Foreword
1Department of Medical Cardiology, Glasgow Royal Infirmary, 10, Alexandra Parade, Glasgow G31 2ER, UK
2Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Room F4-159.2,1105 AZ Amsterdam, The Netherlands
* Corresponding authors. E-mail addresses: stuart.cobbe{at}clinmed.gla.ac.uk and e.randonger{at}amc.ura.nl
The results of recently reported clinical trials of statin therapy have provided persuasive evidence that low-density lipoprotein (LDL-C) targets and initiation cut-points in lipid-lowering therapy have been set too high in individuals at high or moderately high risk of coronary heart disease (CHD). This evidence has resulted in recommendations for modifications of the National Cholesterol Education Program Adult Treatment Panel III (ATP III) lipid-lowering guidelines.1 The recommendations include an optional LDL-C target of <70 mg/dL (1.8 mmol/L) and an optional treatment initiation cut-point of <100 mg/dL (2.6 mmol/L) in high-risk patients, especially those considered to be at very high risk, and an optional target of <100 mg/dL (2.6 mmol/L) and a treatment initiation cut-point of <130 mg/dL (3.4 mmol/L) in patients at moderately high risk. The modifications also recommend that treatment in such patients be initiated at a dose sufficient to produce a reduction in LDL-C of at least 30–40%.
These modifications raise a number of issues, including the precise optimal levels of LDL-C in terms of preventing CHD; how the benefits of treatment can be extended to all at-risk individuals; whether we have the tools necessary to achieve the high intensity of LDL-C lowering increasingly shown to be necessary to optimally reduce risk.
Ole Færgeman uses the results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial2 to emphasize important points regarding the nature of the atherosclerosis epidemic and our efforts to combat it by treating disease in affected individuals. This trial showed that a superior LDL-C-reducing regimen was better at reducing risk for cardiovascular disease than a regimen with putatively greater pleiotropic effects. These results bring us back to the basic understanding of atherosclerotic disease, in which deposition of cholesterol in vessel walls is the driving force of atherogenesis, and reduction of plasma LDL is the central target of treatment. However, the findings should also serve to remind us that the conditions that make atherosclerosis so prevalent—i.e. industrialization and urbanization—will not be eliminated just because we have shown that aggressive LDL-C lowering prevents disease in a sizeable proportion of a clinical trial population.3 On the one hand, Færgeman enjoins us to remain mindful of our therapeutic goal of reducing LDL-C in our at-risk patients. On the other, he reminds us that only with societal change (e.g. political actions to alter agriculture, food, and tobacco policies) or with the complete medicalization of society through dependence on industrialized medicine and progress in biotechnology will population-wide decreases in prevalence of atherosclerotic disease be achieved.
Christie M. Ballantyne reviews the data motivating the recent recommendations for modifications to the ATP III guidelines, including:
- the findings in the Heart Protection Study (HPS), showing benefit of statin therapy in high-risk patients irrespective of initial LDL-C level4
- the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), showing benefit of statin therapy in patients at moderately high risk who would not have been considered candidates for statin therapy based on LDL-C level5
- two surrogate endpoint trials, Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER6) and Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL7), and also PROVE-IT,2 showing the greater benefits of treatment with intensive versus moderate LDL-C-lowering therapy.
The optional lower LDL-C targets in many patients and the recommended intensity of initial LDL-C-lowering therapy make it more important to know the relative LDL-C-lowering effects of available statins. The recent Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial8 comparing widely used statins across their dose ranges has shown that LDL-C reduction with the 10-mg dose of rosuvastatin is equivalent to or greater than reductions achieved with atorvastatin 20 mg, simvastatin 80 mg, and the maximum 40-mg dose of pravastatin. Ballantyne reminds us that although the trend in increasingly lower LDL-C targets in higher-risk patients reflects refinement of therapeutic objectives, a number of ongoing studies will likely provide additional refinement with respect to identifying optimal LDL-C levels in at-risk individuals. Further, ongoing evaluation of additional therapeutic targets, such as non-high-density lipoprotein cholesterol and apolipoprotein B, may make it necessary to ensure that desired reductions in LDL-C are accompanied by achievement of desired levels of the latter lipid risk markers.
