WSJ Article on the Recent Zocor Trial

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Reassessing a Popular Cholesterol Drug

Findings on ZOCOR offer Insight Into Role of Statins; Impact on

High-Risk Patients

BY RON WINSLOW

IN A RARE SETBACK for a member of the class of cholesterol drugs

called statins, Zocor failed in a large study to show a benefit for

very high-risk heart patients while increasing their chances of

developing a rare but dangerous side effect.

The findings of the trial in which patients were treated

aggressively with 80 milligrams of Zocor raised a caution flag

for patients taking high doses of .statins They also offered fresh

insight into the role of statins in treating cardiovascular

disease.

The study is likely to steer some doctors treating severely

ill patients to drugs other than Zocor.

In particular, Pfizer Inc.'s rival statin Lipitor, the largest

sellling drug in the world, could benefit.

Nissen, a cardiologist at the Cleveland Clinic said doctors

should use the 80-milligrm dose of Zocor

tested in the trial with caution in light of the side effect

especially since " other effective agents are available. "

However, researchers said the findings don't alter the

fundamental message to come out of other recent studies that when it

comes to LDL cholesterol, lower is better. And the trial doesn't

undercut the safety or effectiveness of Zocor for the majority of

patients. The study didn't look at the most common use of Zocor in

patients with elevated risk of a heart attack or other

cardiovascular problems who take 20 to 40 milligrams a day.

In addition, researchers said the new study appears to

strengthen the case that statins work not only by lowering LDL but

also by cooling down inflamed coronary arteries that are prone to

rupture and cause heart attacks.

The 4,500-patient study, which was presented at the annual

meetng of the European Society of

Cardiology in Munich, Germany, and Published simultaneously On-line

by the Journal of the American Medical

Association tested an aggressive cholesterol lowering strategy

compared with a moderate approach

for patients hospitalized with severe unstabe chest pain. The

aggressive treatment was 40 milligrams of

Zocor

for one month, followed by 80 milligrams for the next 23 months.

The moderate approach was four months

of placebo followed by 20 milligrams of Zocor.

In a similar study reported just last March, Pftzer Inc.'s

Lipitor at 80 milligrams, its highest dose,

proved significantly more effective in reducing both LDL and the risk

of serious heart problems than

Bristol-Myers Squibb Co.'s pravachol at 40 milligrams. Indeed, the

benefit for Lipito was evident

within 30 days of starting the drug, and the study was an important

reason why cardiology experts in July

recommended that doctors consider aggressive therapy with statins to

enable patients at very high risk

of heart attacks to reduce their levels of LDL, or bad cholesterol,

to below 70. Previously, the target for such

patients was below 100. Moreover, there weren't any serious cases of

muscle side effects in that study.

Cardiologists expected aggressive treatment with Zocor to

reflect the Lipitor findings, especially

since the control group was treated with a placebo or dummy pill

during the first four months of the two-year trial.

Study Findings

High risks patients taking 80 milligram doses of Zocor

experienced:

& #61623; No heart health benefit after four

months

& #61623; No significant benefit after two years

& #61623; More cases of significant muscle pain called myopathy

& #61623; Three cases of rhabdomyolysis, a rare but severe muscle wasting

disease

But despite slashing their LDL levels to 62, aggressively treated

patients at the end of four months had no difference in heart

attacks, death from heart attacks, strokes or hospital readmissions

for heart problems than patients on placebo whose LDL was twice as

high.

After two years, 14.4% patients on aggressive therapy had suffered

negative outcomes compared to 16.70/o on the moderate regimen, but

the difference wasn't considered statistically significant.

" We don't feel our data strongly support 80 milligrams of simvastatin

in this case, " said Blazing, a Duke University cardiologist

and co-lead investigator of the study. Simvastatin is the generic

name for Zocor.

In addition, nine patients on the aggressive treatment

experienced significant muscle pain called myopathy, including three

who had rhabdomyolysis, a rare but severe muscle-wasting condition

that can be fatal. One patient in the moderate treatment suffered

from myopathy. The rate of myopathy among the 80 milligram patients

was 0.4%, consistent with known rates of the side effect with the

drug, but, especially with the three serious cases of rhabdomyolysis,

it raised concern.

W. Bilheimer, a vice president for medical affairs at Merck,

said he was " disappointed " that the study didn't show a benefit for

Zocor and argued that a variety of mitigating factors may have

affected the findings-including fewer than expected poor outcomes in

the control group that left the study underpowered statistically to

demonstrate advantages for high-doses of the drug.

So why weren't the results of the two studies similar? The smaller-

than-expected number of adverse events in the control group is one

possible explanation. Differences in the patients in the two studies

is another: the Zocor patients began treatment within 3.5 days of

admission to the hospital for unstable chest pain known as acute

coronary syndrome. The patients in the March trial waited until

about 10 days, when the effects of their heart problems were likely

significantly more stable.

Meanwhile, the lack of an early benefit was particularly

puzzling. But one possible explanation is the effects statins may

have on inflammation. In the first trial, the levels of a marker of

inflammation called high-sensitivity c-reactive protein was 38

percentage points lower in the Lipitor patients than those on the

moderate strategy. In the Zocor study, the difference was just 17%-

and there wasn't any difference at all after one month, despite a

sharp drop in LDL cholesterol. While differences in the patients

make comparisons speculative, researchers think it is possible

Lipitor's more potent anti-inflammatory effect, rather than LDL

lowering, may be behind the better results in the earlier study.

The new results are " a very interesting finding. that is

tilting our focus toward the anti-inflammation component of statins, "

said Cannon, a cardiologist at Brigham & Women's

Hospital, who led the earlier trial. " It looks like it may be just

as important as treating LDL to the goal. "

Dr. Nissen added. that it is possible anti-inflammatory

effects explain the early benefit of an aggressive treatment

reginlen, while getting LDL down is what 'keeps patients out of

trouble over the long term.

.. Meanwhile, in an editorial accompanying the JAMA paper, Dr. Nissen

said that Merck could have signaled for clinicians earlier that 80

milligrams of Zocor " might border on the toxic threshold " had it

published in scientific journals the fact that its testing of 160

milligrams had turned up muscle side effects at such troublesome

levels it dropped plans to develop that dose. Merck says it

disclosed the findings in a press release in 1997.

A larger study comparing 80 milligrams vs. 20 milligrams of Zocor in

stable patients is currently underway and may shed more light on just

how serious an issue the muscle side effect is for the 80 milligram

version.