The Low-density Lipoprotein Cholesterol Cholesterol Verdict - Lower is Better

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Abstract

Abstract
The debate among cardiologists over whether ‘lower is better’ with regards to serum levels of low-density lipoprotein cholesterol (LDL-C) has raged for years. Three recently completed statin trials – REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering), PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Prevention and Infection Therapy- Thrombolysis in Myocardial Infarction 22) and ALLIANCE (Aggressive Lipid Lowering Initiation Abates New Cardiac Events) – have provided unambiguous evidence that LDL-C levels substantially lower than 100mg/dL (2.6 mmol/L) are associated with a reduced risk of cardiovascular events and with plaque regression, particularly in patients with pre-existing heart disease. The findings from these benchmark studies will likely lead to a re-evaluation of existing cholesterol guidelines and prompt more aggressive management of patients with atherosclerotic disease. To this end, the use of the more efficacious statins in clinical practice holds promise for yielding greater LDL-C reductions in patients with coronary heart disease risk factors and facilitating achievement of lipid targets while minimising the occurrence of adverse events.

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Introduction
The debate among cardiologists over whether ‘lower is better’ with regards to serum levels of LDL-C has raged for years. Some investigators have argued that there is a threshold below which further LDL-C reductions will provide no added benefit, while others have maintained that such a cut-off point, if it does exist, lies far below current National Cholesterol Education Program (NCEP)1 or Joint European2 treatment targets. While 2002’s landmark Heart Protection Study3 suggested that there was no threshold for benefit from lowering LDL-C in individuals with baseline levels in the ‘normal’ range (<120mg/dL [3.1mmol/L]), the overall concept awaited definitive proof. Now, three recently completed statin trials have provided the evidence to reach a verdict and finally put the debate to rest: lower LDL-C is indeed better, particularly in patients with pre-existing heart disease. The findings from these benchmark studies will likely lead to a reevaluation of existing cholesterol guidelines and prompt substantial changes in the management of patients with atherosclerotic disease.

Atherosclerosis Progression After Intensive Lipid Lowering├é┬á – The REVERSAL Trial
REVERSAL4 was the first large, randomised trial to compare the rate of coronary artery disease progression associated with two distinct statin regimens. This imaging study used intravascular ultrasound (IVUS) to measure plaque progression in 502 patients with stable coronary disease treated either with a moderate LDL-C-lowering regimen (40mg pravastatin daily) or an intensive regimen (80mg atorvastatin daily). After 18 months of treatment, high-dose atorvastatin was shown to reduce the primary end-point, atheroma volume, by a mean of 0.4%, compared with an increase of 2.7% in the pravastatin group (p = 0.02). LDL-C levels, which averaged 150.2mg/dL (3.9mmol/L) at baseline, were lowered to a mean of 110mg/dL (2.8mmol/L) in the pravastatin 40mg group, compared with 79mg/dL (2.0mmol/L) among atorvastatin 80mg recipients (p < 0.001). The authors suggested that LDL-C lowering alone could not explain the superior outcome in the atorvastatin group, and that other factors (e.g. reductions in levels of triglycerides and/or C-reactive protein [CRP]) may have played a contributing role.

Figure 1: Comparison of Percentage of LDL-C Reduction and Change in Atheroma Volume in the REVERSAL Trial

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The solid line indicates the relationship between mean change in LDL-C and change in atheroma volume from linear regression analysis; the dashed lines indicate the upper and lower 95% confidence limits for the mean values. Adapted with permission from Nissen et al.4

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References

  1. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), JAMA (2001); 285: pp. 2,486├óÔé¼ÔÇ£2,497.
  2. Second Joint Task Force, ├óÔé¼┼øPrevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and Other Societies on Coronary Prevention├óÔé¼┼Ñ, Eur. Heart J. (1998);19: pp. 1,434├óÔé¼ÔÇ£1,503.
  3. Heart Protection Study Collaborative Group, ├óÔé¼┼øMRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial├óÔé¼┼Ñ, Lancet (2002); 360(9326): pp. 7├óÔé¼ÔÇ£22.
  4. S E Nissen, E M Tuzcu, P Schoenhagen, B G Brown, P Ganz, R A Vogel, et al., ├óÔé¼┼øEffect of intensive compared with moderate lipid lowering therapy on progression of coronary atherosclerosis. A randomized controlled trial├óÔé¼┼Ñ, JAMA (2004);291: pp. 1,071├óÔé¼ÔÇ£1,080.
  5. C P Cannon, E Braunwald, C H McCabe, D J Rader, J L Rouleau, R Belder, et al., ├óÔé¼┼øComparison of intensive and moderate lipid lowering with statins after acute coronary syndromes├óÔé¼┼Ñ, N. Engl. J. Med. (2004);350: pp. 1,495├óÔé¼ÔÇ£1,504.
  6. M Koren and D Hunninghake, on behalf of the ALLIANCE investigators, ├óÔé¼┼øComparison of clinical outcomes in managed care patients with coronary heart disease treated in aggressive lipid lowering programs using atorvastatin versus usual care├óÔé¼┼Ñ, Program and abstracts from the American College of Cardiology 53rd Annual Scientific Session; 7├óÔé¼ÔÇ£10 March, (2004); New Orleans, La.
  7. E J Topol, ├óÔé¼┼øIntensive statin therapy-a sea change in cardiovascular prevention├óÔé¼┼Ñ N. Engl. J. Med. (2004);350: pp. 1,562├óÔé¼ÔÇ£1,564.
  8. EUROASPIRE I and II Group. ├óÔé¼┼øClinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries├óÔé¼┼Ñ, Lancet (2001);357: pp. 995├óÔé¼ÔÇ£1,001.
  9. T A Pearson and I M Laurora, ├óÔé¼┼øTreatment success in patient subgroups in the Lipid Treatment Assessment Project (LTAP)├óÔé¼┼Ñ, Circulation (1997); 96(suppl 8): A361.
  10. P H Jones, M H Davidson, E A Stein, et al., ├óÔé¼┼øComparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses├óÔé¼┼Ñ (STELLAR Trial), Am. J. Cardiol. (2003); 92: pp. 152├óÔé¼ÔÇ£160.
  11. H Schuster, ├óÔé¼┼øRosuvastatin├óÔé¼ÔÇ£a highly effective HMG-CoA reductase inhibitor: review of clinical trial data at 10├óÔé¼ÔÇ£40 mg doses in dyslipidemic patients├óÔé¼┼Ñ, Cardiology (2003); 99: pp. 126├óÔé¼ÔÇ£139.
  12. J M McKenney, P H Jones, M A Adamczyk, V A Cain, B S Bryzinski and J W Blasetto, for the STELLAR Study Group, ├óÔé¼┼øComparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin and pravastatin in achieving lipid goals: results from the STELLAR trial├óÔé¼┼Ñ, Curr. Med. Res. Opin. (2003); 19(8): pp. 689├óÔé¼ÔÇ£698.
  13. H B Brewer, ├óÔé¼┼øBenefit-risk assessment of rosuvastatin 10 to 40 milligrams├óÔé¼┼Ñ, Am. J. Cardiol. (2003); 92(suppl): 23K├óÔé¼ÔÇ£29K.