Intensive lipid-lowering therapy

[Back after a two-month hiatus, due to busy practice, vacation, and time spent/wasted playing with video editing software and a new camcorder…]

In this week’s NEJM, Intensive lipid lowering with atorvastatin in patients with stable coronary disease makes an argument in favor of reducing LDL cholesterol levels for secondary prevention to lower than the current guidelines of 100 mg/dl. Although this may well be justified, the data presented here do not quite make the case but are spun with great skill.

15,464 patients with clinically evident coronary disease and LDL levels between 130 and 250 mg/dl off statin therapy were treated for 8 weeks with 10 mg of atorvastatin. At the end of this period, 10,003 patients whose LDL levels were lowered to under 130 mg/dl were randomized to continue the atorvastatin at 10 mg daily or to 80 mg of atorvastatin daily.

Patients on the 10 mg dose of atorvastatin achieved a mean LDL level of 101 mg/dl; those randomized to 80 mg had their LDL levels reduced to 77 mg/dl. During median follow-up of 4.9 years, there was a significant reduction in cardiovascular events, although not in overall mortality, on the higher dose of atorvastatin.

The problem with the interpretation of these results is that an average LDL level of 100 mg/dl achieved with a fixed, 10 mg dose of atorvastatin is not the same thing as targetting an LDL level of 100 mg/dl (with adjusted statin doses). Since patients in the 10 mg group were only required to have LDL levels under 130 mg/dl, the average level of 100 implies that about half of the patients had levels between 100 and 130. Targetting an LDL level of 100 mg/dl with adjusted doses of a statin would certainly narrow the distribution of values obtained, and would most likely lower the number of patients whose LDL’s were closer to 130 mg/dl.

So what does this study actually show? It demonstrates that CHD patients who achieve LDL levels of less than 130 mg/dl on a dose of 10 mg of atorvastatin have more cardiovascular events than those who are assigned to 80 mg of the drug. Not very surprising. Once again, even though the 10 mg patients studied here achieved an average LDL level of 100 mg/dl, this is a less aggressive approach than actually targetting 100 mg/dl. The LDL target of 100 mg/dl is not given a fair chance in this study.

What do the authors say about their study? In the abstract, they state:

“Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day.”

This statement is justified by the data. But in the Methods section, they state:

“The occurrence of major cardiovascular outcomes was compared in two groups of patients: one group received 10 mg of atorvastatin daily with the goal of an average LDL cholesterol level of 100 mg per deciliter, and the other group received 80 mg of atorvastatin daily with the goal of an average LDL cholesterol level of 75 mg per deciliter.”

This is very fine tap-dancing. The authors carefully avoid saying that the goal LDL level in the 10 mg group was 100 mg/dl, since it wasn’t; rather, they state that the goal in that group was an average LDL cholesterol level of 100 mg/dl. Subtle but significant difference, as noted above. They further blur the distinction between average LDL level achieved and actual targetted LDL level in the final sentences of their paper:

“In summary, our findings demonstrate that the use of an 80-mg dose of atorvastatin to reduce LDL cholesterol levels to 77 mg per deciliter provides additional clinical benefit in patients with stable CHD that is perceived to be well controlled at an LDL level of approximately 100 mg per deciliter. These data confirm and extend the growing body of evidence indicating that lowering LDL cholesterol levels well below currently recommended levels can have clinical benefit.”

It would be very interesting to see how the subgroup that actually achieved an LDL level of 100 or less on the 10 mg atorvastatin dose (presumably half the study group) fared in this trial. I would bet that the difference in event rates is markedly reduced or nil in this subgroup. And I would bet that this information will not be published.



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