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Another Outcomes Test of Intensive Statin Therapy After ACS

Simvastatin, at an intensive target dose of 80 mg/day, showed only trends toward benefit over a more conservative strategy in high-risk acute coronary syndrome patients.

Debate continues about the optimal statin strategy for acute coronary syndrome (ACS) patients. In phase Z (Zocor) of the A to Z trial, researchers randomized 4497 high-risk ACS patients to either early, intensive simvastatin therapy (40 mg/day for 1 month, 80 mg/day thereafter) or a conservative strategy (placebo for 4 months, 20 mg/day of simvastatin thereafter). Most subjects were discharged on other guideline-recommended therapies, including aspirin (98% of patients), beta-blockers (90%), and ACE inhibitors (71%). More than 40% of subjects underwent percutaneous coronary intervention before randomization. The mean baseline LDL level was about 112 mg/dL; the mean time from symptom onset to randomization was 3.7 days.

Mean LDL levels differed significantly between the conservative and intensive groups at 2 years (81 mg/dL vs. 66 mg/dL, respectively; P<0.001); the primary endpoint (cardiovascular death, MI, ACS readmission, or stroke) did not (16.7% vs. 14.4%, P=0.14). Secondary endpoints such as all-cause mortality also showed only nonsignificant trends toward benefit with intensive therapy. Similar proportions of the two groups discontinued the study drug, although the intensive group had more cases of liver-enzyme elevation (19 vs. 8), myopathy (9 vs. 1), and rhabdomyolysis (3 vs. 0). Predisposing factors and contraindications explained most of these side effects.

Comment: In high-risk ACS patients, intensive simvastatin therapy (target dose, 80 mg/day) showed only trends toward outcome benefits over a more conservative strategy. Potential explanations include inadequate early dose titration and low LDL levels achieved in both arms. As an editorialist notes, the early benefit of statins may derive largely from their anti-inflammatory effects; in this study, statin-related reductions in C-reactive protein levels were smaller than in the PROVE-IT trial (N Engl J Med 2004; 350:1495). Most side effects of statin therapy in the current trial occurred in patients with contraindications, which should always be assessed before treatment -- and monitoring of side effects during treatment remains crucial. We will learn more about the safety and relative benefits of intensive and moderate statin therapy from forthcoming trials that test more than one dose of the same drug.

— JoAnne M. Foody, MD

Published in Journal Watch Cardiology October 29, 2004

Citation(s):

de Lemos JA et al. for the A to Z Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: Phase Z of the A to Z trial. JAMA 2004 Sep 15; 292:1307-16.

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• Medline abstract (Free)

Nissen SE. High-dose statins in acute coronary syndromes: Not just lipid levels. JAMA 2004 Sep 15; 292:1365-7.

• Original article (Subscription may be required)
• Medline abstract (Free)