Nonfatal Outcomes in the Primary Prevention of Atherosclerotic Cardiovascular Disease
2014; Lippincott Williams & Wilkins; Volume: 7; Issue: 3 Linguagem: Inglês
10.1161/circoutcomes.114.000871
ISSN1941-7705
AutoresMatthew J. Czarny, Seth S. Martin, Payal Kohli, Thomas S. Metkus, Roger S. Blumenthal,
Tópico(s)Health Systems, Economic Evaluations, Quality of Life
ResumoHomeCirculation: Cardiovascular Quality and OutcomesVol. 7, No. 3Nonfatal Outcomes in the Primary Prevention of Atherosclerotic Cardiovascular Disease Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBNonfatal Outcomes in the Primary Prevention of Atherosclerotic Cardiovascular DiseaseIs All-Cause Mortality Really All That Matters? Matthew J. Czarny, MD, Seth S. Martin, MD, Payal Kohli, MD, Thomas Metkus, MD and Roger S. Blumenthal, MD Matthew J. CzarnyMatthew J. Czarny From the Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD (M.J.C., S.S.M., T.M., R.S.B.); and Division of Cardiology, University of California San Francisco (P.K.). , Seth S. MartinSeth S. Martin From the Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD (M.J.C., S.S.M., T.M., R.S.B.); and Division of Cardiology, University of California San Francisco (P.K.). , Payal KohliPayal Kohli From the Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD (M.J.C., S.S.M., T.M., R.S.B.); and Division of Cardiology, University of California San Francisco (P.K.). , Thomas MetkusThomas Metkus From the Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD (M.J.C., S.S.M., T.M., R.S.B.); and Division of Cardiology, University of California San Francisco (P.K.). and Roger S. BlumenthalRoger S. Blumenthal From the Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD (M.J.C., S.S.M., T.M., R.S.B.); and Division of Cardiology, University of California San Francisco (P.K.). Originally published8 Apr 2014https://doi.org/10.1161/CIRCOUTCOMES.114.000871Circulation: Cardiovascular Quality and Outcomes. 2014;7:481–485Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 There is considerable debate in the literature regarding appropriate end points for studies of primary prevention of atherosclerotic cardiovascular disease (ASCVD), most notably with regard to statin therapy for hypercholesterolemia. Some authors have argued that large clinical trials of primary prevention interventions must demonstrate an overall mortality benefit1,2 or a combined overall mortality and serious morbidity benefit.3 Others feel that such a high bar would lead to the erroneous dismissal of several beneficial strategies that can substantially decrease incident ASCVD.2,4Although several meta-analyses have now shown a modest mortality benefit of statins in primary prevention,5–8 the debate will undoubtedly be rekindled with the recent revision of the American College of Cardiology Foundation/American Heart Association (ACC/AHA) guidelines for the treatment of hypercholesterolemia.9 In this article, we advocate for the importance of nonfatal cardiovascular outcomes (nonfatal myocardial infarction [MI], nonfatal stroke, and peripheral arterial disease) in the assessment of ASCVD primary prevention strategies, illustrate this principle already in use in the management of hypertension, and advocate for the relevance of both nonfatal and fatal ASCVD events in the treatment of hypercholesterolemia in the primary prevention setting.Defining BenefitThe definition of benefit in the primary prevention of clinical ASCVD has recently been debated. Some authors suggest that an improvement in total mortality, of which cardiac death is only one part, is the only relevant benefit.1,2 Prasad and Vandross1 refer to examples of medications that improve surrogate end points but subsequently fail to improve overall survival, such as fibrates and niacin in certain patient populations. Importantly, no distinction is made between clinical, nonmortality end points (eg, nonfatal MI and stroke) and surrogate markers of clinical ASCVD risk (eg, low-density lipoprotein-cholesterol). This line of reasoning suggests that nonmortality end points are simply surrogates and should not be used to guide clinical decision making. In addition, others have argued that a lack of a clear effect on all-cause mortality is enough evidence that there is no meaningful benefit on vascular events.2A distinction should be made between outcomes that are risk factors for nonfatal clinical outcomes and the clinical outcomes themselves (see the Table). Low-density lipoprotein-cholesterol in isolation falls into the first group because a reduction in low-density lipoprotein-cholesterol that does not correlate with improvement in clinical events, such as nonfatal MI or stroke, would not be an appropriate surrogate end point. However, nonfatal MI, nonfatal stroke, and peripheral arterial disease are nonmortality clinical outcomes that greatly impact patients. For this reason, these disease states merit prevention in and of themselves and, therefore, are distinct from surrogate outcomes that do not have value without the clinical