Herbert Schuster reminds us that not all individuals at high risk of CHD, who thus require intensive LDL-C reduction, are readily identified in routine clinical practice; such patients are thus likely to be under-treated. High-risk conditions that would not be identified simply on the basis of application of routine CHD risk assessment include peripheral arterial disease, heterozygous familial hypercholesterolaemia (FH), and the metabolic syndrome. Vigilance for such conditions should be maintained in clinical practice, and additional steps for diagnosis of FH (e.g. family screening) and the metabolic syndrome (use of simple clinical diagnostic criteria) should be adopted. Type 2 diabetes is another CHD risk equivalent warranting highly effective LDL-C reduction, yet it may not be widely appreciated that current evidence indicates that virtually all diabetic patients should receive statin therapy irrespective of their LDL-C level. Again, the issue is confronted of whether current therapeutic tools are adequate to the challenge of the recommended intensity of LDL-C lowering. In patients with FH, comparison of the two most effective LDL-C-reducing statins, rosuvastatin and atorvastatin, shows that both therapies produce profound reductions in LDL-C, with rosuvastatin, producing significantly greater decreases.9 In children with FH, treatment with atorvastatin was shown to reduce atherosclerotic progression without ill effects on growth or development.10 An analysis of the effects of commonly used doses of statins in high-risk patients with the metabolic syndrome in the Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY (MERCURY) I trial showed that LDL-C reductions were similar with statin treatment in patients with and without the metabolic syndrome.11 Significantly more patients with the metabolic syndrome reached the high-risk LDL-C goal of <100 mg/dL with rosuvastatin 10 mg than with atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 40 mg. Two trials comparing rosuvastatin and atorvastatin in patients with type 2 diabetes, COmpare the effect of Rosuvastatin with Atorvastatin on apo B/apo A-1 ratio in patients with type 2 diabetes meLLitus and dyslipidaemia (CORALL)12 and A raNdomized, Double-blind, double-dummy, multicentre phase IIIb parallel group study to compare the efficacy and safety of Rosuvastatin (10 mg and 20 mg) and atOrvastatin (10 Mg and 20 mg) in subjEcts with type II DiAbetes mellitus (ANDROMEDA),13 showed that the majority of patients achieved the LDL-C goal of <100 mg/dL with both agents. However, rosuvastatin again produced significantly greater LDL-C reductions, enabling more patients to achieve their LDL-C goal.
In the decade since the publication of results of the 4S trial, we have learned that statin therapy can effectively reduce CHD risk in a wide range of patients, independently of age, sex, or pre-existing cardiovascular disease and apparently independently of initial LDL-C, at least in those at elevated CHD risk. However, recommendations for lipid-lowering therapy have evolved and will continue to evolve in correspondence with our growing knowledge and continued investigation. The challenge in clinical practice is to correctly identify magnitude of risk in our patients and provide them with treatment adequate to optimally reduce that risk. The availability of statins with highly effective LDL-C-lowering capability provides us with at least part of what is needed to ensure that adequate therapy is provided.
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[Abstract/Free Full Text] - Færgeman O. Coronary Artery Disease. Genes, Drugs and the Agricultural Connection. Amsterdam: Elsevier, 2003.
- Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.[CrossRef][Web of Science][Medline]
- Sever PS, Dahlof B, Poulter NR 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;361:1149–1158.[CrossRef][Web of Science][Medline]
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[Abstract/Free Full Text] - Jones PH, Davidson MH, Stein EA et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003;92:152–160.[Web of Science][Medline]
- Stein EA, Strutt K, Southworth H et al. Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia. Am J Cardiol 2003;92:1287–1293.[CrossRef][Web of Science][Medline]
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[Abstract/Free Full Text] - Stender S, Schuster H, Barter P et al. Comparison of rosuvastatin with atorvastatin, simvastatin, and pravastatin in achieving cholesterol goals and improving plasma lipids in hypercholesterolaemic patients with or without the metabolic syndrome (MERCURY I trial). Diabetes Obes Metab, in press.
- Franken A, Wolffenbuttel B, Vincent H. Cholesterol-lowering effects of rosuvastatin compared with atorvastatin in patients with type 2 diabetes. (Abstract M513). Atheroscler Suppl 2004;5:118.
- Betteridge J, Gibson M, on behalf of the ANDROMEDA study investigators. Effect of rosuvastatin and atorvastatin on LDL-C and CRP levels in patients with type 2 diabetes: results of the ANDROMEDA study. Poster presentation at: the 74th European Atherosclerosis Society Congress; April 17–21, 2004; Seville, Spain.
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