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• W2137079256 abstract "HomeCirculationVol. 103, No. 3Statins for Stroke: The Second Story? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBStatins for Stroke: The Second Story? Jorge Plutzky and Paul M. Ridker Jorge PlutzkyJorge Plutzky From the Division of Cardiovascular Diseases (J.P., P.M.R.), the Vascular Disease Prevention Program (J.P.), and the Center for Cardiovascular Disease Prevention (P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. Search for more papers by this author and Paul M. RidkerPaul M. Ridker From the Division of Cardiovascular Diseases (J.P., P.M.R.), the Vascular Disease Prevention Program (J.P.), and the Center for Cardiovascular Disease Prevention (P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. Search for more papers by this author Originally published23 Jan 2001https://doi.org/10.1161/01.CIR.103.3.348Circulation. 2001;103:348–350In the 100 years since Ignatovski demonstrated that high-fat diets promote atherosclerosis in rabbits,1 cardiologists have witnessed an extraordinary evolution in our understanding of atherothrombosis and lipid reduction, culminating in the publication of 5 landmark trials of HMG-CoA reductase inhibition within the past 6 years.23456 In each of these trials, statin therapy was shown to significantly reduce the risks of coronary heart disease in populations with progressively lower degrees of overall risk. These data have had profound effects on preventive medicine and established the first clear success story for this class of therapy.Despite these triumphs, questions remain in our understanding of statins, how they work, and in what settings. As a result, clinical paradigms regarding cholesterol reduction continue to shift. In this sense, the large meta-analysis from the Prospective Pravastatin Pooling Project, which was published in this issue of Circulation, addresses a question that may represent a second success story for the statins.7 Does statin therapy lower the risk of stroke and, if so, why, given the controversy over the role of LDL cholesterol as a risk factor for stroke?These are some of the issues that Byington and colleagues7 address in their analysis of cerebrovascular events in the Prospective Pravastatin Pooling Project, a carefully performed systematic overview including 19 768 patients enrolled in the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial, the Cholesterol and Recurrent Events (CARE) study, and West of Scotland Coronary Prevention Study (WOSCOPS), each of which randomly allocated study participants between 40 mg of pravastatin or placebo. As outlined in their article, a reduction in stroke events was observed in all 3 of these major trials, which, when pooled, demonstrate a statistically significant 22% reduction in total stroke and a 25% reduction in nonfatal stroke attributable to pravastatin. The prevented events were almost entirely atherothrombotic in origin; pravastatin had no effect on the rates of hemorrhagic stroke.On initial review, these data are not surprising: prior publications from the CARE8 and LIPID9 investigators have already shown stroke reductions in those trials, and a benefit on stroke was also observed in the Scandinavian Simvastatin Survival Study (4S), which was performed among postinfarction patients with hyperlipidemia.510 However, the pooled data for pravastatin command attention for several reasons. Foremost is the size of the study group, which accrued 102 559 person-years of follow-up and almost 600 incident stroke events. Thus, these data provide definitive evidence that pravastatin reduces stroke risk and convincingly suggest that these effects are consistent across all major subgroups analyzed, including those on prophylactic aspirin. Evidence on this issue is important because as recently as 1995, a meta-analysis of nonstatin forms of lipid-lowering therapy showed no statistically significant impact on stroke.11Why do statins seem to decrease cerebrovascular risk when other forms of cholesterol-lowering have not? Although the answer to this question is uncertain, several pathophysiological issues may provide insight into this apparent paradox. First, stroke has many causes, and benefit might be seen only after segregating ischemic from hemorrhagic events. In this regard, the Prospective Pravastatin Pooling Project showed no effect on hemorrhagic stroke; these data are reassuring given the results from the Multiple Risk Factor Intervention Trial, which suggested an increase