Natural Statins and Stroke Risk
1999; Lippincott Williams & Wilkins; Volume: 99; Issue: 2 Linguagem: Inglês
10.1161/01.cir.99.2.185
ISSN1524-4539
Autores Tópico(s)Antiplatelet Therapy and Cardiovascular Diseases
ResumoHomeCirculationVol. 99, No. 2Natural Statins and Stroke Risk Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBNatural Statins and Stroke Risk Curt D. Furberg Curt D. FurbergCurt D. Furberg From the Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC. Originally published19 Jan 1999https://doi.org/10.1161/01.CIR.99.2.185Circulation. 1999;99:185–188The Burden of StrokeIn the United States, ≈600 000 persons experience a clinical stroke (first or recurrent) annually.1 Although the case-fatality rate has declined over the past decades, it is still high. The annual death toll is ≈150 000, which qualifies stroke as the third leading cause of death, behind coronary heart disease (CHD) and cancer. The clinical sequelae of a stroke are often devastating. Among the more than 3 million stroke survivors, approximately one half have hemiparesis, one third are clinically depressed, one quarter cannot walk, and one sixth are aphasic.2 Stroke is the leading cause of serious disability in the United States.1 Thus, evidence of promising preventive therapies that can reduce the human and societal costs of stroke is welcome news.The burden of stroke goes well beyond those cases that are clinically recognized. New imaging techniques of the brain have revealed a remarkably high prevalence of so-called infarct-like lesions (ILLs), or silent strokes. The NHLBI-sponsored Cardiovascular Health Study obtained cerebral MRIs on 3658 men and women ≥65 years old. ILLs ≥3 mm were found in 31% of all subjects.3 Fewer than 15% of those with such lesions had a clinical history of stroke. The prevalence of ILLs increased with age; 22% of subjects 65 to 69 years old had ILLs, compared with 43% in subjects ≥80 years old. Subjects with ILLs were more likely to be hypertensive or to have a history of stroke, atrial fibrillation, or dilated cardiomyopathy. Importantly, the presence of these lesions was associated with a decline in cognitive function and impaired motor coordination. It is intriguing to speculate that the memory loss associated with aging may be due in part to unrecognized multiple ILLs, a condition that when advanced is called multi-infarct dementia. Whether brain lesions can be prevented and cognitive function preserved is the focus of an ongoing placebo-controlled, randomized clinical trial of pravastatin, the Prospective Study of Pravastatin in the Elderly Risk (PROSPER).Risk Factors of Incident StrokeThe predictors of clinically recognized incident stroke are numerous and vary with age.4 The risk factors among older adults, who suffer the highest rates of strokes, were recently examined in the Cardiovascular Health Study cohort.4 In both men and women ≥65 years old, age was a strong independent risk factor for incident stroke. In subjects ≥80 years old, the annual risk was >2.0%. History of hypertension, use of antihypertensive drugs, and systolic (but not diastolic) blood pressure were, as expected, associated with the risk of stroke. History of diabetes and impaired glucose tolerance were also independent risk factors. Hypertension and diabetes are also strong predictors of acute myocardial infarction in older adults. Several measures of subclinical disease—abnormal left ventricular wall motion and increased left ventricular mass on echocardiography, ultrasound-defined carotid stenosis, and atrial fibrillation—also predicted stroke risk. In middle-aged populations, smoking, decreased physical activity, increased alcohol intake, high fibrinogen levels, and previous heart disease have also been shown to predict incident strokes.The absence of a consistent and strong association between serum cholesterol and stroke risk is puzzling.5 However, stroke is not a single disease. A positive relationship of serum cholesterol with atherothrombotic stroke has been reported.6 Conversely, there may be a negative association between serum cholesterol and hemorrhagic stroke, fatal hemorrhagic stroke in particular.6Stroke PreventionPharmacological treatment of hypertension clearly reduces the risk of stroke.7 Although scientific documentation is lacking, it seems prudent to recommend a healthy diet, smoking cessation, and regular exercise as a general approach to