Early use of aggressive statin therapy may offer some benefit for coronary patients

Statins initiated early after a patient experiences an acute coronary syndrome (ACS) event at dosages above the typical starting dose may help reduce subsequent cardiovascular events, but the high dose regimen used may increase the risk for muscle-related complications, according to the results from the Phase Z portion of the A to Z Trial released on the JAMA website today.

According to background information in the article, “Long-term therapy with statin drugs has been shown to reduce the risk for death, myocardial infarction (MI) [heart attack], and stroke among patients with established coronary artery disease, even when low-density lipoproteins (LDL) cholesterol levels are not elevated.” The authors write that previous clinical trials evaluating statins enrolled patients who were stable for several months following their coronary events. “Phase Z of the A to Z trial was designed to evaluate a strategy of early initiation of intensive treatment with simvastatin in ACS patients compared with a delayed, less intensive strategy.”

James A. de Lemos, M.D., from University of Texas Southwestern Medical Center, Dallas, and colleagues from the A to Z trial, enrolled 4, 497 patients with ACS between December 29, 1999 and January 6, 2003 at 322 centers in 41 countries. The average time from symptom onset to randomization in phase Z was 3.7 days. The patients were randomized to either an early intensive statin treatment strategy (40mg/per day of simvastatin for 30 days and then 80 mg/d of simvastatin thereafter) or to a less aggressive strategy (placebo for 4 months and then 20 mg/d of simvastatin thereafter). There were 2,265 patients in the early intensive treatment group and 2,232 in the less aggressive treatment group. Clinical and laboratory assessments (including, lipid levels, high sensitivity C-reactive protein serum chemistries, and liver function tests) were performed prior to the study drug initiation and at months 1, 4, 8 and then every four months until the trial completion. Patients were followed-up for at least 6 months and up to 2 years.

“In the placebo plus simvastatin group, median LDL cholesterol levels increased by 11 percent during the 4-month placebo period from 111mg/dL to 124 mg/dL and then decreased to 77 mg/dL at month 8 after the initiation of 20 mg of simvastatin (31 percent change from baseline),” the researchers report. “In the simvastatin only group, the median LDL cholesterol level decreased by 39 percent to 68 mg/dL over the first month during treatment with 40 mg/d of simvastatin and then decreased an additional 6 percent to 62 mg/dL at month 4 following the increase to the 80 mg/d of simvastatin.” The researchers continue, “the primary end point of cardiovascular death, MI, readmission for ACS, and stroke occurred in 343 patients (16.7 percent) in the placebo plus simvastatin group compared with 309 (14.4 percent) in the simvastatin only group.” The researchers also note a high level of participants discontinued use of the study drugs for various reasons, including a low number of muscle-related adverse events.

“The traditional approach to lipid management following ACS has been to begin with dietary management and then to initiate a statin agent at a low dose and increase the dose stepwise to achieve target LDL cholesterol levels. The findings from the A to Z trial, as well as from MIRACL and PROVE IT [previous intensive statin therapy trials], support a strategy of aggressive LDL cholesterol lowering following ACS to prevent death and major cardiovascular events. Statins should be initiated early after ACS, with consideration of dosages well above the typical starting dose, and they should be down-titrated [decreased] or discontinued if important adverse effects, such as myopathy or significant liver abnormalities develop.”