in hemorrhagic cerebrovascular events at LDL cholesterol levels <70 mg/dL.12 LDL cholesterol lowering to this extent was unlikely in the Prospective Pravastatin Pooling Project given the fixed dose of drug used and the above-average baseline cholesterol levels among most study participants. This issue will be of interest as statin trials comparing “moderate LDL lowering” with “aggressive LDL lowering” are completed in coming years.Second, because LDL cholesterol is not a strong risk factor for stroke, it is possible that nonlipid mechanisms associated with statin use may be more important for cerebrovascular disease than previously appreciated. In this regard, statins have been shown to have several antithrombotic and anti-inflammatory effects. For example, statins reduce inflammatory markers such as C-reactive protein in an LDL-independent fashion,13 and they may be more effective in terms of event reduction in the presence of elevated C-reactive protein levels.14 This issue is of clinical interest because epidemiological studies have demonstrated that C-reactive protein is a potent risk factor for thromboembolic stroke,1516 although total and LDL cholesterol are not. Such data support the view that plaque stabilization may be an important process by which statins reduce vascular event rates. This may be of particular significance in the cerebral vessels, where increasing evidence suggests plaque rupture is a pathogenic mechanism.1718Although observations regarding statins and stroke are intriguing, these effects may not be unique. In the secondary prevention Veterans Affairs HDL Intervention Trial (VA-HIT), gemfibrozil led to a 59% decrease in transient ischemic attacks, a 65% decrease in carotid endarterectomy (both P<0.001), and a 25% reduction in strokes (P=0.10) among patients with baseline low LDL (104 mg/dL) and low HDL (32 mg/dL) levels.19 As with statins, a specific vascular drug effect could also be invoked to explain these data, given the fact that gemfibrozil is a possible ligand for the PPARα nuclear receptor, which transcriptionally regulates important vascular and lipid targets.2021 The broader importance of the VA-HIT data may be that, for both coronary heart disease and for stroke, event rates were reduced with a form of lipid-lowering therapy that had very little effect on LDL cholesterol levels.For the clinician, information regarding statin effects on stroke have several implications. Among patients with a prior history of myocardial infarction, such as those enrolled in the CARE, LIPID, and 4S trials, statins significantly reduce future stroke event rates and, thus, provide yet another reason to place patients on these agents. Stroke stands as a devastating event in the lives of patients and their families, often irrevocably changing independence, productivity, and quality of life. Patients understand this, with clinical experience suggesting perhaps a greater fear of stroke than heart attack. As such, clinicians may be able to use results like those from the Prospective Pravastatin Pooling Project to foster greater patient acceptance and adherence to prescribed statin therapy.That being said, it is important to put the absolute risk reduction for stroke seen in the Prospective Pravastatin Pooling Project into perspective and to compare this to reductions in risk that can be expected for coronary heart disease. As Byington and colleagues7 note, the number of patients who need to be treated (NNT) for 1 year to prevent 1 stroke event is relatively large. Specifically, among patients with a prior history of myocardial infarction who were enrolled in the CARE and LIPID trials, the NNT for 1 year to prevent 1 stroke was 588, whereas the NNT among primary prevention participants enrolled in WOSCOPS was 3333. As shown in the Figure, stroke event rates in each of these trials and the expected risk reductions in stroke attributable to pravastatin are smaller than those observed for coronary heart disease. Thus, from an absolute risk reduction perspective, the principal use of these agents will largely remain in the prevention of coronary heart disease. At the same time, evidence of a stroke benefit with statins underscores the need to broaden our approach to prevention and consider all vascular beds, not just the coronary arteries, as targets for the treatment of atherosclerosis. Through this widened lens, improved patient outcomes may come not only from the cerebrovascular and peripheral arterial systems, but also from the treatment of concomitant