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Statin drugs for most adults - a matter of concern
(February 2005)

Two recent reports suggest that a very large proportion of the adult population should be taking statin drugs. Both studies compared a standard dose of pravastatin (Pravachol) with a very large dose of atorvastatin (Lipitor). The first study was published in the March3, 2004 issue of the Journal of the American Medical Association . All participants, average age 56years, had evidence of significant obstruction of at least one coronary blood vessel of the heart. Total cholesterol blood levels were moderately elevated at an average of 232milligrams per deciliter (normal less than 200milligrams); blood levels of the dangerous component of cholesterol, low-density lipoprotein cholesterol (LDL, bad cholesterol) were also moderately elevated at an average of 150milligrams (normal up to 130milligrams).

Pravachol, 40 milligrams, was given for 18 months to 249 participants and Lipitor 80milligrams was given to 253 participants. The two groups were well matched in regard to relevant variables at the start of the study. The main outcome measurement was progression of the obstruction, measured by threading a catheter into the area of obstruction and examining the area by an ultrasound test.

The results were dramatic. Pravachol, 40milligrams, reduced cholesterol and LDL levels by 18 and 25 percent, respectively; Lipitor, 80 milligrams, reduced cholesterol levels by 34 percent and LDL levels by 46 percent. The final cholesterol level in the Pravachol group was a low 188 milligrams, but in the Lipitor participants, it was a very low 151 milligrams. Those on Pravachol experienced some progression of obstruction during the followup period, whereas no disease progression was found in the Lipitor group. There was no evidence of an increase in adverse effects for those receiving the high Lipitor dose.

Although Lipitor, 80 milligrams, stopped progression for the total group when averaged, some patients showed actual regression of the obstruction and some showed progression.

The second study involved 4,612 patients hospitalized with a heart attack or severe heart pain. They were given either Pravachol, 40 milligrams or Lipitor (80 milligrams) and were followed for an average of two years to determine the occurrence of a new heart attack, death from coronary heart disease, severe heart pain requiring hospitalization, stroke, or required surgery for blocked arteries of the heart. At the beginning of the study, total cholesterol levels were low (180 milligrams per 100 milliliters of blood) and LDL, on average, was 106 milligrams. On Pravachol, LDL levels fell to 83 milligrams, on average, whereas with the larger dose of Lipitor, they were cut in half, to 52 milligrams, a highly significant difference.

Of those receiving Pravachol, 26.3 percent developed one of the severe cardiovascular events, compared to 22.4 percent of those on the large Lipitor dosage. That16 percent reduction on Lipitor was statistically highly significant. The greatest benefit was found for those whose LDL at the start of the study was at least 125 milligrams (high normal). They showed a 34 percent reduction in cardiovascular events, whereas among those with LDL levels below 125, there was only a 7 percent reduction.

Although serious side effects were not found, liver enzyme abnormalities were found three times as often in the high dose Lipitor group.

The authors note that, in patients with evidence of coronary heart disease, the goal is to get LDL levels to less than 100 milligrams, but, in this study, the best results were achieved when LDL concentrations were reduced to about half that level. The authors say that the 16percent reduction in cardiovascular events with the intensive high dose Lipitor treatment suggests that we have to re-evaluate the goals of treatment, use higher doses of statins, and try to get LDL levels to extraordinarily low levels.

Commentary: These are two interesting studies, but we should be cautious in urging intensive, high dose treatment as the standard. The tradeoff for a modest decrease in new cardiovascular events is likely to be increased adverse effects due to the higher dosage.

It is important to stress that these studies on intensive, high dose statins were carried out on people with established coronary heart disease, not on healthy people with borderline high or high total cholesterol and LDL levels. It is critical that careful studies be carried out on "healthy" persons to determine benefits and adverse effects before subjecting people without clinical evidence of coronary heart disease to high dose treatment. We still have a lot to learn about intensive statin treatment.

If long-term high dose intensive treatment is to be used routinely, we had better be sure we know the frequency of adverse and toxic effects of high doses.

Statin drugs are very effective in reducing total cholesterol and LDL levels. The usual dictum with medications is: use the smallest amount that is predictably effective. These studies turn that around completely, suggesting that very high doses of statins provide additional benefit (at least in people who already have established coronary heart disease). The statin enthusiasts argue that, in the United States, 36million people should be taking statins, but only 11million are actually taking the drugs. If the notion of high dose intensive statin therapy takes hold, that 36million figure could become much higher - we could see recommendations that the clear majority of adults over age 40 take statins. That would cost a huge amount of money. We had also better be careful that the adverse effects of high dose long-term statin treatment is properly evaluated.

Nissen, S.E., et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary arteriosclerosis. Journal of the American Medical Association. Vol291 (March3) Pgs1071-1080. 2004.

Cannon, C.P., et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. The New England Journal of Medicine. Vol350 (April8) Pgs1495-1504. 2004.

[see editorial this issue]

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