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T h e n e w e ng l a n d j o u r na l o f m e dic i n e The HALTS Trial — Halting Atherosclerosis
or Halted Too Early?
Roger S. Blumenthal, M.D., and Erin D. Michos, M.D., M.H.S.
In patients with elevated cholesterol levels, statin not that surprising, since previously published therapy reduces the incidence of cardiovascular studies showed that, as compared with placebo, events by 25 to 45%. Despite the administration niacin therapy, alone or in combination with of a statin, many patients require additional lipid- simvastatin or colestipol, was associated with a lowering therapy because their target lipid-level reduction in the rate of cardiovascular events, as goals are not reached or they have a cardiovascular well as stabilization or modest regression of event. Treatment can be intensified through fur- coronary or carotid atherosclerosis.2-4 ther reductions in low-density lipoprotein (LDL) Though the ARBITER 6–HALTS authors prin- cholesterol or attempts to raise high-density lipo- cipally attribute the benefit of niacin to the re- lated increases in the serum HDL cholesterol lev- In this issue of the Journal, Taylor et al.1 report el, full-dose niacin (2 g daily) generally lowers LDL the results of a thought-provoking study of the cholesterol levels, triglyceride levels, and Lp(a) lipo- use of ezetimibe or extended-release niacin in pa- protein levels by about 15%. Because of the plei- tients who were receiving statin therapy and who otropic effects of niacin, the ARBITER 6–HALTS had or were at high risk for atherosclerotic vas- study does not conclusively show that pharma- cular disease, and who had a “therapeutic” se- cologically increasing the serum HDL cholesterol rum LDL cholesterol level (<100 mg per deciliter level is more beneficial than augmenting the de- [2.6 mmol per liter]) and a moderately low serum crease in the LDL cholesterol level. Previous stud- HDL level (mean, 42 mg per deciliter [1.1 mmol ies of therapies that increase serum HDL choles- per liter]). The ARBITER 6–HALTS (Arterial Biol- terol levels have failed to show clinical benefit, and ogy for the Investigation of the Treatment Effects in some cases the therapies have been harmful.5 of Reducing Cholesterol 6–HDL and LDL Treat- The ARBITER 6–HALTS study has several lim- ment Strategies) study (ClinicalTrials.gov number, itations. First, its premature termination (as rec- NCT00397657) was an open-label randomized ommended by an independent data advisory com- trial of two adjunctive medications that modify mittee) was unfortunate and may exaggerate any cholesterol levels conducted over a relatively short potential benefit of niacin therapy; more than treatment period (14 months). A surrogate mark- 40% of the patients did not undergo the mea- er for the progression of atherosclerosis (i.e., the surement at 14 months of the carotid intima– change in the common carotid intima–media media thickness (the primary end point). There thickness) was the primary end point.
was no loss of clinical equipoise in this trial, as Even though 363 patients were enrolled in there are no formal stopping boundaries for trials the study, it was stopped prematurely (thus in- of carotid intima–media thickness (a surrogate cluding data for only 208 patients) after an in- marker). The investigators could have presented terim analysis showed that niacin was superior analyses of the 8-month data for all participants, to ezetimibe in effecting the regression of ca- rather than presenting the 8-month data only for rotid intima–media thickness. These results are those who completed the 14-month study. A Downloaded from www.nejm.org on November 18, 2009 . For personal use only. No other uses without permission. Copyright 2009 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e larger sample size may have either strengthened uating Rosuvastatin [JUPITER] study), despite not the provocative results regarding the major ad- causing regression of carotid intima–media thick- verse cardiovascular events or, alternatively, reduced ness in a large study.6,10,11 any evidence of meaningful clinical differences.