cardiovascular health, including stroke prevention. Despite widespread use of hypoglycemic agents in type 2 diabetic patients, we still do not know whether these agents reduce the macrovascular complications of diabetes. In patients with atrial fibrillation, warfarin especially, but also aspirin, reduces the risk of embolic stroke.8 However, the role of aspirin in the primary prevention of ischemic stroke is controversial.4 Epidemiological studies suggest that prevention of CHD and its progression might be associated with a lower risk of incident stroke.9In this issue of Circulation, Plehn and coworkers10 report on the favorable effect of pravastatin on stroke incidence, a predefined secondary outcome in the CARE study. In a large group of patients with a recent history of myocardial infarction and moderately elevated LDL cholesterol, pravastatin in a fixed dose of 40 mg/d reduced the relative risk of stroke significantly, by 32%, over a median follow-up period of 5 years. In absolute terms, the stroke risk was reduced from 7.3/1000 person-years to 5.0/1000 person-years. This translates into a number-needed-to-treat for 1 year to prevent 1 stroke of 435. The stroke findings were supported by a similar and parallel reduction in the incidence of transient ischemic attacks. Although the statistical power was limited for subgroup analyses, the reductions in stroke were similar in subgroups defined by sex and history of hypertension, diabetes, or previous stroke. In an exploratory analysis, a trend toward greater benefit was noted for those with the highest baseline LDL cholesterol.The CARE findings are similar to those reported from the Scandinavian Simvastatin Survival Study (4S).11 In this trial of coronary patients with elevated levels of serum cholesterol, simvastatin 20 to 40 mg/d reduced the combined incidence of stroke by 29%. The incidence of stroke in the placebo group was 7.7/1000 person-years, similar to that in CARE. The observations from these 2 large secondary prevention trials are supported by data from a pooled analysis of 4 regression studies of pravastatin12 and a small trial of lovastatin.13Clinical trials always raise questions about the interpretation and extrapolation of the findings, and CARE is no exception.What Are the Postulated Mechanisms Behind Stroke Reduction With Statins?The reduction in stroke observed in CARE and 4S might be a direct result of retardation of atherosclerosis progression, plaque stabilization, or improved endothelial function. Another intriguing explanation is about to be reported (Marco Pahor, MD, July 25, 1998, written personal communication). In a placebo-controlled crossover trial designed to assess treatment effect on blood pressure in patients with hypertension, pravastatin significantly reduced both systolic and diastolic blood pressure and blunted the hypertensive response to a cold pressor test. Pravastatin may cause vasodilation and a fall in blood pressure by modulating the sympathetic and endothelial regulation of vasomotor tone.Statins may reduce stroke risk indirectly. Because coronary events and revascularizations are both related to increased stroke risk, one would predict that reductions in such events/procedures might lead to a decreased incidence of stroke.Do the Findings From CARE and 4S Extend to Non-CHD Patients?In our recent review,19 we reported a highly statistically significant reduction in stroke risk of 30% in pooled analysis of published secondary prevention trials of statin use in CHD patients. These trials evaluated pravastatin, simvastatin, or lovastatin. The experience from primary prevention and mixed trials was more limited, and the pooled estimates of overall stroke reduction did not reach statistical significance. The point estimates were 11% (95% CI, −31% to 40%) for the primary prevention trials and 30% (−132% to 79%) for the mixed trials. Thus, available clinical trial data do not support a recommendation for the general use of statins for prevention of incident stroke in subjects with no manifest CHD.Do All Lipid-Lowering Agents Reduce Stroke Risk?Meta-analyses of published trials have not shown a consistent lowering of the risk of stroke.914 Most trials reported a small number of events. Two of the agents examined, clofibrate and high doses of estrogen, may even be associated with an excess risk of stroke. Reductions in serum cholesterol level with the nonstatins were