stroke in populations free of vascular disease at baseline have suggested that blood cholesterol is positively associated with the risk of ischaemic stroke, although the strength of this association is considerably weaker than that observed for coronary heart disease.1215 The lack of association between cholesterol and total stroke risk is probably explained by a weak inverse association with haemorrhagic stroke risk, perhaps particularly among individuals with higher blood pressure.13,14,1620 These observational data are consistent with the evidence of benefits of lipid lowering in high-risk populations in preventing coronary events and first ischaemic stroke, although no effect on haemorrhagic stroke has emerged to date.6,21

The current analyses also suggest some congruence between the epidemiological results and the data currently available from clinical trials with respect to the association between lipids and the risk of vascular events among patients with established cerebrovascular disease. We found that total, LDL, and HDL cholesterol levels were associated with the risk of MI. This is consistent with the results of HPS, which indicated a reduction in major vascular (largely, coronary) events with statin therapy in patients with cerebrovascular disease, including a further subgroup of individuals with prior stroke and no coronary heart disease at baseline.6

Conversely, we did not find any evidence of an association between lipid variables and overall stroke risk in the PROGRESS study population. HPS also did not provide evidence of any benefits of therapy with simvastatin on total stroke among patients with cerebrovascular disease.6 However, stroke is a heterogeneous condition, and the effects of simvastatin on the incidence of ischaemic stroke among patients with cerebrovascular disease in HPS, though not separately significant, were consistent with the beneficial effects seen in the remainder of the HPS population. It must be noted that the analyses of patients in HPS with pre-existing cerebrovascular disease were post hoc and included a relatively small number of events (~300 strokes).6 Despite our study probably being the largest epidemiological analysis to have examined the association between lipids and vascular events (including recurrent stroke) in patients with established cerebrovascular disease to date, the power to detect meaningful associations for stroke outcomes was also limited. Post hoc computations suggest that the ischaemic stroke study had 90% power to detect odds ratios of 0.6 or 1.6 for individuals grouped in the highest vs. the lowest third of total cholesterol level, whereas the haemorrhagic stroke study could only detect odds ratios of 0.3 or 3.6 with the same power. Thus, one interpretation of our results is that these studies had too few stroke events to reliably detect more modest but still clinically meaningful associations; an alternative interpretation requires postulating biological differences in the role of lipids in initial vs. recurrent stroke. Definitive evidence about the role of statin therapy in preventing recurrent ischaemic stroke is awaited, and at least one large clinical trial is ongoing.22

These analyses have other limitations. As with any observational data, the reported associations between lipid variables and vascular events may be subject to residual confounding. A further limitation relates to lack of independent verification of heart failure events, although restricting the definition to those cases that resulted in death, hospitalization, or withdrawal of randomized therapy (in order to commence an open-label ACE-Inhibitor) is likely to have minimized the risk of misclassification. Furthermore, an important strength of this study is the independent external adjudication of all strokes and cases of MI.

In conclusion, plasma levels of total cholesterol, LDL cholesterol, and HDL cholesterol are independent determinants of MI among patients with established cerebrovascular disease. Our data are strongly consistent with the results of interventional studies which support the use of cholesterol-lowering therapy to prevent major coronary events in these high-risk patients. Furthermore, the PROGRESS trial has provided reliable evidence about the efficacy of blood pressure lowering for the prevention of both major coronary events23 and recurrent stroke8 in patients with cerebrovascular disease. Our data do not show an association between plasma lipids and ischaemic stroke, and more definitive clinical trial data about the role of statin therapy in preventing recurrent ischaemic stroke are pending.22


