Total cholesterol +/- blood pressure ^ together 4 vascular mortality?

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Hi All, The blood level of total cholesterol matters much for vascular mortality. The total cholesterol varied from 4.5-8.0 mM, and was directly proportional for all age groups to the log of the cholesterol level. The below (1, 2) papers are pdf-availed. 1. The paradox of cholesterol and strokeThe Lancet, Volume 370, Issue 9602, 2007 Dec. 2007, Pages 1803-4Pierre Amarenco and P Steg Total blood cholesterol predicts mortality from coronary artery disease. Statins reduce both blood cholesterol and mortality, a benefit that is independent of baseline total cholesterol, blood pressure treatment, and hypertension,1 and is maintained for up to 10 years.2 In today's Lancet, the Prospective Study Collaboration reports a very large individual-data meta-analysis of observational studies on blood

cholesterol and cardiovascular risk in otherwise healthy individuals, as a function of age, sex, and blood pressure.3 The relation between cholesterol and death from ischaemic heart disease holds true across age and blood-pressure categories. Across the ages, a 1 mmol/L lower total cholesterol leads to about a third lower ischaemic heart disease mortality. At each age, blood pressure is uncorrelated with the absolute difference in risk per unit difference in blood cholesterol. Because risk is higher in older people, however, the absolute number of events related to cholesterol might be higher in older patients. Interestingly, total/HDL cholesterol ratio is more informative in this meta-analysis than HDL, non-HDL, or total cholesterol. This result parallels the observation in the INTERHEART study that ApoB/ApoA1 ratio was the most informative variable.4 These findings argue for applying the benefits of statins to high-risk patients, regardless of age and blood pressure, and

suggest that clinicians might need to consider the ratio of total/HDL cholesterol rather than the LDL cholesterol level to which they have become accustomed. An earlier meta-analysis by the Prospective Study Collaboration found weak or no associations between blood cholesterol and stroke mortality,5 but the relations of age and hypertension with stroke might have concealed a weaker association with cholesterol. Moreover, stroke is a heterogeneous condition and the subtypes had been considered together. The MRFIT study showed an association between higher total cholesterol and ischaemic stroke, and, at least in hypertensive patients, between lower cholesterol and haemorrhagic stroke.6 Today's meta-analysis found no clear association between cholesterol and stroke, except in people aged 40–59 years and in patients with normal or high-normal blood pressure. Again, however, the various causes of ischaemic stroke might have different associations

with cholesterol.7 Whilst myocardial infarction almost always follows atherothrombotic disease, brain infarction stems from conditions ranging from rheumatic heart disease to atherosclerotic carotid stenosis. Blood cholesterol is associated with carotid stenosis, and carotid stenosis causes stroke,8 so observational studies including stroke associated with carotid stenosis might mimic the findings with ischaemic heart disease. Trials show that statins slow progression of carotid atherosclerosis, and a meta-analysis showed that reduced LDL cholesterol impeded progression of carotid atherosclerosis.9 In patients with established coronary artery disease, hypertension, diabetes, or at high vascular risk, statins have led to a 17–21% reduction in relative risk of incident stroke per 1 mmol/L difference in LDL cholesterol.1 The greater the reduction in LDL cholesterol, the lower the risk of stroke.9 Stroke risk-reduction with statins was recently

confirmed in SPARCL in the secondary prevention of stroke or transient ischaemic attack:10 the lower the achieved LDL cholesterol over the course of the trial, the greater the reduction in the risk of recurrent stroke.11 However, as in another trial,12 baseline LDL cholesterol was not predictive of stroke; and the treatment effect was observed regardless of baseline LDL cholesterol.13 Because most of the benefit of statins in preventing cardiovascular events can be ascribed to the LDL reduction,[1] and [9] it is puzzling that LDL cholesterol is not associated with stroke risk, particularly because non-LDL-related effects appear unlikely to account for a substantial fraction of statins' clinical benefit.14 Inset picture and text: Atheroma in artery Science Photo Library Today's meta-analysis shows a moderately negative association of blood cholesterol with stroke in older patients, particularly those with high

systolic blood pressure. However, and although analyses were standardised by age to avoid survival bias, patients who die from coronary heart disease at earlier ages cannot contribute to a later risk of atherothrombotic stroke. Hence, the proportion of patients with atherothrombotic disease at risk of stroke decreases over time relative to other causes that increase with age (eg, intracranial small vessel disease or atrial fibrillation) and that may have a different association with blood cholesterol. Selection could also explain the protection conferred by high cholesterol against haemorrhagic stroke observed in today's meta-analysis, by progressively decreasing the proportion of patients with atherothrombotic disease and subsequently increasing the proportion of other cerebral vessel diseases or conditions in the elderly that cause haemorrhagic stroke (eg, amyloid angiopathy, use of oral anticoagulants) with unknown relations with blood cholesterol. Today's meta-analysis

