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• W2070315290 abstract "In a wide variety of patient populations, including those with acute coronary syndromes,1Cannon CP Braunwald E McCabe CH Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators et al.Intensive versus moderate lipid lowering with statins after acute coronary syndromes [published correction appears in N Engl J Med. 2006; 354 (7):778].N Engl J Med. 2004 Apr 8; 350 (Epub 2004 Mar 8.): 1495-1504Crossref PubMed Scopus (4312) Google Scholar established coronary artery disease,2MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.Lancet. 2002; 360: 7-22Abstract Full Text Full Text PDF PubMed Scopus (7643) Google Scholar, 3LaRosa JC Grundy SM Waters DD Treating to New Targets (TNT) Investigators et al.Intensive lipid lowering with atorvastatin in patients with stable coronary disease.N Engl J Med. 2005 Apr 7; 352 (Epub 2005 Mar 8.): 1425-1435Crossref PubMed Scopus (3014) Google Scholar, 4Pedersen TR Faergeman O Kastelein JJ Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group 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: 2437-2445Crossref PubMed Scopus (1375) Google Scholar diabetes,2MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.Lancet. 2002; 360: 7-22Abstract Full Text Full Text PDF PubMed Scopus (7643) Google Scholar, 5Colhoun HM Betteridge DJ Durrington PN CARDS investigators et al.Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.Lancet. 2004; 364: 685-696Abstract Full Text Full Text PDF PubMed Scopus (3259) Google Scholar and high-risk hypertension,6ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research GroupMajor outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).JAMA. 2002; 288: 2998-3007Crossref PubMed Scopus (1190) Google Scholar, 7Sever PS Dahlöf B Poulter NR ASCOT investigators et al.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: 1149-1158Abstract Full Text Full Text PDF PubMed Scopus (3347) Google Scholar 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been convincingly shown to reduce the risk of cardiovascular events. Whether statins are also beneficial in primary prevention, specifically in patients without coronary artery disease or diabetes mellitus (a well-defined “coronary disease equivalent”),8Haffner SM Lehto S Rönnemaa T Pyörälä K Laakso M Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.N Engl J Med. 1998; 339: 229-234Crossref PubMed Scopus (5902) Google Scholar remains a subject of debate. This potential benefit of statins for primary prevention was best assessed by the landmark West of Scotland Coronary Prevention Study (WOSCOPS)9Shepherd J Cobbe SM Ford I West of Scotland Coronary Prevention Study Group et al.Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.N Engl J Med. 1995; 333: 1301-1307Crossref PubMed Scopus (7469) Google Scholar and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).10Downs JR Clearfield M Weis S AFCAPS/TexCAPS Research Group et al.Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS.JAMA. 1998; 279: 1615-1622Crossref PubMed Scopus (4995) Google Scholar The WOSCOPS found a 31% reduction in coronary events with pravastatin compared with placebo, but unfortunately the study recruited only men and included a small population of patients with symptomatic atherosclerosis. The AFCAPS/TexCAPS excluded the latter and recruited both men and women (a population that had a generally lower risk than that in WOSCOPS) and still found a 37% reduction in first coronary event with lovastatin. Later, 2 other large trials examined the effect of statins in high-risk patients with hypertension,6ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research GroupMajor outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).JAMA. 2002; 288: 2998-3007Crossref PubMed Scopus (1190) Google Scholar, 7Sever PS Dahlöf B Poulter NR ASCOT investigators et al.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: 1149-1158Abstract Full Text Full Text PDF PubMed Scopus (3347) Google Scholar but the inclusion of substantial numbers of patients with coronary heart disease equivalents (including diabetes and insulin resistance) limited their applicability toward general prevention. As a result, the National Cholesterol Education Panel (despite a push toward aggressive therapy for higher-risk patients) has not recently changed its recommended guidelines toward primary prevention.11Grundy SM Cleeman JI Merz CN Coordinating Committee of the National Cholesterol Education Program et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Circulation. 2004; 110: 227-239Crossref PubMed Scopus (5066) Google Scholar In fact, some editorials and reanalyses recently concluded that the practice of using statins for primary prevention may need to be reconsidered and even restricted.12Abramson J Wright JM Are lipid-lowering guidelines evidence-based?.Lancet. 2007; 369: 168-169Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar The pendulum is likely to swing back toward aggressive therapy with the newly published Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial.13Ridker PM Danielson E Fonseca FA JUPITER Study Group et al.Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.N Engl J Med. 2008; 359: 2195-2207Crossref PubMed Scopus (5263) Google Scholar In that study, 17,802 men older than 50 years and women older than 60 years with no known cardiovascular disease or diabetes, low-density lipoprotein cholesterol (LDL-C) level less than 130 mg/dL (to convert to mmol/L, multiply by 0.0259), and high-sensitivity C-reactive protein level of 2 mg/L (to convert to nmol/L, multiply by 9.524) or higher were treated with rosuvastatin at 20 mg/d. The participants taking rosuvastatin had a 44% reduction in clinical events and a 20% reduction in mortality compared with those taking placebo. However, because of the inclusion and exclusion criteria of that trial, results apply only to a subsegment of the population eligible for primary prevention, and nearly 90,000 patients had to be screened to identify the eventual cohort. Cost containment has become an absolute necessity in our modern-day health care system.14Mayes R Hurley RE Pursuing cost containment in a pluralistic payer environment: from the aftermath of Clinton's failure at health care reform to the Balanced Budget Act of 1997.Health Econ Policy Law. 2006; 1: 237-261Crossref PubMed Google Scholar Although it is well established that the absolute risk reduction is greatest in patients at highest risk of cardiovascular events15Ballantyne CM Low-density lipoproteins and risk for coronary artery disease.Am J Cardiol. 