modest or 50% to 33% of the reductions obtained with statins. The reasons for the difference between early lipid-lowering trials and the recent trials of statins are unclear and may include offsetting secondary drug actions (clofibrate, estrogen), inadequate reductions in serum cholesterol, insufficient statistical power, and/or favorable nonlipid actions of the evaluated statins. It should be noted that niacin treatment in the Coronary Drug Project was associated with a significant reduction in stroke risk.In summary, scientific evidence supporting the use of lipid-lowering agents other than statins in the prevention of stroke is limited.How Much of the Benefit of Statins Is Mediated Through Cholesterol Reduction?In our recent meta-analysis,15 we reported that adding the results from the statin trials strengthened the relationship (slope) between lowering of cholesterol and reduction in CHD/total mortality, with the standard error of the estimated slopes decreasing by ≈50%. Despite this stronger association, it would be improper to infer that the entire or even the majority of the overall or net clinical benefit of lipid-lowering agents is mediated through cholesterol reduction, because the variability around the slope is still substantial. The proportion of variability of the observed mortality benefit that statistically can be attributed to reductions in total (and LDL) cholesterol is influenced by multiple factors, including other drug-related mechanisms of action. We know that certain cholesterol-lowering drugs (fibrates and hormones) increase non-CHD mortality, offsetting the decrease in CHD mortality attributed to a reduction in serum cholesterol.15 The variability is likely to decrease further if individual data on initial cholesterol level, concomitant medications, and medical history and trial data on treatment duration are considered. However, a proportion of the variance will remain, and nonlipid effects are probably among the sources of unexplained variation, even for the statins. A recent report from the CARE trial raised questions about the role of an anti-inflammatory effect of pravastatin.16Are All Statins Created Equal?Two subtypes of statins are currently on the US market: the fermentation-derived, or natural, statins (lovastatin, pravastatin, and simvastatin) and the synthetic statins (atorvastatin, cerivastatin, and fluvastatin). The chemical structures of the 3 natural statins are very similar. However, the structures of the 3 synthetic statins are dissimilar, and all 3 are very different from the natural ones (Figure).Pharmacokinetically, the statins differ, but these differences do not always follow the subtypes. All statins are metabolized by the liver. Lovastatin, simvastatin, atorvastatin, and cerivastatin have a common metabolic pathway through cytochrome P-450 3A4. The metabolic enzyme for fluvastatin is cytochrome P-450 2C9. Pravastatin has multiple metabolic pathways. These differences could have clinical relevance because the metabolic pathways define the potential interactions with other drugs that are metabolized through the same pathways, as illustrated by the mibefradil experience.17 However, clinical practice suggests that these drugs are not often involved with drug interactions. The plasma half-life is 2 to 3 hours for all statins except atorvastatin, which has a half-life of 14 to 20 hours. Pravastatin is the most hydrophilic and simvastatin the most lipophilic, although the clinical relevance of the differences in solubility among the statins is unknown.The statins also vary in their potency, the clinical relevance of which is debated. With proper dose titration, reductions of 33% to 55% in LDL cholesterol are often achieved with the natural statins and atorvastatin. Fluvastatin and cerivastatin are less effective. The optimal goal of LDL cholesterol reduction has not been scientifically established. Whether additional health benefits result from lowering LDL cholesterol to 50%, as well as changes in the molecular structure of fibrinogen. The relevance of these observations, if confirmed, needs to be examined.What Are the Clinical Implications?The practice of medicine should be based primarily on meaningful clinical evidence from properly designed randomized, controlled clinical trials. Substantial documentation of clinical benefit—reductions in stroke and coronary events—and long-term safety is available only for