correlation.Table. Examples of Surrogate and Clinical Outcomes in Atherosclerotic Cardiovascular DiseaseClinical outcomes All-cause mortality Cardiovascular mortality Nonfatal MI Nonfatal stroke Heart failure Incident peripheral arterial disease Percutaneous revascularization Coronary artery bypass grafting HospitalizationSurrogate outcomes Blood pressure LDL-C HDL-C Triglycerides Coronary artery calcium scoreHDL-C indicates high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol, and MI, myocardial infarction.Indeed, some of these important end points lie along a spectrum in terms of morbidity and impact on quality of life. Although some MIs and strokes will be relatively minor in severity, many will dramatically impact their victims.10 The concept of quality-adjusted life years was introduced to help solve this problem in part, but it is fraught with difficulties including the inaccuracies and subjective variability of having healthy people anticipate the impact of an event on their lives.11 However, the wide spectrum of severity of these outcomes and the difficulty in quantifying their impact on individual lives should not lead us to discount them entirely.Regardless of the severity of events for individual patients, however, the morbidity of incident clinical ASCVD on the population as a whole is great. According to the AHA, each year an estimated 635 000 Americans will have a new MI or coronary heart disease death, and 610 000 will suffer a new stroke,10 for a total of >1.2 million incident ASCVD events.Imagine that a medication can prevent these new ASCVD events but does not result in improved all-cause mortality. A medication could have this property if the middle- to older-age people who would have suffered the ASCVD events died instead from a competing risk from another, unrelated cause (eg, cancer, pulmonary disease, accident, etc) before the time the downstream effects of the avoided ASCVD event (eg, systolic heart failure due to ischemic cardiomyopathy) would have resulted in death. In such a case, insisting that an all-cause mortality benefit be demonstrated before prescribing the medication would be to say that the angina-free, bypass surgery–free, heart failure–free, or hemiparesis-free months or years before noncardiac death do not constitute a significant benefit. Hartzband and Groopman11 summarize this view, stating that "basing decisions on the outcome of death ignores vital dimensions of life that are not easily quantified."Additionally, there is a difference between short-term mortality benefit and the alteration of the lifetime risk trajectory, such that mortality benefits become evident decades after treatment has been started. An example of this principle is seen in the treatment of patients with familial hypercholesterolemia with statins at <16 years of age. These patients have a risk of MI at a much earlier age and far in excess of that of the general population, but statin treatment from an early age reduces their risk to that of the general population.12–14 Although the absolute 10-year risk of an MI in a group of adolescents with familial hypercholesterolemia is minimal, statin treatment beginning early in life alters the risk trajectory, such that the risk of MI is no greater than that of the general population. Although there may be no 10-year mortality benefit, the 20- or 30-year morbidity and mortality benefit is striking. Therefore, relying on short-term mortality measures can result in major long-term benefits being missed. Perhaps a lifetime risk, as is done for breast cancer,15 may be more appropriate in the primary prevention of ASCVD.Finally, other authors define benefit even more narrowly; they define a serious adverse event as a composite of all-cause mortality and serious intervention-related morbidity and argue that any trial of a primary prevention intervention must demonstrate an improvement in serious adverse events. They reason that an intervention that reduces all-cause mortality but causes off-target morbidity does not constitute a meaningful benefit.3Although both all-cause mortality and serious morbidities are important, utilizing a summary measure such as the serious adverse event confuses the fundamental risk–benefit principle. A serious adverse event counts every event as equal,16 and death, hospitalization, nonfatal MI, and incident diabetes mellitus are not equivalent events. Furthermore, rare side effects may occur in a few patients that are largely reversible by simply discontinuing the medication or intervention, such as severe myopathy or rhabdomyloysis with statin use. These events need not affect the overall balance of the benefit of the intervention for the target population as a whole. The balance between benefits and harms is what needs to be assessed, so combining them into a summary measure and weighing each equally ignores the careful evaluation of each component that is necessary to make an educated, reasoned decision as to the value of an intervention.To summarize, short-term all-cause mortality is