1998; 82: 3Q-12QAbstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar and thus most cost-effective in this population, it is also important to recognize the large costs to society (including disability and work loss) of such first events as a myocardial infarction or stroke.16Zethraeus N Molin T Henriksson P Jönsson B Costs of coronary heart disease and stroke: the case of Sweden.J Intern Med. 1999; 246: 151-159Crossref PubMed Scopus (79) Google Scholar Waiting for these events to occur before initiating therapy seems neither wise nor ethical. Further complicating the practice of modern medicine, health care payers have actively encouraged the use of less expensive medications,17Sloan FA Whetten-Goldstein K Wilson A Hospital pharmacy decisions, cost containment, and the use of cost-effectiveness analysis.Soc Sci Med. 1997; 45: 523-533Crossref PubMed Scopus (75) Google Scholar often on the basis of a perceived “class effect.” Whether all statins are truly equivalent remains uncertain and controversial. Several small studies have directly compared the lipid-lowering capabilities and patient tolerability of different statins. A few studies have also compared the ability of these drugs to alter surrogate end points for cardiovascular events such as inflammatory markers and endothelial function. To date, however, few comparative outcome studies have been published. The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study found that atorvastatin (80 mg/d) reduced the subsequent risk of cardiovascular events in patients with acute coronary syndrome by 16% compared with pravastatin (40 mg/d),1Cannon CP Braunwald E McCabe CH Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators et al.Intensive versus moderate lipid lowering with statins after acute coronary syndromes [published correction appears in N Engl J Med. 2006; 354 (7):778].N Engl J Med. 2004 Apr 8; 350 (Epub 2004 Mar 8.): 1495-1504Crossref PubMed Scopus (4312) Google Scholar whereas the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study found that atorvastatin (80 mg/d) reduced the risk of major coronary heart disease events by 11% (only a statistical trend) and cardiovascular disease events by 16% compared with simvastatin (20 mg/d) in patients with prior myocardial infarction.4Pedersen TR Faergeman O Kastelein JJ Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group 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: 2437-2445Crossref PubMed Scopus (1375) Google Scholar Unfortunately, no randomized trial has directly compared different statins in the primary prevention of cardiovascular events, and it is unlikely that such a trial will ever be performed. As a result, the best data will come from large, prospectively collected, administrative databases. In this issue of Mayo Clinical Proceedings, Jacobson et al18Jacobson TA Wertz DA Hoy T Kuznik A Grochylski D Cziraky M A comparison of cardiovascular event rates in managed care patients without prior cardiovascular disease newly initiated on atorvastatin or simvastatin.Mayo Clin Proc. 2008; 83: 1316-1325Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar present such a study by examining the clinical outcomes of more than 200,000 patients in whom statin therapy was initiated during a 4-year period, presumably for primary prevention of cardiovascular disease. The authors directly compared clinical outcomes on the basis of whether patients were selected for treatment with simvastatin or atorvastatin, the 2 most widely prescribed statins in the United States. Because these data were collected from an administrative database, there is no direct way of knowing why the physicians selected the particular drug or dose or what the presumed treatment goals were. However, the large study population allowed the authors the ability to painstakingly control for all available baseline differences (potential confounders). Methodologically, it remains impossible to account for all confounders in such a study, some of which may elude simple measurement. The strengths of the study by Jacobson et al include its stringent selection criteria (attempting to exclude any patients who underwent secondary prevention), its large size (permitting proper statistical adjustments), the duration of available follow-up (longer than previous studies of similar design), and the extensive degree of data collection (particularly thorough demographic information and clinical characteristics). Weaknesses of the study include the inclusion of patients with diabetes, a higher risk group, which could account for the higher than expected event rate of just less than 2% per year. For comparison, the 5-year cumulative cardiovascular event rate with treatment was approximately 3% in the AFCAPS/TexCAPS.10Downs JR Clearfield M Weis S AFCAPS/TexCAPS Research Group et al.Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS.JAMA. 1998; 279: 1615-1622Crossref PubMed Scopus (4995) Google Scholar Additionally, the study by Jacobson et al was industry-sponsored with pharmaceutical-employee authors, and most physicians are well aware of the current marketplace competition between generic simvastatin and brand-name atorvastatin. In the Jacobson et al study, patients taking atorvastatin experienced a statistically significant 1.8% absolute risk reduction (20% relative risk reduction) in cardiovascular events during the 4-year follow-up period compared with patients receiving simvastatin. This suggests that 56 patients would need to be treated with atorvastatin instead of simvastatin during this period to prevent a single patient from having a cardiovascular event, although the number needed to treat should generally not be calculated from a cohort study. However, this difference was seen before adjustment for clinical differences between the 2 patient populations. After correction, the authors still found a 13% relative risk reduction in events with atorvastatin that remained statistically significant, and they describe a number of plausible explanations for their findings, including the difference in pleiotropic effects (beneficial effects that extend beyond the benefit of LDL-C reduction) between the 2 agents. A potentially important explanation for the difference in clinical events that bears further examination is the dosing difference between the 2 agents. Prior dosing studies have found that the lowering effect of the LDL-C level with 10 mg of atorvastatin is roughly equivalent to that with 40 mg of simvastatin.19Jones P Kafonek S Laurora I Hunninghake D 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: 582-587Abstract Full Text Full Text PDF PubMed Scopus (1081) Google Scholar According to the “rule of 7” that appears to apply to each of these agents, for each doubling of statin dosage, one should expect to see a 7% reduction in LDL-C.20Roberts WC The rule of 5 and the rule of 7 in lipid-lowering by statin drugs [editorial].Am J Cardiol. 1997; 80: 106-107Abstract Full Text PDF PubMed Scopus (207) Google Scholar Furthermore, a large meta-analysis suggested that for each approximately 1% reduction in LDL-C with statin therapy, an approximately 1% reduction in cardiovascular events was seen.21LaRosa JC He J Vupputuri S Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials.JAMA. 1999; 282: 2340-2346Crossref PubMed Scopus (1152) Google Scholar In the study by Jacobson et al, the mean dose of atorvastatin was 17 mg, which equates to 68 mg of simvastatin (considerably higher than the 29 mg used). Thus, the dose of simvastatin was only 43% of the equivalent dose of atorvastatin. However, even after accounting for this difference using the above logic, nearly half the difference in events (approximately 6%) cannot be explained. Of note, the authors did attempt to correct for intensity of dosing in further analysis, and a difference in outcomes was still seen. Although the dose of simvastatin may have been too low in this study, it is critical to recognize that this is a “real-world” study. Physicians were using medication at the doses that they thought were most appropriate for their patients. Despite fairly comparable lipid levels (in those for whom data were available), physicians chose to use a less efficacious dose of simvastatin. This may have been due to a fear of inducing muscle complications with higher doses of simvastatin, as previously seen in the Aggrastat to Zocor (A to Z) trial22de Lemos JA Blazing MA Wiviott SD A to Z Investigators 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 Sep 15; 292 (Epub 2004 Aug 30.): 1307-1316Crossref PubMed Scopus (1190) Google Scholar and the Conversion to Atorvastatin in Patients Intolerant or Refractory to Simvastatin Therapy (CAPISH) study.23Krasuski RA Doeppenschmidt D Henry JS et al.Conversion to atorvastatin in patients intolerant or refractory to simvastatin therapy: the CAPISH study.Mayo Clin Proc. 2005; 80: 1163-1168Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Prior conversion studies have also recognized an underdosing of simvastatin compared with atorvastatin. Moreover, patients may be reluctant to take medications they perceive to be at the upper limit of dosing because of a perceived risk of adverse effects. Regardless of the reason, physicians were less likely to treat patients with higher doses of simvastatin, and event rates were higher. Whether more aggressive dosing could have bridged this gap remains unknown. The Jacobson et al study is important for 2 main reasons: it provides further data about the importance of statin therapy in the prevention of cardiovascular disease, and it suggests that important differences may exist in the efficacy of the individual agents within this important class of drugs. What remains most important when selecting therapies for use in an individual patient is their effect on clinical outcome. In concert with this, the treating physician also needs to consider patient tolerability and cost of the drug. If patients leave an office, emergency department, or hospital bed with a prescription for a medication they will not fill or take because they cannot afford it or the adverse effects are unbearable, clinical outcome will obviously not be favorably affected. In the real-world study by Jacobson et al that compared statins, patients prescribed atorvastatin experienced a significant reduction in cardiovascular events compared with patients prescribed simvastatin. This difference in events appears to exceed the difference in comparative dosing and suggests that atorvastatin may be the better evidence-based choice for prevention of cardiovascular disease. Whether these benefits are worth the additional costs will undoubtedly fuel further controversy. Comparison of Cardiovascular Event Rates in Patients Without Cardiovascular Disease in Whom Atorvastatin or Simvastatin Was Newly InitiatedMayo Clinic ProceedingsVol. 83Issue 12PreviewTo compare cardiovascular (CV) event rates and risk in patients without previous CV disease in whom atorvastatin or simvastatin was newly initiated in a managed care setting. Full-Text PDF" @default.
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• W2070315290 title "Primary Prevention and Statins: Is It Just About Going to Class?" @default.
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