occult atherosclerosis lurking in the arteries.Despite the statin database, clinical questions persist. What is the ideal LDL level after a myocardial infarction? What is the clinical relevance of the non-LDL effects of statins on atherosclerosis? How do we integrate HDL and triglyceride treatment into patient management? If the foundation for the progress in cholesterol was laid in basic science stretching from Ignatovski to Brown and Goldstein122 and beyond, the first floor was no doubt built from the unequivocal results from the statin trials. With emerging data like that regarding stroke, clearly the “second story” is going up.Drs Plutzky and Ridker have previously received investigator-initiated grant support from Merck, Pfizer, and Bristol-Myers Squibb, which manufacture cholesterol-lowering agents.Download figureDownload PowerPoint Figure 1. Event rates for stroke and coronary heart disease in WOSCOPS, CARE, and LIPID trials, according to random allocation to 40 mg of pravastatin or to placebo.FootnotesCorrespondence to Dr Paul Ridker, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Avenue East, Boston, MA 02215. E-mail [email protected] References 1 McMillan GC. Historical review of research on atherosclerosis. Adv Exp Med Biol.1995; 369:1–6.CrossrefMedlineGoogle Scholar2 Shepard J, Cobb SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med.1995; 333:1301–1307.CrossrefMedlineGoogle Scholar3 Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med.1996; 335:1001–1009.CrossrefMedlineGoogle Scholar4 Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med.1998; 339:1349–1357.CrossrefMedlineGoogle Scholar5 Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet.1994; 344:1383–1389.MedlineGoogle Scholar6 Downs JR, Clearfield M, Weis S, et al, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA.1998; 279:1615–1622.CrossrefMedlineGoogle Scholar7 Byington RP, Davis BR, Plehn JF, et al. Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) Project. Circulation.2001; 103:387–392.CrossrefMedlineGoogle Scholar8 Plehn JF, Davis BR, Sacks FM, et al. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) Study Circulation.1999; 99:216–223.CrossrefMedlineGoogle Scholar9 White HD, Simes RJ, Anderson NE, et al. Pravastatin therapy and the risk of stroke. N Engl J Med.2000; 343:317–326.CrossrefMedlineGoogle Scholar10 Pedersen TR, Kjekshus J, Pyorala K, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol.1998; 81:333–335.CrossrefMedlineGoogle Scholar11 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 Scholar12 Iso H, Jacobs DR Jr, Wentworth D, et al. Serum cholesterol levels and six-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 Scholar13 Ridker PM, Rifai N, Pfeffer M, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation.1999; 100:230–235.CrossrefMedlineGoogle Scholar14 Ridker PM, Rifai N, Pfeffer MA, et al, 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 Scholar15 Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med.1997; 336:973–979.CrossrefMedlineGoogle Scholar16 Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular events in women. N Engl J Med.2000; 342:836–843.CrossrefMedlineGoogle Scholar17 Fayad ZA, Fuster V. Characterization of atherosclerotic plaques by magnetic resonance imaging. Ann N Y Acad Sci.2000; 902:173–186.CrossrefMedlineGoogle Scholar18 Lammie GA, Sandercock PA, Dennis MS. Recently occluded intracranial and extracranial carotid arteries: relevance of the unstable atherosclerotic plaque. Stroke.1999; 30:1319–1325.CrossrefMedlineGoogle Scholar19 Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group N Engl J Med.1999; 341:410–418.CrossrefMedlineGoogle Scholar20 Marx N, Sukhova GK, Collins T, et al. PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation.1999; 99:3125–3131.CrossrefMedlineGoogle Scholar21 Plutzky J. Peroxisome proliferator activated receptors in vascular biology and atherosclerosis: emerging insights for evolving paradigms. Curr Atheroscler Rep.2000; 2:327–335.CrossrefMedlineGoogle Scholar22 Raju TN. The Nobel chronicles: Joseph Leonard Goldstein (b 1940), Michael Stuart Brown (b 1941). Lancet.2000; 355:416.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails January 23, 2001Vol 103, Issue 3Article InformationMetrics Download: 97 Copyright © 2001 by American Heart Associationhttps://doi.org/10.1161/01.CIR.103.3.348 Originally publishedJanuary 23, 2001 KeywordsEditorialsheart diseasesstatinscholesterolstrokelipidsPDF download" @default.
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