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
This study was funded by a Pfizer Cardiovascular Lipid Research Grant (Australia). PROGRESS was funded by grants from Servier, the Health Research Council of New Zealand, and the National Health and Medical Research Council of Australia. D.J.C. and B.N. are recipients of Career Development Awards from the National Heart Foundation of Australia.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Hartmann A, Rundek T, Mast H, Paik MC, Boden-Albala B, Mohr JP, Sacco RL. Mortality and causes of death after first ischemic stroke. The Northern Manhattan Stroke Study. Neurology 2001;57:2000–2005.[Abstract/Free Full Text]
  2. Kelly R, Staines A, MacWalter R, Stonebridge P, Tunstall-Pedoe H, Struthers AD. The prevalence of treatable left ventricular dysfunction in patients who present with noncardiac vascular episodes. J Am Coll Cardiol 2002;39:219–224.[Abstract/Free Full Text]
  3. Hardie K, Hankey GJ, Jamrozik K, Broadhurst RJ, Anderson C. Ten-year risk of first recurrent stroke and disability after first-ever stroke in the Perth Community Stroke Study. Stroke 2004;35:731–735.[Abstract/Free Full Text]
  4. Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Anderson CS. Long-term disability after first-ever stroke and related prognostic factors in the Perth Community Stroke Study, 1989–1990. Stroke 2002;33:1034–1040.[Abstract/Free Full Text]
  5. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) Collaborative Group. Effects of a perindopril-based blood pressure-lowering regimen on disability and dependency in 6105 patients with cerebrovascular disease: a randomized controlled trial. Stroke 2003;34:2333–2338.[Abstract/Free Full Text]
  6. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757–767.[CrossRef][ISI][Medline]
  7. PROGRESS Management Committee. Blood pressure lowering for the secondary prevention of stroke: rationale and design for PROGRESS. J Hypertens 1996;15(Suppl. 2):S41–S46.[ISI]
  8. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033–1041.[CrossRef][ISI][Medline]
  9. Woodward M. Epidemiology: Study Design and Data Analysis. 2nd ed. Boca Raton: Chapman and Hall/CRC Press; 2005.
  10. Clarke R, Shipley M, Lewington S, Youngman L, Collins R, Marmot M, Peto R. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol 1999;150:341–353.[Abstract]
  11. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease. Part 1. Prolonged differences in blood pressure: prospective observational studies corrected for regression dilution bias. Lancet 1990;335:765–774.[CrossRef][ISI][Medline]
  12. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989;320:904–910.[Abstract]
  13. The Asia Pacific Cohort Studies Collaboration. Cholesterol, coronary heart disease and stroke in the Asia Pacific region. Int J Epidemiol 2003;32:563–572.[Abstract/Free Full Text]
  14. Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. BMJ 1994;309:11–15.[Abstract/Free Full Text]
  15. Wannamethee SG, Shaper AG, Ebrahim S. HDL-cholesterol, total cholesterol, and the risk of stroke in middle-aged British men. Stroke 2000;31:1882–1888.[Abstract/Free Full Text]
  16. Rodriguez BL, D'Agostino R, Abbott RD, Kagan A, Burchfiel CM, Yano K, Ross GW, Silbershatz H, Higgins MW, Popper J, Wolf PA, Curb JD. Risk of hospitalized stroke in men enrolled in the Honolulu Heart Program and the Framingham Study: a comparison of incidence and risk factor effects. Stroke 2002;33:230–236.[Abstract/Free Full Text]
  17. Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinonen OP. Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke 1999;30:2535–2540.[Abstract/Free Full Text]
  18. Iribarren C, Jacobs DR, Sadler M, Claxton AJ, Sidney S. Low total serum cholesterol and intracerebral hemorrhagic stroke: is the association confined to elderly men? The Kaiser Permanente Medical Care Program. Stroke 1996;27:1993–1998.[Abstract/Free Full Text]
  19. Yano K, Reed DM, MacLean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke 1989;20:1460–1465.[Abstract/Free Full Text]
  20. Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J. Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling Project. Circulation 2001;103:387–392.[Abstract/Free Full Text]
  21. Amarenco P, Bogousslavsky J, Callahan AS, Goldstein L, Hennerici M, Sillsen H, Welch MA, Zivin J for the SPARCL Investigators. Design and baseline characteristics of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study. Cerebrovasc Dis 2003;16:389–395.[CrossRef][ISI][Medline]
  22. Chen D, Roman GC, Wu GX, Wu ZS, Yao CH, Zhang M, Hirsch RP. Stroke in China (Sino-MONICA-Beijing study) 1984–1986. Neuroepidemiol 1992;11:15–23.[CrossRef][ISI][Medline]
  23. PROGRESS Collaborative Group. Effects on a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease. Eur Heart J 2003;24:475–484.[Abstract/Free Full Text]

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