Friday, September 3, 2004

A to Z, Z Phase: More Is Not Necessarily Better for Statin
By Pat French

For patients with unstable angina or heart attack, early and aggressive treatment with a higher dose of the “statin” drug simvastatin does not improve outcomes significantly and is associated with more adverse muscular effects compared with less aggressive treatment, according to a recent DCRI trial.

Led by the DCRI’s Dr. Michael Blazing, the Z Phase of the Aggrastat (tirofiban) to Zocor (simvastatin) study (A to Z) enrolled 4497 patients at 322 centers in 41 countries. Some of these had participated in the A phase the trial, which tested anticoagulation with enoxaparin versus heparin in patients with recent acute coronary syndromes (ACS, unstable angina or heart attack). The Z-phase patients, who also were required to have a cholesterol level ≤ 250 mg/dL, were randomly assigned to receive 1) 40 mg of simvastatin daily for 1 month, followed by 80 mg daily or 2) placebo for 4 months, followed by 20 mg of simvastatin daily.

Michael A. Blazing, MD

Over the median follow-up period of almost 2 years, patients who received the statin-only regimen showed no significant difference in the primary end point—cardiovascular death, heart attack, readmission for ACS, or stroke—compared with patients given the placebo followed by lower-dose statin (14.4% vs. 16.7%, respectively; P=0.14). In a secondary analysis, patients in the statin-only group did do significantly better than those in the placebo/statin group between 4 months after randomization and the rest of the study period (6.8% vs. 9.3%; P=0.02).

Of note, the lack of significant difference in the primary endpoint occurred despite the fact that the statin-only group showed significant reductions in total cholesterol and low-density lipoprotein (LDL), the “bad” cholesterol, at 1, 4, 8, and 24 months.

A major adverse effect associated with statin drugs is muscular complications. By 6 months, similar numbers of patients in the statin-only (1.8%) and placebo/statin groups (1.5%) had stopped taking their assigned treatment because of muscle-related complaints. A total of 10 patients showed evidence of muscle damage (0.22%); 9 were in the statin-only group and 1 was in the placebo/statin group. Three of the 9 patients with muscle damage in the statin-only group met the definition for rhabdomyolysis, a rare condition in which the muscle cells are destroyed.

In addition, although the overall rate was very low, more than twice as many patients in the statin-only group showed high levels of liver enzymes on 2 consecutive measurements (0.9% vs. 0.4%, P=0.05), indicating that their liver function had been impaired.

During a press conference at the European Society of Cardiology Congress 2004, where the results were first presented, Blazing stated, "We do not feel that our data strongly support the use of simvastatin 80 mg. But stronger doses of other statins have been studied and have shown evidence of demonstrating benefit.”

Accordingly, in the full results published online in the Journal of the American Medical Association, the A to Z Steering Committee recommended that physicians start patients with ACS on statins early during treatment, and consider using doses higher than the traditional levels, but also reduce the dose or stop the drug if major side effects occur.

Other DCRI staff involved the Z phase of the A to Z trial include Dawn Bailey, Rob Califf, Marianna Chambliss, Tia Denby-Ulmer, Miriam Donohue, Arleen Eppinger, Laura H. Gardner, Ghazala Haque, Lynn Harrelson, Vic Hasselblad, Kenneth Mahaffey, Craig McLendon, Carmel Scharenbroich, Phillip Smith, and Kim Travis. The trial was funded by Merck & Company.