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MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.

Heart Protection Study Collaborative Group.

BACKGROUND: Throughout the usual LDL cholesterol range in Western populations, lower blood concentrations are associated with lower cardiovascular disease risk. In such populations, therefore, reducing LDL cholesterol may reduce the development of vascular disease, largely irrespective of initial cholesterol concentrations. METHODS: 20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average compliance: 85%) or matching placebo (average non-study statin use: 17%). Analyses are of the first occurrence of particular events, and compare all simvastatin-allocated versus all placebo-allocated participants. These "intention-to-treat" comparisons assess the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1.0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily). Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity. FINDINGS: All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p=0.0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5.7%] vs 707 [6.9%]; p=0.0005), a marginally significant reduction in other vascular deaths (194 [1.9%] vs 230 [2.2%]; p=0.07), and a non-significant reduction in non-vascular deaths (547 [5.3%] vs 570 [5.6%]; p=0.4). There were highly significant reductions of about one-quarter in the first event rate for non-fatal myocardial infarction or coronary death (898 [8.7%] vs 1212 [11.8%]; p<0.0001), for non-fatal or fatal stroke (444 [4.3%] vs 585 [5.7%]; p<0.0001), and for coronary or non-coronary revascularisation (939 [9.1%] vs 1205 [11.7%]; p<0.0001). For the first occurrence of any of these major vascular events, there was a definite 24% (SE 3; 95% CI 19-28) reduction in the event rate (2033 [19.8%] vs 2585 [25.2%] affected individuals; p<0.0001). During the first year the reduction in major vascular events was not significant, but subsequently it was highly significant during each separate year. The proportional reduction in the event rate was similar (and significant) in each subcategory of participant studied, including: those without diagnosed coronary disease who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separately, women; those aged either under or over 70 years at entry; and--most notably--even those who presented with LDL cholesterol below 3.0 mmol/L (116 mg/dL), or total cholesterol below 5.0 mmol/L (193 mg/dL). The benefits of simvastatin were additional to those of other cardioprotective treatments. The annual excess risk of myopathy with this regimen was about 0.01%. There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause. INTERPRETATION: Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularisation by about one-quarter. After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third. Hence, among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone.

[COLOR=Red]And those results were obtained during 5 years...year after year into the future the gap will widen and widen and widen between the treated and untreated.[/COLOR]
[QUOTE=rahod]I understand that for TRIGS UNDER 250 or so, that the calculated method is fairly accurate. Certainly good enough to get a handle on the LDL levels. I have seen tabulated results that compare calculated with ACTUAL and they're VERY CLOSE. In this case, since he said 200+, I assumed it wasn't 300.[/QUOTE]

There are several studies that have demonstrated the importance of directly calculating LDL-C instead of estimating it. Here is a typical one.

A Clinical Comparison of Calculated Versus Direct Measurement of Low-Density Lipoprotein Cholesterol Level
Posted 03/01/2004
Cameron C. Lindsey, Pharm.D.; Maqual R. Graham, Pharm.D.; Thomas P. Johnston, Ph.D.; Chelsea G. Kiroff, Pharm.D.; Anna Freshley
Abstract and Introduction

Study Objectives: To determine if, and to what extent, the low-density lipoprotein cholesterol (LDL) level is underestimated when it is calculated by the Friedewald formula compared with the LDL level measured by a direct method. A secondary objective was to determine and compare the percentages of patients meeting LDL goal using each of these two methods.
Design: Retrospective chart review.
Setting: Kansas City Veterans Affairs Medical Center.
Subjects: Patients aged 18 years or older and whose laboratory results reflected a complete lipid profile for 1 year.

Measurement and Main Results: Calculated LDL level (C-LDL) was derived using the Friedewald formula and was compared with Wako method-derived direct LDL level (D-LDL) to ascertain whether a positive correlation existed. The absolute difference between the methods for each sample was determined and compared overall and for various subgroups. The number of patient samples achieving National Cholesterol Education Program-defined LDL goal was determined and compared for both methods. A total of 20,224 lipid profiles were generated and 19,343 were included in the analysis. A strong correlation was found between D-LDL and C-LDL (r = 0.94). The absolute difference between the two methods demonstrated an underestimation of C-LDL of 19.5 11.8 mg/dl. The degree of underestimation increased as the triglyceride level increased (p<0.05). Age within the fifth and sixth decades resulted in significantly higher differences compared with age in the eighth decade or greater (p<0.05). Female sex and elevated body mass index also resulted in increased discrepancies between the two methods (p<0.05 for both). Seventy-six percent of the lipid profiles were derived from patients with coronary heart disease (CHD) or a CHD risk equivalent. Approximately one half of these patients met their LDL goal when LDL level was measured versus calculated (p<0.0001).

[B]Conclusion: When compared with D-LDL, an underestimation of approximately 20 mg/dl was found with C-LDL, resulting in a loss of LDL goal attainment for half of the patients with CHD or a CHD risk equivalent.

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