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HDL cholesterol and stroke type
- Rizaldy Pinzon (1 March 2009)
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Can the association of cholesterol and cardiovascular disease be understood if the role of blood rheology is ignored ?
- Les O. Simpson (2 March 2009)
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HDL no, LDL yes: wrong conclusion, bad analysis.
- Eddie Vos (3 March 2009)
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Is LDL reduction really the key?
- Andreas Waltering, Hilda Bastian, head of health information department, Guido Skipka, medical biometry department, Peter T. Sawicki, institute director (15 March 2009)
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bad cholesterol is good marketing
- Cleaves M. Bennett MD FACP (25 March 2009)
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Relation between Lipid Modification and Outcome: Identifying the Appropriate Therapeutic Targets for Lipid Modifying Therapies
- Ilan Goldenberg, Shlomo Behar M.D. (11 April 2009)
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Rizaldy Pinzon, Neurologist Bethesda hospital Yogyakarta Indonesia 55224
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An increasing number of studies have addressed the issue of cholesterol subfractions, in particular, HDL-C and have generally found that the inverse relationship between HDL-C and stroke is not a consistent finding. The study from Briel (2009) showed that there is no correlation between HDL level and the risk of cardiovascular event. The amount of LDL is strongest predictor. The future research should also address the type of stroke.The development of atherosclerotic plaques and the degree of carotid atheroma has been repeatedly related to serum lipid levels, directly with both total and LDL-cholesterol as well as triglycerides and inversely with HDL-CHigher HDL-C levels were thought to be more protective against atherosclerosis ischaemic strokes as opposed to non-atherosclerosis ischaemic strokes Competing interests: None declared |
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Les O. Simpson, retired experimental pathologist Dunedin, New Zealand 9077
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Briel and 20 collaborators invested a great deal of time and expertise to conclude that their findings, "...raises questions about the development of therapeutic agents that increase high density lipoprotein cholesterol." The fact that such agents have been developed probably reflects the refusal by clinicians to recognise that blood rheology is the system most affected by high levels of plasma cholesterol. When plasma cholesterol levels are raised, blood viscosity increases and red cell deformability is reduced because of an increase in the amount of cholesterol in the red cell membrane. Agents which reduce cholesterol levels lower blood viscosity and enhance red cell deformability so that the flow properties of blood are increased. In 1964, Mayer (1) reported that in both sexes, blood viscosity was higher in those suffering from coronary heart disease than in healthy subjects. Lowe et al (2) in 1980 reported in the Br Med J that blood viscosity was increased in men with evidence of coronary artery disease. Dormandy et al (3) reported in 1981 that blood samples from patients with proven myocardial infarction showed reduced filterability ( an assessment of red cell deformability) which fell to a minimum 7 to 16 hours after the onset of symptoms. Lee et al (4) in 2004 reported a study of the rheological properties of red cells from hypercholesterolemic males. They concluded that, "...high levels of cholesterol LDL or HDL in vivo alters the morphology and flow behaviour of blood cells that can subsequently increase the risk of impairing function and microcirculation." As similar findings have been reported by others, it seems strange that an increase in HDL cholesterol could be expected to have beneficial effects. There is sufficient published information to justify the claim that whether viewed from the perspective of plasma cholesterol level or from that of coronary heart disease, the active agent is altered blood rheology. Because omega-3 fatty acids improve red cell deformability and lower blood viscosity, the 1985 report by Kromhout et al (5) is relevant. They found that a daily intake of about 30 grams of oily fish lowered the incidence of heart disease by 50% in a 20 year follow-up study. It could be noteworthy, that in the Briel et al report, there was no clear statement which considered why cholesterol levels should be associated with coronary heart disease. References. 1. Mayer GA. Blood viscosity in healthy subjects and patients with coronary heart disease. Canad Med Assn J 1964;91: 951-4. 2. Lowe GDO, Drummond M, Lorimer AR, et al. Relation between extent of coronary artery disease and blood viscosity. Br Med J 1980; i :673-4. 3. Dormandy J, Boyd M, Ernst E. Filterability and vascular disease: 2. Red cell filterability after myocardial infarction. Scand J Clin Invest 1981; 156 (suppl): 195-8. 4. Lee CY, Kim KC, Park HW, et al. Rheological properties of erythrocytes from male hyper-cholesterolemia. Microvas Res 2004; 67:133- 8. 5. Kromhout D, Bosschieter EA, Coulander C, et al. The inverse relation between fish concumption and 20 year mortality from coronary heart disease. N Engl J Med 1985; 312: 1205-9. Competing interests: None declared |