the natural statins. The strongest evidence relates to patients with CHD. Highly statistically significant reductions have been reported for stroke, cardiovascular mortality, nonfatal myocardial infarction, all-cause mortality, and need for cardiovascular procedures. The only event data on synthetic statins originate from a small angiographic study of fluvastatin.It is unknown whether and to what extent differences in pharmacokinetics, half-life, solubility, potency, lipid and nonlipid mechanisms, and effects on other risk factors influence the clinical benefits. These critical and urgent questions can only be answered by large, long-term clinical trials comparing different statins. It is not appropriate to assume that the untested drugs will be as effective as the proven drugs.The potential fallacy of relying on surrogates, such as reductions in LDL cholesterol, in clinical decision-making and regulatory approval is well documented from multiple fields of medicine.22 Prescribing an unproven drug in place of a proven drug may expose patients to the unnecessary risk of not benefitting from the documented treatment. The natural statins should be used as first-line drugs in the prevention of stroke and coronary events. Until they are proved to be superior or equivalent, synthetic statins and other cholesterol-lowering agents should be reserved for patients who do not respond to natural statins.23The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Download figureDownload PowerPoint Figure 1. Chemical structures of fermentation-derived, or natural, statins and synthetic statins.FootnotesCorrespondence to Dr Curt D. Furberg, Professor and Chairman, Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1063. E-mail [email protected] References 1 1995Heart and Stroke Facts. Dallas, Tex: American Heart Association;1996.Google Scholar2 Post-Stroke Rehabilitation Guideline Panel. Post-Stroke Rehabilitation: Clinical Practice Guidelines No. 16. Rockville, Md: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research; 1995. AHCPR publication 95–0662.Google Scholar3 Bryan RN, Wells SW, Miller TJ, Elster AD, Jungreis CA, Poirier VC, Lind BK, Manolio TA. Infarctlike lesions in the brain: prevalence and anatomic characteristics at MR imaging of the elderly: data from the Cardiovascular Health Study. Radiology.1997; 202:47–54.CrossrefMedlineGoogle Scholar4 Manolio TA, Kronmal RA, Burke GL, O'Leary DH, Price TR, for the CHS Collaborative Research Group. Short-term predictors of incident stroke in older adults: the Cardiovascular Health Study. Stroke.1996; 27:1479–1486.CrossrefMedlineGoogle Scholar5 Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet.1995; 346:1647–1653.CrossrefMedlineGoogle Scholar6 Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and 6-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med.1989; 320:904–910.CrossrefMedlineGoogle Scholar7 Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, Lemaitre RN, Wagner EH, Furberg CD. Health outcomes associated with antihypertensive therapies used as first-line agents. JAMA.1997; 277:739–745.CrossrefMedlineGoogle Scholar8 Stroke Prevention in Atrial Fibrillation Study Group Investigators. Preliminary report of the Stroke Prevention in Atrial Fibrillation Study. N Engl J Med.1990; 322:863–868.CrossrefMedlineGoogle Scholar9 Crouse JR III, Byington RP, Furberg CD. HMG-CoA reductase inhibitor therapy and stroke risk reduction: an analysis of clinical trials data. Atherosclerosis.1998; 138:11–24.CrossrefMedlineGoogle Scholar10 Plehn JF, Davis BR, Sacks FM, Rouleau JL, Pfeffer MA, Bernstein V, Cuddy TE, Moyé LA, Piller LB, Rutherford J, Simpson LM, Braunwald E, for the CARE Investigators. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) Study. Circulation. 1999;99:216–223.Google Scholar11 Pedersen TR, Kjekshus J, Pyörälä K, Olsson AG, Cook TJ, Musliner TA, Tobert JA, Haghfelt T. