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Getting LDL cholesterol down

Clinical bottom line

The evidence from large clinical trials suggests that coronary events are highly correlated with the level of LDL cholesterol, and that lowering LDL cholesterol is a very good idea. A good target is LDL cholesterol below 2 mmol/L.


Reference

JC LaRosa et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. New England Journal of Medicine 2006 352: 1425-1435.

Background

Many studies have demonstrated that lipid lowering is reduces a number of vascular events, like heart attack and stroke, especially where there is pre-existing heart disease. The degree by which cholesterol, and especially low density cholesterol, needs to be lowered is less well characterised. This study was a large randomised comparison of low and high doses of atorvastatin in patients with established coronary disease, to investigate whether there was any benefit from more intensive therapy.

Study

The trial enrolled 10,001 men and women aged 35-75 years with clinical evidence coronary heart disease (previous heart attack, angina, or history of revascularisation procedures). To be randomised, they had to have a LDL cholesterol level of between 3.4 and 6.5 mmol/L in a washout period without lipid lowering drugs, and entered an open run in period on 10 mg atorvastatin daily for eight weeks. Those with an LDL cholesterol level of less than 3.4 mmol/L were then randomised to either 10 mg daily or 80 mg daily for up to six years.

The primary outcome was occurrence of a major cardiovascular event, including death from coronary heart disease, non-fatal procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or non-fatal stroke.

Results

At baseline patents had an average age of 61 years, were 80% male, and 94% white, with an average body mass index of 28 kg/sq metre. Baseline LDL cholesterol was 4.5 mmol/L, LDL cholesterol 2.5 mmol/L, and HDL cholesterol 1.2 mmol/L. The median duration of follow up was 4.9 years.

Before the run in period on 10 mg atorvastatin, the mean LDL cholesterol level was 3.9 mmol/L, which fell to a mean of 2.6 mmol/L on 10 mg atorvastatin daily. LDL cholesterol did not change further in to 10 mg group, but fell to 2.0 mmol/L on 80 mg atorvastatin daily.

The primary outcome occurred significantly less frequently with 80 mg of atorvastatin compared with 10 mg, with an NNT of 44 (Table 1). Hospital admission for heart failure was also lower, as was the outcome of any cardiovascular event. All cause mortality was not significantly different.

Table 1: Main outcomes of the trial

 
Percent with atorvastatin
 
Event
10 mg
80 mg
Relative risk
(95% CI)
NNTp
(95% CI)
Total major cardiovascular events
10.9
8.7
0.79 (0.70 to 0.89)
44 (29 to 92)
Hospital admission for heart failure
3.3
2.4
0.75 (0.60 to 0.94)
120 (67 to 550)
All cause mortality
5.6
5.7
1.0 (0.6 to 1.2)
not calculated
Any cardiovascular event
33.5
28.1
0.84 (0.79 to 0.89)
19 (14 to 28)

 

Adverse events

Adverse events of all types occurred more frequently with the higher dose (8.1%) than the lower (5.8%). Myalgia was not different between the groups, with about 4.8% affected with both doses. Rhabdomyolysis occurred in two patients on 80 mg and three on 10 mg. Elevated liver enzymes were more common with the higher dose.

Comment

This is a large and well-conducted trial in people with established coronary heart disease. It shows that more intensive therapy has additional benefits over less intensive therapy, with an additional 24% reduction in LDL cholesterol.

Perhaps the most impressive result comes in the discussion of this paper, which shows the relationship between LDL cholesterol and event rates for some of the large randomised trials (including 4S, CARE, LIPID, and HPS; Figure 1). It shows that with LDL cholesterol above 2 mmol/L, event rates can still be high, even on treatment. This does suggest that 2 mmol/L should be the target for LDL cholesterol on statin treatment, and that lowering levels well below current guidelines can have clinical benefit.

Figure 1: Relationship between LDL cholesterol and event rate in large randomised trials (including active and placebo treatment groups)