Early, intensive simvastatin does not reach endpoint

High dose linked to muscle-related adverse effects

Some physicians advocate early, aggressive therapy to help reduce low-density lipoprotein (LDL) cholesterol levels. One new study, however, indicates that patients treated with high-dose simvastatin (Zocor) did not show a significant reduction in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, readmission for acute coronary syndrome (ACS), and stroke. In addition, the higher dose was associated with an increased risk of muscle-related adverse events.

"Both the lack of efficacy and the unfavorable adverse event profile would seem improbable to those familiar with the statin clinical trial literature," says Steven E. Nissen, MD, medical director of the Cardiovascular Coordinating Center in the department of cardiovascular medicine at the Cleveland Clinic. He made his comments in an editorial that accompanied the published results of the study in the Sept. 15 issue of the Journal of the American Medical Association.

Two other trials have shown safety and efficacy of high-dose statins in ACS patients. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial compared 80 mg/d of atorvastatin (Lipitor) with placebo for four months in 3,086 patients and showed a 16% reduction in events. The Pravastatin or Atorvastatin Evaluation and Infection Therapy trial (PROVE IT) compared outcomes of 4,162 patients receiving 80 mg/d atorvastatin or 40 mg/d pravastatin (Pravachol) and also showed a significant 16% event reduction.

"It is hazardous to assume that similar agents always yield identical results," Nissen says. "While a class effect for statins is likely, each agent requires careful testing in clinical trials to establish the extent of benefit and risk."

The international, randomized, double-blind trial studied patients with ACS. One group of 2,265 patients received 40 mg/d of simvastatin for one month followed by 80 mg/d thereafter, compared with a group of 2,232 ACS patients receiving placebo for four months followed by 20 mg/d simvastatin. These patients were enrolled in phase Z of the A to Z trial between Dec. 29, 1999, and Jan. 6, 2003, and were followed up for at least six months and up to 24 months.

Among the patients in the placebo plus simvastatin group, the median LDL level was 122 mg/dL at one month while on placebo and 77 mg/dL at eight months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin only group, the median LDL level achieved at one month while taking 40 mg/d simvastatin was 68 mg/dL and 63 mg/dL at eight months while taking 80 mg/d simvastatin. A total of 343 patients (16.7%) in the placebo plus simvastatin group experienced the primary endpoint compared with 309 (14.4%) in the simvastatin-only group.

No difference was evident during the first four months between the groups for the primary endpoint, but from four months through the end of the study, the primary endpoint was significantly reduced in the simvastatin only group. Myopathy occurred in nine patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin, and in one patient receiving placebo.

Analyzing the risk-benefit ratio

Taken together, the MIRACL, PROVE IT, and A to Z trials "demonstrate that the beneficial effects of statin therapy in ACS cannot be predicted entirely from the degree of LDL cholesterol reduction," Nissen says. He notes that the difference in C-reactive protein between treatment subgroups in the MIRACL and PROVE IT trials was 34% and 37%, respectively at the end of the trials. In the A to Z trial, the between-group reduction was 16.7%.

"This finding suggests an intriguing hypothesis, specifically, that the early benefits of statin therapy are derived largely from the anti-inflammatory effects of the drugs; whereas, the delayed benefits are lipid-modulated," he explains.

Practicing physicians and patients need to be reassured that the unfavorable risk-benefit relationship observed in the A to Z trial does not in any way diminish the value of intensive statin treatment in secondary prevention, including ACS patients, Nissen says.

"There was a trend toward reduced events in the A to Z trial, a finding that supports the lower is better concept. The increased myopathy rate applies only to a specific dose of a single agent and should not tarnish this remarkable class of drugs. It must also be emphasized that simvastatin in doses of up to 40 mg/d has shown excellent safety and efficacy in a series of clinical trials. For now, though, the 80 mg/d dose of simvastatin should be used with caution, particularly because other effective agents are available."