evaluated the relationships between blood cholesterol and fatal stroke. Because most patients survive stroke, and die later from myocardial infarction rather than another stroke or from non-vascular disease,15 stroke patients contribute more to cardiac deaths than to stroke death, which may also be reflected in today's meta-analysis. In trials, an increase in the risk of brain haemorrhage with statin therapy, by lowering blood cholesterol, has not been found,1 except in patients with a previous stroke in SPARCL,10 and perhaps in the Heart Protection Study.16 However, in SPARCL, the increased risk of brain haemorrhage was not associated with LDL lowering.11 Cholesterol is a strong risk factor for ischaemic heart disease irrespective of age and blood pressure, and statins are associated with reductions in cholesterol and coronary event rates. A link between cholesterol and stroke risk probably exists (at least with atherothrombotic stroke), and

there is good evidence that lowering blood cholesterol with statins reduces stroke risk and carotid atherosclerosis, independently of blood cholesterol, blood pressure, and age. Whether raising HDL cholesterol, lowering triglyceride, or reducing inflammation and high-sensitivity C-reactive protein will further decrease stroke risk remains to be evaluated in randomised trials. PA has received honoraria and speaker's fees from Pfizer, Sanofi-Aventis, AstraZeneca, Daiichi-Sankyo, Merck, Novartis, Boehringer-Ingelheim, Servier, Eli-Lilly, Paion, and Lundbeck, and research funding from Pfizer, Sanofi-Aventis, Eisai, and Boehringer-Ingelheim. PGS has received consulting or speaker's fees from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, GlaxoKline, Merck Sharpe and Dohme, Nycomed, Sanofi-Aventis, Servier, Takeda, The Medicines Company, and ZLB-Behring, and research funding from Sanofi-Aventis. 2. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deathsLancet 370 (9602) 2007 Dec. 1-7 29-1839Prospective Studies Collaboration Rerred to and referred by: The paradox of cholesterol and strokeThe Lancet, Volume 370, Issue 9602, 2007 Dec. 2007, Pages 1803-4Pierre Amarenco and P Steg Summary Background Age, sex, and blood pressure could modify the associations of total cholesterol (and its main two fractions, HDL and LDL cholesterol) with vascular mortality. This meta-analysis combined prospective studies of vascular mortality that recorded both blood pressure and total cholesterol at baseline, to determine the joint relevance of these two risk factors. Methods Information was obtained from 61 prospective observational studies, mostly in western Europe or North America, consisting of almost 900 000 adults without previous disease and with baseline measurements of total cholesterol and blood pressure. During nearly 12 million person years at risk between the ages of 40 and 89 years, there were more than 55 000 vascular deaths (34 000 ischaemic heart disease [iHD], 12 000 stroke, 10 000 other). Information about HDL cholesterol was available for 150 000 participants, among whom there were 5000 vascular deaths (3000 IHD, 1000 stroke, 1000 other). Reported associations are with usual cholesterol levels (ie, corrected for the regression dilution bias). Findings 1 mmol/L lower total cholesterol was associated with about a half (hazard ratio 0·44 [95% CI 0·42–0·48]), a third (0·66 [0·65–0·68]), and a sixth (0·83 [0·81–0·85]) lower

IHD mortality in both sexes at ages 40–49, 50–69, and 70–89 years, respectively, throughout the main range of cholesterol in most developed countries, with no apparent threshold. The proportional risk reduction decreased with increasing blood pressure, since the absolute effects of cholesterol and blood pressure were approximately additive. Of various simple indices involving HDL cholesterol, the ratio total/HDL cholesterol was the strongest predictor of IHD mortality (40% more informative than non-HDL cholesterol and more than twice as informative as total cholesterol). Total cholesterol was weakly positively related to ischaemic and total stroke mortality in early middle age (40–59 years), but this finding could be largely or wholly accounted for by the association of cholesterol with blood pressure. Moreover, a positive relation was seen only in middle age and only in those with below-average blood pressure; at older ages (70–89 years) and, particularly, for those with

systolic blood pressure over about 145 mm Hg, total cholesterol was negatively related to haemorrhagic and total stroke mortality. The results for other vascular mortality were intermediate between those for IHD and stroke. Interpretation Total cholesterol was positively associated with IHD mortality in both middle and old age and at all blood pressure levels. The absence of an independent positive association of cholesterol with stroke mortality, especially at older ages or higher blood pressures, is unexplained, and invites further research. Nevertheless, there is conclusive evidence from randomised trials that statins substantially reduce not only coronary event rates but also total stroke rates in patients with a wide range of ages and blood pressures. ... All of the writing committee (except NQ) work in the CTSU, which has a policy of staff not accepting fees, honoraria, or

consultancies. The CTSU is, however, involved in clinical trials of cholesterol modification therapy with funding from the MRC, BHF, and/or various companies (Merck, Schering, Solvay) as research grants to (and administered by) Oxford University. NQ works in Oxon Clinical Epidemiology Limited, and has stock options in Glaxo Kline. ... Merck helped support the 1996 meeting of collaborators. ... -- Al Pater, alpater@...

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