Statins started early after an acute coronary syndrome event at dosages above typical starting dose may help reduce future cardiovascular events, but may also increase risk for myopathy, according to an article released online August 30th by the Journal of the American Medical Association. The study from which the present results were derived, Phase Z of the A to Z trial, was designed to evaluate a strategy of early initiation of intensive treatment with simvastatin in acute coronary syndrome patients compared with a delayed, less intensive strategy.

The authors noted that previous clinical trials evaluating statins enrolled patients who were stable for several months following their coronary events.

James A. de Lemos, MD, and his colleagues from the A to Z trial, enrolled 4,497 patients with an acute coronary syndrome event 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. Patients were randomized to either an early intensive statin strategy (40mg/day simvastatin for 30 days and 80 mg/day simvastatin thereafter) or to a less aggressive strategy (placebo for 4 months and 20 mg/day 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 study drug initiation, at months 1, 4, 8 and then every 4 months until trial completion. Patients were followed for at least 6 months and up to 2 years.

“In the placebo plus simvastatin group, median low-density lipoprotein 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 reported. “In the simvastatin only group, the median low-density lipoprotein 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 primary end point of cardiovascular death, myocardial infarction, readmission for acute coronary syndrome, 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 noted 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 acute coronary syndrome 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 low-density lipoprotein 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 low-density lipoprotein cholesterol lowering following acute coronary syndrome to prevent death and major cardiovascular events. Statins should be initiated early after acute coronary syndrome, with consideration of dosages well above the typical starting dose, and they should be down-titrated or discontinued if important adverse effects, such as myopathy or significant liver abnormalities, develop.”

In an accompanying editorial, Steven E. Nissen, MD, wrote “Phase Z of the Aggrastat to (A to Z) Zocor Trial published in this issue of JAMA, is to date the largest trial testing the effects of aggressive statin therapy in acute coronary syndrome. … The high dose regimen failed to show a statistically significant benefit for reducing the primary composite endpoint of cardiovascular death, myocardial infarction, readmission for acute coronary syndrome, or stroke. In addition, the high-dose simvastatin regimen was associated with an unusually high rate of myopathy.”

“It is important to reassure practicing physicians and patients 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 acute coronary syndrome patients. 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 up to 40 mg/day has shown excellent safety and efficacy in a series of clinical trials. For now, though, the 80 mg/day dose of simvastatin should be used with caution, particularly because other effective agents are available. Finally, in an era when criticism of selective reporting of positive trial results is common, the A to Z investigators are to be commended for their prompt and thorough reporting of a critically important major trial that did not meet its original objectives.”