not the only relevant end point in a large-scale strategy for the prevention of clinical ASCVD. To focus on all-cause mortality is to miss the significant impact of incident MIs, strokes, and peripheral arterial disease on the daily existence of patients affected by 1 of these life-altering10 diseases. Furthermore, to focus on only short-term mortality misses the modifications to risk trajectory that result in long-term mortality benefits that are difficult to demonstrate in typical clinical trials with 5 or 10 years of follow-up. These principles are already at work in our management of hypertension, and the treatment of hyperlipidemia must be held to the same standard.Principles in Practice: Treatment of HypertensionAs an illustration, hypertension is an excellent example. Hypertension is a major risk factor for clinical ASCVD, and the treatment of systolic blood pressures of <160 mm Hg has never been definitively shown in a randomized controlled trial to result in a decrease in all-cause mortality. More than a decade ago, a reanalysis of Framingham data by Port et al17 suggested that instead of being a continuous risk factor, blood pressure had a threshold that was age- and sex-dependent, below which there was no increased risk of ASCVD. The authors noted no mortality benefit of treating systolic pressures 20% 10-year Framingham risk, respectively) have conclusively been shown to decrease cardiac death and ASCVD and have recently also been found to have a modest all-cause mortality benefit. Multiple large, randomized, controlled clinical trials27–32 have demonstrated significant improvements in incident MI, stroke, and coronary death, and the JUPITER trial showed a reduction in all-cause mortality (hazards ratio, 0.80, 95% confidence interval, 0.67–0.97). Furthermore, a recently updated Cochrane meta-analysis6 of 18 randomized clinical trials including 56 934 patients without clinically apparent ASCVD demonstrated a 14% improvement in all-cause mortality, a 27% reduction in fatal and nonfatal coronary events, and a 22% reduction in fatal and nonfatal stroke.Another meta-analysis5 included data from 27 trials with a total of 174 149 patients and found a 19% to 38% reduction in major vascular events per 1.0 mmol/L (39 mg/dL) decrease in low-density lipoprotein-cholesterol across a spectrum of 5-year major vascular event risk ranging from 30%. Lastly, an all-cause mortality benefit from statins in primary prevention was not conclusive but was strongly suggested in the frequently cited meta-analysis by Ray et al33 (relative risk, 0.91, 95% confidence interval, 0.83–1.01).Critics of statin therapy for the primary prevention of ASCVD also focus on the side effects associated with statin therapy, including rhabdomyolysis, myalgias, cognitive dysfunction, cancer, and new-onset diabetes mellitus. However, several large meta-analyses5,6,34 have shown that statins are generally safe with no increased incidence of cancer, cancer mortality, myalgias, or rhabdomyolysis (which was quite rare). Furthermore, myalgias are not specific for statin-induced myopathy, and frequently patients can tolerate rechallenge of the same statin. Finally, a recent review found no evidence to support short-term adverse cognitive effects in patients without baseline cognitive dysfunction and suggested a possible long-term benefit on dementia.35It is important to note that the Cochrane meta-analysis6 reported a small increase in incident diabetes mellitus, although only 2 trials provided data, and the finding was largely driven by the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which was enriched with metabolic syndrome.30 Further analysis of the JUPITER data found that those with ≥1 risk factors for diabetes mellitus were at higher risk of developing diabetes mellitus while on statin therapy, but that 134 vascular events or deaths were avoided for every 54 incident diabetes mellitus cases.36 In addition, they estimated that statin therapy accelerated the time to the diagnosis of diabetes mellitus by only 5.4 weeks. The authors concluded that the benefits of statins in terms of ASCVD event and mortality prevention exceed the risk of incident diabetes mellitus.There is convincing evidence that the benefits of statin therapy added to diet and lifestyle interventions outweigh the harms in patients at intermediate to high risk for the development of ASCVD. As the preceding discussion shows, statins can prevent 20% to 40% of incident ASCVD in this population; the increased risk of diabetes mellitus conferred by statin therapy is more than offset by the reduction in ASCVD; and the other side effects (myalgias, rhabdomyolysis, etc) are easily detectable with close follow-up and reversible with cessation of statin therapy. Importantly, the direction and magnitude of effect sizes for outcomes other than total mortality for statins in primary prevention are commensurate with those demonstrated in the well-accepted and better-powered secondary prevention trials of statins, in which a total mortality benefit