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Disapointment with Simvastatin

High-dose Zocor fails to meet endpoints

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Updated September 06, 2004

Updated September 06, 2004
By DrRich

This week, at the European Society of Cardiology meetings in Munich, investigators reported that high-dose simvastatin (Zocor, Merck) failed to significantly lower the risk of death, heart attack, hospital readmission or stroke, in patients having angioplasty and/or stenting. This result must be considered a disappointment, especially in light of the recent PROVE-IT trial, showing that high-dose atorvastatin (Lipitor, Pfizer) did significantly reduce similar endpoints. Investigators and others medical observers are scrambling to explain these results.

In the A to Z trial, nearly 4500 patients admitted to the hospital for angioplasty and/or stenting were randomized to receive either early high-dose therapy with simvastatin (80 mg per day), or conservative therapy (4 months of placebo followed by low-dose simvastatin using 20 mg per day.) The average baseline LDL cholesterol levels in both groups was 112 mg/dL. In the high-dose group, the average LDL cholesterol level was reduced to 62 mg/dL, whereas in the control group the LDL levels were not reduced at all at 4 months, and reached 82 mg/dL at 8 months. Despite the very low LDL levels achieved in the high-dose group, while there was a trend toward clinical benefit in the high-dose group as compared to the low-dose group, that trend did not reach statistical significance.

Furthermore, 9 patients in the high-dose simvastatin group (compared to 1 patient in the low-dose group) developed muscle toxicity requiring the drug to be discontinued. Three of these had rhabdomyolysis - a condition in which enough muscle damage occurs to be considered potentially life-threatening. In contrast, in the PROVE-IT trial, no muscle toxicity was seen with high-dose atorvastatin.

Investigators, and the accompanying press release, offered that the results from the A to Z trial actually confirm the results of the PROVE-IT trial - that is, high-dose statin therapy that significantly reduces LDL cholesterol improves clinical outcomes. They reach this interpretation because high-dose simvastatin showed a tendency toward improving outcomes (though statistical significance was not reached.) Thus, taken together, these two major clinical trials both point toward supporting a "the lower the better" strategy regarding LDL cholesterol. However, the fact remains that - with similar resulting LDL levels - high-dose atorvastatin yielded significant clinical benefit while high-dose simvastatin did not.

DrRich Comments

While DrRich agrees that it still appears true that very low LDL levels are better than merely low LDL levels (a hypothesis recently endorsed by the NCEP panel.) Yet, these new results suggest that it makes a difference as to whether you achieve those very low levels with atorvastatin or simvastatin. Though the investigators and other top scientists may be reluctant to say so, DrRich is struck by the evidence that these two drugs are not equally effective or equally safe when used in high doses.

These drugs have different effects on high-sensitivity CRP levels(a measure of inflammation.) So in explaining the differences in outcome it may be important that high-dose atorvastatin achieved a much more impressive reduction in CRP levels (a 35 - 38% reduction) than did high-dose simvastatin (a 17% reduction.) It may be that high-dose atorvastatin achieved an early clinical response more by reducing inflammation than by reducing cholesterol levels.

Furthermore, these drugs appear to differ in their propensity to cause muscle toxicity in high doses, with simvastatin being apparently much more likely to produce this problem.

Whatever the explanation for the difference, it is becoming clearer and clearer to DrRich that, contrary to the beliefs of the people who compile HMO drug formularies, the statins are not all equal.

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