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Eddie Vos, maitains health-heart.org Sutton (Qc) Canada J0E 2K0
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It is interesting how a statistical exercise financed by Pfizer about HDL-cholesterol winds up suggesting that raising HDL does not matter while lowering LDL-cholesterol does - in cardiovascular events and all-cause deaths(1). This study has flaws. First, the exclusion of positive studies not fitting limiting modeling criteria, like the Coronary Drug Project regarding niacin vs. placebo and that significantly prevented second heart attacks with a post-study all-cause mortality benefit(2). No niacin only study fit the inclusion criteria while niacin (very high dose vitamin B3) is the undisputed therapy to raise HDL-cholesterol. On the other hand, the inclusion criteria captured most LDL-lowering controlled and dose/drug-comparison studies with the sponsor's atorvastatin (Lipitor), a statin not raising HDL-cholesterol (ASCOT; Table 2 in ref. W40 in (1)) and that never lowered mortality in anyone (W33-W35, 56, W57 in (1)). Moreover, atorvastatin found no "event" benefit in women (ref. W40 in (1)) as indeed no LDL-lowering study ever found a mortality benefit in women, including statins(3). Thirdly, there is no biological rationale for LDL adjustment when studying HDL since HDL is a blood particle with about 80 (presumably useful) associated proteins, while "LDL-cholesterol" represents the concentration of a single-protein lipid transport particle of which the composition (in trans-fats, omega-3, carotenoids, homocysteine, other) varies widely depending upon food intakes. Fourthly, analysis including "events" are confounded by statin's well known "nitroglycerin mimicking" effect, promoting NO/eNOS, an unadjusted confounder(4) that may explain, for example, much of the uniquely male non -fatal event benefit in ASCOT. The unspoken message of statin benefit, including total deaths, for all is unsupported by placebo controlled studies where "Numbers Needlessly Treated" approach infinity regarding all-cause mortality in women, and in men regarding atorvastatin, while HDL raising niacin therapy remains an option with trial support. vos{at}health-heart.org 1. Briel M, Ferreira-Gonzalez I, You JJ, Karanicolas PJ, Akl EA, Wu P, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ. 2009 Feb 16;338:b92. Medline 19221140 http://www.bmj.com/cgi/content/full/338/feb16_1/b92 2. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986 Dec;8(6):1245-55. Medline 3782631 3. Walsh JME, Pignone M. Drug Treatment of Hyperlipidemia in Women. JAMA. 2004;291:2243-2252. Medline 15138247 http://jama.ama-assn.org/cgi/content/full/291/18/2243 4. Laufs U. Beyond lipid-lowering: effects of statins on endothelial nitric oxide. Eur J Clin Pharmacol. 2003 Mar;58(11):719-31. Medline 12634978 Competing interests: None declared |
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Andreas Waltering, health information department Institute for Quality and Efficiency in Health Care (IQWiG), 51105 Cologne, Germany, Hilda Bastian, head of health information department, Guido Skipka, medical biometry department, Peter T. Sawicki, institute director
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Dear Editors, We read the article by Briel at al. [1] with interest. However, the conclusion, that LDL-cholesterol reduction should be the primary target of therapy requires, in our view, some clarification. The results as presented could lead to the conclusion that there is a causal relation between a 10 mg/dl reduction in LDL-cholesterol levels and absolute reduction of cardiovascular endpoints. As the authors point out, this is not a result of an intervention study aiming at different LDL-targets, but rather an observational meta-regression which risks bias by confounding and cannot support causal interpretation. During treatment with statins patients with higher LDL-cholesterol values might be more likely to have a greater reduction in serum cholesterol and at the same time a greater reduction of cardiovascular events. In addition, this approach ignores the pleiotropic effect of the statins. That cannot be quantified and the