Fourth, the ARBITER 6–HALTS study does not Second, the use of the carotid intima–media inform us as to whether more aggressive attempts thickness as a surrogate marker for coronary ath- to reduce LDL cholesterol levels, with higher doses erosclerosis is controversial. Although in observa- of statin, is as effective as adding a second agent tional studies the carotid intima–media thickness that modifies lipid levels. In the ARBITER has been shown to predict future cardiovascular 6–HALTS patients, the moderate dose of statin events, it is not certain how much the pathobio- was associated with a mean serum LDL choles- logic processes underlying the two measures over- terol level of 82 mg per deciliter (2.1 mmol per lap. For example, a locus on chromosome 9p is liter). In patients with advanced atherosclerosis, a strong genetic risk factor for coronary arterial many clinicians now consider a serum LDL cho- disease but not carotid intima–media thickness.6 lesterol level of less than 70 mg per deciliter (1.8 Furthermore, there are therapies other than nia- mmol per liter) to be the appropriate target. cin that retard the progression of carotid intima– Previously published studies of a small number media thickness (i.e., estrogen and thiazolidin- of high-risk patients who were receiving high- ediones) but do not reduce the incidence of dose statin monotherapy or combination therapy cardiovascular events. Thus, it is unknown wheth- consisting of a statin and ezetimibe showed re- er a reduction in the progression, or a regression, gression of the carotid intima–media thickness of the carotid intima–media thickness after phar- that was similar with either treatment when the macologic treatment is consistently associated target serum LDL cholesterol level was less than with a reduction in the risk of coronary athero- 70 mg per deciliter.12,13 The current study did sclerosis and cardiovascular events. Measures of not address whether this target should be reached carotid plaque volume or area are better predic- by means of further increases in statin mono- tors of vulnerable plaque than carotid intima– therapy (i.e., increasing the current statin dose or media thickness,6,7 and measurements of the switching to a more potent statin) or the addition internal carotid artery (which were not obtained of a second agent.
in this study) more aptly reflect changes in ath- Several large clinical trials of combination ther- erosclerosis progression than measurements in apy with statin and niacin or ezetimibe are cur- rently in progress and should address this issue. Third, the putative negative effects of ezetimibe These trials include AIM-HIGH (Atherothrombosis (i.e., increase in the carotid intima–media thick- Intervention in Metabolic Syndrome with Low HDL/ ness) espoused by the authors are unsubstantiated. High Triglycerides and Impact on Global Health In the 111 patients in the ezetimibe group with Outcomes; NCT00120289), HPS2-THRIVE (Heart data reported in the study, the carotid intima– Protection Study 2: Treatment of HDL to Reduce media thickness at 14 months was not signifi- the Incidence of Vascular Events; NCT00461630), cantly different from the thickness at baseline. and IMPROVE-IT (Improved Reduction of Out- These results are concordant with those in a re- comes: Vytorin Efficacy International Trial; cently published study of 720 subjects showing NCT00202878). that combined therapy with ezetimibe and sim- In patients with an elevated risk of vascular vastatin for 24 months did not result in a signifi- events, there is substantial evidence for the ini- cant difference in changes in carotid intima– tial use of a statin, with adjustment of the dose media thickness, as compared with simvastatin to reach the target serum LDL cholesterol level. alone.9 Conclusions regarding the clinical effect After a potent statin is used at the maximal tol- of ezetimibe cannot be extrapolated from mea- erated dose, a second agent should be chosen on surements of the carotid intima–media thickness. the basis of evidence. If the lipid goal cannot be For instance, rosuvastatin therapy has been as- reached with a potent statin alone, the choices of sociated with a reduction in the incidence of car- adjunctive therapy remain a fibrate, niacin, a bile- diovascular events (in the Justification for the Use acid sequestrant, n−3 fatty acid supplements, or of Statins in Prevention: an Intervention Trial Eval- ezetimibe.
Downloaded from www.nejm.org on November 18, 2009 . For personal use only. No other uses without permission. Copyright 2009 Massachusetts Medical Society. All rights reserved. Unfortunately, the premature termination of cin or ezetimibe and carotid intima–media thickness. N Engl J the ARBITER 6–HALTS trial, the small number Med 2009;361. DOI: 10.1056/NEJMoa0907569.
