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)
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Abstract |
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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 casecontrol 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: 1.303.09) for total cholesterol and 0.58 (95% CI: 0.370.90) 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 casecontrol study Ischaemic stroke Haemorrhagic stroke Myocardial infarction Heart failure
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Introduction |
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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 casecontrol 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.
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Methods |
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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 casecontrol studies of lipid variables was taken as all those who had blood samples taken at entry into PROGRESS. From this base population, four nested casecontrol 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 casecontrol 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 casecontrol 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 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 =0.05, and no adjustments were made for multiple testing.
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Results |
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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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Discussion |
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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
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Acknowledgements |
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References |
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