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol.1998; 81:333–335.CrossrefMedlineGoogle Scholar12 Byington RP, Jukema JW, Salonen JT, Pitt B, Bruschke AV, Hoen H, Furberg CD, Mancini J. Reduction in cardiovascular events during pravastatin therapy: pooled analysis of clinical events of the Pravastatin Atherosclerosis Intervention Program. Circulation.1995; 92:2419–2425.CrossrefMedlineGoogle Scholar13 Furberg CD, Adams HP, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA, Young B, for the Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation.1994; 90:1679–1687.CrossrefMedlineGoogle Scholar14 Hebert PR, Gaziano JM, Hennekens CH. An overview of trials of cholesterol lowering and risk of stroke. Arch Intern Med.1995; 155:50–55.CrossrefMedlineGoogle Scholar15 Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction yields clinical benefit: impact of statin trials. Circulation.1998; 97:946–952.CrossrefMedlineGoogle Scholar16 Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E, for the Cholesterol, and Recurrent Events (CARE) Investigators. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation.1998; 98:839–844.CrossrefMedlineGoogle Scholar17 Roche Laboratories announces withdrawal of Posicor from the market. US Food and Drug Administration. US Department of Health and Human Services, Public Health Service, Rockville, Md. June 8, 1998.Google Scholar18 Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn JL, Weiss SR, Keilson LM, Brown WV, Miller VT, Shurzinske LJ, Black DM. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA.1996; 275:128–133.CrossrefMedlineGoogle Scholar19 Stein EA, Lane M, Laskarzewski P. Comparison of statins in hypertriglyceridemia. Am J Cardiol.1998; 81:66A–69A.CrossrefMedlineGoogle Scholar20 Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES Study). Am J Cardiol.1998; 81:582–587.CrossrefMedlineGoogle Scholar21 Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA.1998; 279:1643–1650.CrossrefMedlineGoogle Scholar22 Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med.1996; 125:605–613.CrossrefMedlineGoogle Scholar23 Atorvastatin. The Medical Letter. March 27, 1997.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Peymani P, Dehesh T, Aligolighasemabadi F, Sadeghdoust M, Kotfis K, Ahmadi M, Mehrbod P, Iranpour P, Dastghaib S, Nasimian A, Ravandi A, Kidane B, Ahmed N, Sharma P, Shojaei S, Bagheri Lankarani K, Madej A, Rezaei N, Madrakian T, Los M, Labouta H, Mokarram P and Ghavami S (2021) Statins in patients with COVID-19: a retrospective cohort study in Iranian COVID-19 patients, Translational Medicine Communications, 10.1186/s41231-021-00082-5, 6:1, Online publication date: 1-Dec-2021. Huang K and Aggarwal R (2020) Dietary Considerations in Myositis Managing Myositis, 10.1007/978-3-030-15820-0_34, (335-344), . Li K, Tse G, Liu T and Yan G (2020) Anti-arrhythmic Effects of Non-anti-arrhythmic Drugs or Therapies Management of Cardiac Arrhythmias, 10.1007/978-3-030-41967-7_26, (597-619), . Larbi A, Combet Aspray E, Pawelec G, Khalil A and Fulop T (2019) Effect of Intrinsic and Extrinsic Lipids on T Cell Signaling Handbook of Immunosenescence, 10.1007/978-3-319-99375-1_69, (2661-2677), . Liao K, Wang S, Lu C, Chen C and Huang Y (2019) The influence of statins on aortic aneurysm after operation, Medicine, 10.1097/MD.0000000000015368, 98:17, (e15368), Online publication date: 1-Apr-2019. Larbi A, Combet Aspray E, Pawelec G, Khalil A and Fulop T (2018) Effect of Intrinsic and Extrinsic Lipids on T-Cell Signaling Handbook of Immunosenescence, 10.1007/978-3-319-64597-1_69-1, (1-18), . Galiullina L, Aganova O, Latfullin I, Musabirova G, Aganov A and Klochkov V (2017) Interaction of different statins with model membranes by NMR data, Biochimica et Biophysica Acta (BBA) - Biomembranes, 10.1016/j.bbamem.2016.12.006, 1859:3, (295-300), Online publication date: 1-Mar-2017. Amamou T, Normandin E, Pouliot J, Dionne I, Brochu M and Riesco E (2016) Effect of a high-protein energy-restricted diet combined with resistance training on metabolic profile in older individuals with metabolic impairments, The journal of nutrition, health & aging, 10.1007/s12603-016-0760-8, 21:1, (67-74), Online publication date: 1-Jan-2017. Ye X and Devasthale P (2016) Carboxylic Acids and Lactones as HMG-CoA Reductase Inhibitors Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals, 10.1002/9783527693931.ch6, (71-85) Musset L, Allenbach Y, Benveniste O, Boyer O, Bossuyt X, Bentow C, Phillips J, Mammen A, Van Damme P, Westhovens R, Ghirardello A, Doria A, Choi M, Fritzler M, Schmeling H, Muro Y, García-De La Torre I, Ortiz-Villalvazo M, Bizzaro N, Infantino M, Imbastaro T, Peng Q, Wang G, Vencovský J, Klein M, Krystufkova O, Franceschini F, Fredi M, Hue S, Belmondo T, Danko K and Mahler M (2016) Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study, Autoimmunity Reviews, 10.1016/j.autrev.2016.07.023, 15:10, (983-993), Online publication date: 