results of Briel et al. do not control for such effects. Especially in placebo-controlled trials, the observed effect on cardiovascular outcomes could be misleadingly attributed to the extent of the LDL reduction alone. People with CHD for example should still be offered statins, even if the have normal LDL- levels. It is not disputed that statins reduce the risk of cardiovascular morbidity and mortality regardless of both the extent of absolute reduction of LDL cholesterol and the baseline value before therapy. However, the results of relevant trials [2-5] comparing intensive versus moderate statin therapy are inconsistent. Meta-analyses have shown no significant reduction of all-cause mortality by intensive treatment despite the achievement of noticeably lower LDL levels [6,7]. Adverse effects were significantly higher [6]. Cannon et al. also did not find a significant reduction of cardiovascular mortality by intensive therapy [7]. Only combining different cardiovascular outcomes led to significant findings in favour of aggressive LDL cholesterol reduction. The latest results of the SEARCH trial, reported at an AHA scientific meeting in November 2008, also showed no significant benefit of intensive therapy in terms of the primary cardiovascular endpoint. Even under study conditions a lot of participants in the intensive therapy arm never achieve target LDL values – or they have to taper the high dose because of adverse effects. One should assume that this proportion will be even higher outside trials. To define a therapy target that will not be reached by the majority of affected patients does not seem to be very useful. The results of Briel et al. should not be mistaken for a proof of beneficial effects of aggressive target-driven statin therapy aiming for a maximum reduction of LDL cholesterol. Such therapy may even be counterproductive, leading to an increase in dose- dependent side effects and to frustration of patients and physicians, with consequent adverse effects on adherence. Recent surveys by German health insurance companies show that, despite its undoubted efficacy, between 30-40% of patients with a known cardiovascular disease do not get any statin at all. It seems more important to provide these under-treated patients with at least a fixed- dose statin therapy before we focus on further and still ambiguous issues. 1. Briel M, Ferreira-Gonzalez I, You JJ, Karanicolas PJ, Akl EA, Wu P et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 2009; 338: b92. 2. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350(15): 1495-1504. 3. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292(11): 1307-1316. 4. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352(14): 1425-1435. 5. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005; 294(19): 2437-2445. 6. Afilalo J, Majdan AA, Eisenberg MJ. Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials. Heart 2007; 93(8): 914-921. 7. Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta- analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006; 48(3): 438-445. Competing interests: None declared |
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Cleaves M. Bennett MD FACP, retired physician and Prof Medicine Austin, TX 78669
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You should point out to your MD readers that “relative risk reduction” as it applies to large groups of patients is very different than “absolute risk reduction” as it applies to an individual patient facing her doctor at the office. An important statistic when facing a patient is the “number needed to treat” to benefit 1 patient, or NNT. Pfizer used to run an ad for Lipitor showing the results of a double blind, placebo controlled study of 10,000 high risk (more than 3 risk factors) patients for 5 years. Lipitor reduced the heart attack relative risk by 50%, shown by a large downwards facing arrow. The absolute risk reduction tells a very different story. Heart attacks fell from 2% to 1%, for a NNT of 100. Beyond 5 years Pfizer and all the other makers of statins have no data. No patients would agree to take a placebo for >5years since the populace has been scared silly by all the hoopla about “bad” cholesterol. Would any doctor hand a patient an Rx for Lipitor and say “You will need to take this pill every day for the rest of your life. But for the next 5 years there is only a 1% chance that it will actually benefit you in any way except for dropping the cholesterol number on the lab sheet. Beyond 5 years we don’t know if it is still helping you because no one has done the research on that question.” Competing interests: None declared |
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Ilan Goldenberg, Senior Cardiologist Heart Institute and Meufeld cardiac Research Institute, Tel Hashomer, Israel 52621, Shlomo Behar M.D.