has been convincingly demonstrated.37 To require that clinical trials of statins in primary prevention redemonstrate this benefit when there is no suggestion (let alone evidence) that statins are somehow a different medication with different effects in the primary as compared with secondary prevention setting would be unnecessary and, perhaps, unethical. Therefore, statin therapy should be strongly considered for intermediate to high-risk patients after a discussion about the potential benefits and side effects has taken place.ConclusionsIf the medical community accepted the conclusions of Port et al and ignored the totality of evidence linking stage I hypertension to the development of cardiovascular morbidity, many patients would have missed out on proven preventive therapies, and the epidemics of end-stage renal disease and heart failure would likely have accelerated. The same is true if we ignore the evidence of the benefit of statins in the primary prevention of ASCVD for individuals at intermediate and high risk over the next decade. Relying on short-term all-cause mortality as the sole relevant end point does not take into account reductions in very morbid conditions including MI, disabling stroke, and lifestyle-limiting peripheral arterial disease over the lifetime. These end points matter in and of themselves, and therefore a reduction in these can and should be enough benefit to recommend an intervention as safe as statin and antihypertensive therapy for the millions of individuals who stand to benefit. Because of this, the revised ACC/AHA guidelines for the reduction of cardiovascular events9 include nonmortality outcomes as relevant end points when deciding whether to initiate statin therapy.AcknowledgmentsM.J.C., S.S.M., P.K., T.M., and R.S.B. contributed to study concept and design; M.J.C. and R.S.B. contributed to drafting the article; M.J.C., S.S.M., P.K., T.M., and R.S.B. contributed to critical revision of the article for important intellectual content.Sources of FundingS.S.M. is supported by the Pollin Cardiovascular Prevention Fellowship, as well as the Marie-Josée and Henry R. Kravis endowed fellowship. R.S.B. is supported by the Kenneth Jay Pollin Professorship in Cardiology.DisclosuresNone.FootnotesCorrespondence to Matthew J. Czarny, MD, Division of Cardiology, The Johns Hopkins Hospital, 600 N Wolfe St, Carnegie 568, Baltimore, MD 21287. E-mail [email protected]References1. Prasad V, Vandross A. How high should we set the bar?Arch Intern Med. 2012; 172:656–659.CrossrefMedlineGoogle Scholar2. Mitka M. Statin therapy in primary CVD prevention remains a hot-button topic for some.JAMA. 2011; 306:2077–2078.CrossrefMedlineGoogle Scholar3. Wright JM, Bassett KL, Tejani AM. Raise the bar even higher for primary prevention interventions.Arch Intern Med. 2012; 172:1352–1353; author reply 1353.CrossrefMedlineGoogle Scholar4. Minder CM, Blaha MJ, Tam LM, Muñoz D, Michos ED, Kaul S, Blumenthal RS. Making the case for selective use of statins in the primary prevention setting.Arch Intern Med. 2011; 171:1593–1594.CrossrefMedlineGoogle Scholar5. Cholesterol Treatment Trialists' Collborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.Lancet. 2012; 380:581–590.CrossrefMedlineGoogle Scholar6. Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S. Statins for the primary prevention of cardiovascular disease.Cochrane Database Syst Rev. 2013; 1:CD004816.Google Scholar7. Naci H, Brugts JJ, Fleurence R, Tsoi B, Toor H, Ades AE. Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials.Eur J Prev Cardiol. 2013; 20:641–657.CrossrefMedlineGoogle Scholar8. Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, de Craen AJ, Knopp RH, Nakamura H, Ridker P, van Domburg R, Deckers JW. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials.BMJ. 2009; 338:b2376.CrossrefMedlineGoogle Scholar9. Stone NJ, Robinson JG, Lichtenstein AH, Bairery Merz CN, Lloyd-Jones DM, Blum CB, McBride P, Eckel RH, Schwartz JS, Goldberg AC, Shero ST, Gordon D, Smith SC, Levy D, Watson K, Wilson PWF. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults [published online ahead of print November 12, 2013].J Am Coll Cardiol. doi:10.1161/01.cir.0000437738.63853.7a. Accessed November 18, 2013.Google Scholar10. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Nichol G, Paynter NP, Schreiner PJ, Sorlie PD, Stein J, Turan TN, Virani SS, Wong ND, Woo D, Turner MB. Heart disease and stroke statistics - 2013 update: a report from the American Heart Association.Circulation. 2013; 127:e6–e245.LinkGoogle Scholar11. Hartzband P, Groopman J. There is more to life than death.N Engl J Med. 2012; 367:987–989.CrossrefMedlineGoogle Scholar12. Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P, Seed M, Humphries SE. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study.Eur Heart J. 2008; 29:2625–2633.CrossrefMedlineGoogle Scholar13. Robinson JG, Goldberg AC; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.J Clin Lipidol. 2011; 5(3 suppl):S18–S29.CrossrefMedlineGoogle Scholar14. Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, Heeringa J, Witteman JC, Lansberg PJ, Kastelein JJ, Sijbrands EJ. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.BMJ. 2008; 337:a2423.CrossrefMedlineGoogle Scholar15. National Cancer Institute. Breast cancer risk assessment tool.http://www.cancer.gov/bcrisktool/. Accessed November 7, 2013.Google Scholar16. Prasad V, Vandross A. In reply.Arch Intern Med. 2012; 172:1353.Google Scholar17. Port S, Demer L, Jennrich R, Walter D, Garfinkel A. Systolic blood pressure and mortality.Lancet. 2000; 355:175–180.CrossrefMedlineGoogle Scholar18. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension.JAMA. 1991; 265:3255–3264.CrossrefMedlineGoogle Scholar19. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhäger WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O' Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.Lancet. 1997; 350:757–764.CrossrefMedlineGoogle Scholar20. Psaty BM, Furberg CD, Kuller LH, Cushman M, Savage PJ, Levine D, O'Leary DH, Bryan RN, Anderson M, Lumley T. Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study.Arch Intern Med. 2001; 161:1183–1192.CrossrefMedlineGoogle Scholar21. Kannel WB, Vasan RS, Levy D. Is the relation of systolic blood pressure to risk of cardiovascular disease continuous and graded, or are there critical values?Hypertension. 2003; 42:453–456.LinkGoogle Scholar22. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jones DW, Materson BJ, Oparil S, Wright JT, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.JAMA. 2003; 289:2560–2572.CrossrefMedlineGoogle Scholar23. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F; Task Force Members. 2013 ESH/ESC guidelines for the management of arterial hypertension.Eur Heart J. 2013; 34:2159–2219.CrossrefMedlineGoogle Scholar24. Redberg RF, Katz MH. Healthy men should not take statins.JAMA. 2012; 307:1491–1492.CrossrefMedlineGoogle Scholar25. Redberg RF, Katz M, Grady D. Diagnostic tests: another frontier for less is more.Arch Intern Med. 2011; 171:619.CrossrefMedlineGoogle Scholar26. Redberg RF, Katz M, Grady D. To make the case - evidence is required.Arch Intern Med. 2011; 171:1594.CrossrefMedlineGoogle Scholar27. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels.JAMA. 1998; 279:1615–1622.CrossrefMedlineGoogle Scholar28. Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW, Cobbe SM. Long-term follow up of the West of Scotland Coronary Prevention Study.N Engl J Med. 2007; 357:1477–1486.CrossrefMedlineGoogle Scholar29. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, Nakaya N, Nishimoto S, Muranaka M, Yamamoto A, Mizuno K, Ohashi Y. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial.Lancet. 2006; 368:1155–1163.CrossrefMedlineGoogle Scholar30. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JR, Glynn RJ. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.N Engl J Med. 2008; 359:2195–2207.CrossrefMedlineGoogle Scholar31. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.Lancet. 2003; 361:1149–1158.CrossrefMedlineGoogle Scholar32. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.N Engl J Med. 1995; 333:1301–1307.CrossrefMedlineGoogle Scholar33. Ray KK, Seshasai S, Erqou S, Sever P, Jukema JW, Ford I, Sattar N. Statins and all-cause mortality in high-risk primary prevention.Arch Intern Med. 2010; 170:1024–1031.CrossrefMedlineGoogle Scholar34. Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials.Circ Cardiovasc Qual Outcomes. 2013; 6:390–399.LinkGoogle Scholar35. Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects.Mayo Clin Proc. 2013; 88:1213–1221.CrossrefMedlineGoogle Scholar36. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial.Lancet. 2012; 380:565–571.CrossrefMedlineGoogle Scholar37. Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials.Lancet. 2010; 376:1670–1681.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Martin S, Sperling L, Blaha M, Wilson P, Gluckman T, Blumenthal R and Stone N (2015) Clinician-Patient Risk Discussion for Atherosclerotic Cardiovascular Disease Prevention, Journal of the American College of Cardiology, 10.1016/j.jacc.2015.01.043, 65:13, (1361-1368), Online publication date: 1-Apr-2015. Martin S, Blaha M, Muse E, Qasim A, Reilly M, Blumenthal R, Nasir K, Criqui M, McClelland R, Hughes-Austin J and Allison M (2015) Leptin and incident cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis (MESA), Atherosclerosis, 10.1016/j.atherosclerosis.2014.12.033, 239:1, (67-72), Online publication date: 1-Mar-2015. Naci H, van Valkenhoef G, Higgins J, Fleurence R and Ades A (2014) Evidence-Based Prescribing, Circulation: Cardiovascular Quality and Outcomes, 7:5, (787-792), Online publication date: 1-Sep-2014. May 2014Vol 7, Issue 3 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCOUTCOMES.114.000871PMID: 24714601 Originally publishedApril 8, 2014 Keywordshypertensionatherosclerosisrisk factorsprevention and controlhypercholesterolemiaPDF download Advertisement SubjectsEpidemiologyEthics and PolicyPrimary Prevention
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