1-Oct-2016. Mercer D, Lavoie K, Ditto B, Pelletier R, Campbell T, Arsenault A and Bacon S (2014) The interaction between anxiety and depressive symptoms on brachial artery reactivity in cardiac patients, Biological Psychology, 10.1016/j.biopsycho.2014.07.012, 102, (44-50), Online publication date: 1-Oct-2014. Motawi T, Atta H, Sadik N and Azzam M (2013) The Therapeutic Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Simvastatin in a Rat Model of Liver Fibrosis, Cell Biochemistry and Biophysics, 10.1007/s12013-013-9698-1, 68:1, (111-125), Online publication date: 1-Jan-2014. Zong H, Zhuge B, Fang H, Cao Y, Mu L, Fu W, Song J and Zhuge J (2012) Advances in the bioconversion mechanism of lovastatin to wuxistatin by Amycolatopsis sp. CGMCC 1149, Applied Microbiology and Biotechnology, 10.1007/s00253-012-4341-4, 97:2, (599-609), Online publication date: 1-Jan-2013. Reitz C (2013) Dyslipidemia and the Risk of Alzheimer's Disease, Current Atherosclerosis Reports, 10.1007/s11883-012-0307-3, 15:3, Online publication date: 1-Mar-2013. Masadeh M, Mhaidat N, Alzoubi K, Al-azzam S and Alnasser Z (2012) Antibacterial activity of statins: a comparative study of Atorvastatin, Simvastatin, and Rosuvastatin, Annals of Clinical Microbiology and Antimicrobials, 10.1186/1476-0711-11-13, 11:1, (13), . Seydametova E, Salihon J, Zainol N and Convey P (2012) Production of Lovastatin by Penicillium spp. Soil Microfungi, International Journal of Chemical Engineering and Applications, 10.7763/IJCEA.2012.V3.213, (337-339), . Aly A, Debbab A and Proksch P (2011) Fifty years of drug discovery from fungi, Fungal Diversity, 10.1007/s13225-011-0116-y, 50:1, (3-19), Online publication date: 1-Sep-2011. Wang Q, Yan J, Chen X, Li J, Yang Y, Weng J, Deng C and Yenari M (2011) Statins: Multiple neuroprotective mechanisms in neurodegenerative diseases, Experimental Neurology, 10.1016/j.expneurol.2010.04.006, 230:1, (27-34), Online publication date: 1-Jul-2011. Yang D, Knight R, Han Y, Karki K, Zhang J, Ding C, Chopp M and Seyfried D Vascular recovery promoted by atorvastatin and simvastatin after experimental intracerebral hemorrhage: magnetic resonance imaging and histological study, Journal of Neurosurgery, 10.3171/2010.7.JNS10163, 114:4, (1135-1142) Du X and Soon J (2011) Mild to moderate aortic stenosis and coronary bypass surgery, Journal of Cardiology, 10.1016/j.jjcc.2010.07.009, 57:1, (31-35), Online publication date: 1-Jan-2011. Sathyapalan T, Atkin S and Kilpatrick E (2010) Disparate Effects of Atorvastatin Compared With Simvastatin on C-Reactive Protein Concentrations in Patients With Type 2 Diabetes, Diabetes Care, 10.2337/dc10-0201, 33:9, (1948-1950), Online publication date: 1-Sep-2010. Panagiotoglou T, Ganotakis E, Kymionis G, Moschandreas J, Fanti G, Charisis S, Malliaraki N and Tsilimbaris M (2010) Atorvastatin for Diabetic Macular Edema in Patients with Diabetes Mellitus and Elevated Serum Cholesterol, Ophthalmic Surgery, Lasers and Imaging Retina, 10.3928/15428877-20100430-04, 41:3, (316-322), Online publication date: 1-Jan-2010. Haan M (2010) Can Statins Prevent Dementia in Older Adults?, Journal of the American Geriatrics Society, 10.1111/j.1532-5415.2010.02907.x, 58:7, (1393-1394), Online publication date: 1-Jul-2010. Barrios-González J and Miranda R (2009) Biotechnological production and applications of statins, Applied Microbiology and Biotechnology, 10.1007/s00253-009-2239-6, 85:4, (869-883), Online publication date: 1-Jan-2010. Ahmad H and Cheng-Lai A (2010) Pitavastatin, Cardiology in Review, 10.1097/CRD.0b013e3181ebdb2f, 18:5, (264-267), Online publication date: 1-Sep-2010. Hasler P and Flammer J (2010) Predictive, preventive and personalised medicine for age-related macular degeneration, EPMA Journal, 10.1007/s13167-010-0017-2, 1:2, (245-251), Online publication date: 1-Jun-2010. Pericleous C and Ioannou Y (2010) New therapeutic targets for the antiphospholipid syndrome, Expert Opinion on Therapeutic Targets, 10.1517/14728222.2010.524207, 14:12, (1291-1299), Online publication date: 1-Dec-2010. Sathyapalan T, Atkin S and Kilpatrick E (2010) Low density lipoprotein-cholesterol variability in patients with type 2 diabetes taking atorvastatin compared to simvastatin: justification for direct measurement?, Diabetes, Obesity and Metabolism, 10.1111/j.1463-1326.2009.01190.x, 12:6, (540-544), Online publication date: 1-Jun-2010. Bakhireva L, Shainline M, Car
Referência(s)