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Briel et al (1) have carried out an extensive meta-analysis, comprising nearly 300,000 participants in randomized clinical trials of lipid modifying therapies, which failed to identify a statistically significant association between changes in high-density lipoprotein- cholesterol (HDL-C) levels and cardiovascular outcomes. The results of this analysis contradict data from all major fibrate trials, that have consistently shown a significant association between on-treatment HDL-C increments and major reductions in cardiovascular events in both primary and secondary prevention settings (2-4). These apparently conflicting data can be attributed to important differences in the selected populations among the studies. Briel et al, have chosen to focus their analysis mainly on statin trials (n=62), which were designed to reduce LDL-C in patients with moderately to high baseline LDL-C levels and a mean baseline HDL-C that was in the normal range (47 mg/dL), whereas fibrate trials evaluated the benefit of lipid modifying therapies among high-risk patients with the common raised triglycerides-low HDL-C dyslipidaemia. Accordingly, the results of the present meta-analysis are biased to a patient population within which lipid modifying therapies resulted in major on-treatment LDL- C reductions and relatively minor HDL-C increments. To evaluate the benefit associated with on-treatment HDL-C increments, we have carried out a subanalysis of the Bezafibrate Infarction Prevention (BIP) Trial, comprising 3020 coronary heart disease patients with the raised triglycerides-low HDL-C dyslipidaemia (2). Our data demonstrate that, in this high-risk patient subset, 5 mg/dL increments in HDL-C were independently associated a significant 27% (p<0.001) reduction in cardiac mortality, whereas on-treatment reductions in LDL-C did not contribute to outcome after adjustment for HDL -C changes. The long-term survival benefit associated with of HDL-C modification was also substantiated in an extended 16-year follow-up study of the BIP trial (5). Furthermore, in a recent analysis of the BIP population (6), we have shown that the benefit of raising HDL-C is related to baseline serum levels of LDL-C. Thus, HDL-C modification was associated with an enhanced survival benefit among patients with low baseline LDL-C (< 130 mg/dL), whereas a significant benefit of LDL-C modification was evident only among patients with elevated baseline LDL-C (>130 mg/dL) (6). These results further demonstrate the substantial benefit associated with increasing HDL-C, provided appropriate selection of patients and therapeutic modalities. We are concerned that the findings by Briel et al may provide erroneous and misleading implications for an important proportion of currently treated patients with the common raised triglycerides-low HDL-C dyslipidaemia, who have a high risk for major cardiac events even when their LDL-C levels are in the normal- or low-range (7). This important subset of patients should receive a more comprehensive lipid modifying therapeutic approach, designed also to raise HDL-C and reduce triglycerides, rather than a narrow approach that is based solely on LDL-c modification as suggested by Briel et al. References 1. Briel M, Ferreira-Gonzalez I, You JJ, Karanicolas PJ, Akl EA, Wu P, Blechacz B, Bassler D, Wei X, Sharman A, Whitt I, Alves da Silva S, Khalid Z, Nordmann AJ, Zhou Q, Walter SD, Vale N, Bhatnagar N, O'Regan C, Mills EJ, Bucher HC, Montori VM, Guyatt GH. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ. 2009;338:b92. doi: 10.1136/bmj.b92. 2. Goldenberg I, Goldbourt U, Boyco V, Behar S, Reicher-Reiss H. Relationship between on-treatment increments in serum HDL levels and cardiac events in patients with coronary heart disease: an extended follow -up of the Bezafibrate Infarction Prevention Trial. Am J Cardiol. 2006;97:466-471. 3. Manninen V, Elo MO, Frick MH, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988;260:641-651. 4. Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, McNamara JR, Kashyap ML, Hershman JM, Wexler LF, Rubins HB; VA-HIT Study Group. Veterans Affairs High-Density Lipoprotein Intervention Trial. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001;285:1585 -1591. 5. Goldenberg I, Boyko V, Tennenbaum A, Tanne D, Behar S, Guetta V. Long-term benefit of high-density lipoprotein cholesterol-raising therapy with bezafibrate: 16-year mortality follow-up of the bezafibrate infarction prevention trial.Arch Intern Med. 2009;169:508-514 6. Goldenberg I, Benderly M, Sidi R, Boyko V, Tenenbaum A, Tanne D, Behar S.Relation of clinical benefit of raising high-density lipoprotein cholesterol to serum levels of low-density lipoprotein cholesterol in patients with coronary heart disease (from the Bezafibrate Infarction Prevention Trial). Am J Cardiol. 2009;103:41-45 7. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-1310. Competing interests: None declared |
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