2. Brown BG, Zhao X-Q, Chait A, et al. Simvastatin and niacin,
of patients studied, and the limited duration of antioxidant vitamins, or the combination for the prevention of follow-up preclude us from conclusively declaring coronary disease. N Engl J Med 2001;345:1583-92.
niacin the adjunctive agent of choice on the basis 3. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary
artery disease as a result of intensive lipid-lowering therapy in of the evidence. A decrease of 0.014 mm in the men with high levels of apolipoprotein B. N Engl J Med carotid intima–media thickness over 14 months 1990;323:1289-98.
does not necessarily merit changes in our lipid- 4. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arte-
rial Biology for the Investigation of the Treatment Effects of lowering guidelines at this time. However, in Reducing cholesterol (ARBITER) 2. Circulation 2004;110:3512-7. conjunction with another, smaller, recently pub- [Errata, Circulation 2004;110:3615, 2005;111(24):e446.] lished study involving magnetic resonance im- 5. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetra-
pib in patients at high risk for coronary events. N Engl J Med aging of the carotid artery,14 for now, we would 2007;357:2109-22.
support the use of niacin as the preferred ad- 6. Sharma K, Blaha MJ, Blumenthal RS, Musunuru K. Clinical
junctive agent to be used in combination with and research applications of carotid intima-media thickness. the maximal dose of a potent statin in persons 7. Finn AV, Kolodgie FD, Virmani R. Correlation between ca-
who have low levels of HDL cholesterol and es- rotid intimal/medial thickness and atherosclerosis: a point of tablished cardiovascular disease. However, we view from pathology. Arterioscler Thromb Vasc Biol 2009 Au- await the completion of the definitive clinical tri- 8. Mackinnon AD, Jerrard-Dunne P, Sitzer M, Buehler A, von
Kegler S, Markus HS. Rates and determinants of site-specific In summary, the ARBITER 6–HALTS results progression of carotid artery intima-media thickness: the ca- rotid atherosclerosis progression study. Stroke 2004;35:2150-4.
are provocative and are an important contribu- 9. Kastelein JJ, Akdim F, Stroes ESG, et al. Simvastatin with or
tion to preventive cardiology research. However, without ezetimibe in familial hypercholesterolemia. N Engl J the secondary choices for optimizing cholesterol- Med 2008;358:1431-43. [Erratum, N Engl J Med 2008;358:1977.] 10. Crouse JR III, Raichlen JS, Riley WA, et al. Effect of rosuva-
lowering therapy, constituting part of the “C” statin on progression of carotid intima-media thickness in low- component of the “ABCDEs” of secondary pre- risk individuals with subclinical atherosclerosis: the METEOR vention of cardiovascular disease, should not Trial. JAMA 2007;297:1344-53.
11. Ridker PM, Danielson E, Fonesca FAH, et al. Rosuvastatin to
overshadow the importance of the rest of the prevent vascular events in men and women with elevated C-reac- ABCDEs: assessment of risk, antiplatelet therapy, tive protein. N Engl J Med 2008;359:2195-207.
blood-pressure management, cholesterol modifi- 12. Fleg JL, Mete M, Howard BV, et al. Effect of statins alone
versus statins plus ezetimibe on carotid atherosclerosis in type cation and cigarette-smoking cessation, dietary 2 diabetes. The SANDS (Stop Atherosclerosis in Native Diabetics and weight modification, and exercise habits.15 Study) trial. J Am Coll Cardiol 2008;52:2198-205.
13. Meaney A, Ceballos G, Asbun J, et al. The VYtorin on Ca-
No potential conflict of interest relevant to this article was re- rotid intima-media thickness and overall rigidity (VYCTOR) study. J Clin Pharmacol 2009;49:838-47.
14. Lee M, Robson MD, Yu LM, et al. Effects of high-dose mod-
From the Johns Hopkins Ciccarone Center for the Prevention of ified-release nicotinic acid on atherosclerosis and vascular func- tion: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol 2009;54:1787-94.
This article (10.1056/NEJMe0908838) was published on No- 15. Blaha MJ, Bansal S, Rouf R, Golden SH, Blumenthal RS,
Defilippis AP. A practical “ABCDE” approach to the metabolic syndrome. Mayo Clin Proc 2008;83:932-41.
1. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release nia-
Copyright 2009 Massachusetts Medical Society. Downloaded from www.nejm.org on November 18, 2009 . For personal use only. No other uses without permission. Copyright 2009 Massachusetts Medical Society. All rights reserved.

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Correspondence Infant mortality (per thousand livebirths) group on HIV in women and children. Mortality among infected and uninfectedAfrica: a pooled analysis. Lancet 2004; 364: Abrams EJ, Wiener J, Carter R, et al. Maternalhealth factors and early pediatric antiretroviraltherapy influence the rate of perinatal HIV-Idisease progression in children. AIDS , 2003; Table: Infant m

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