Early statin therapy: Do let that door hit you on the way out

There is now substantial evidence that treatment with statins improves clinical outcomes in patients with acute as well as chronic coronary heart disease, and in older¹ as well as younger patients. Debate continues, however, as to the merit of more intensive lipid lowering with a high-dose statin compared with standard-dose therapy.

In the research presented in this issue, Hulten and colleagues conducted a meta-analysis of 13 randomized, controlled clinical trials involving 17,963 patients to evaluate the effect of intensive statin therapy begun within 14 days of acute coronary syndrome (ACS) on cardiovascular death, recurrent ischemia, and recurrent nonfatal myocardial infarction. Outcomes for the 13 trials in the study were pooled with meta-analysis using hazard ratios and survival curves. Nine of the trials compared statins to placebo, 2 compared intensive and less intensive regimens, and 2 compared intensive statin therapy to usual care. The authors found a significant benefit of intensive statin therapy (24% hazard reduction) at 6 months (but not at 4 months) and that the benefit remained significant throughout the 2 years of follow-up. Benefits extended beyond what could be explained by low-density lipoprotein cholesterol (LDL-C) reduction alone, and the authors hypothesized that the additional benefit resulted from pleiotropic effects of the statins. Intensive statin therapy had comparable adverse events as usual care, although slightly higher rates of asymptomatic aspartate aminotransferase/alanine aminotransferase elevations were noted.

The findings of this meta-analysis support the results of recent clinical trials and another meta-analysis involving 27,548 patients from 4 large clinical outcomes trials of patients with stable cardiovascular disease and those with ACS.² Although this meta-analysis found a benefit at 6 months but not at 4 months, the large clinical outcome trial, PROVE-IT—TIMI 22, showed clinical benefit as early as 30 days, with a significant reduction in adverse cardiovascular events (all-cause mortality, myocardial infarction, unstable angina requiring rehospitalization, revascularization performed 30 days postrandomization, or stroke) as early as 4 months.³

The findings of a benefit beyond that explained by the LDL-C lowering effects of statins are consistent with those from the PROVE-IT—TIMI 22 study in which patients who had high-sensitivity C-reactive protein (hs-CRP) reductions (< 2 mg/dL) in addition to LDL-C reductions derived additional benefit. The early benefits of statin may be related to their pleiotropic effects, since in PROVE-IT–TIMI 22 those patients who achieved the lowest LDL and the lowest hs-CRP levels at 30 days after ACS had the lowest risk of acute cardiac events.

The finding that aggressive LDL-C reduction was safe is important since concerns have been raised about the safety of aggressive LDL-C lowering. However, this too was addressed in another meta-analysis^2,4 in which the investigators found that intensive statin therapy reduced cardiovascular events and that very low levels of LDL-C could be achieved safely.

The take-home message of this study is that statin therapy begun early following ACS reduces cardiovascular events and that such therapy is safe. Patients with ACS should receive aggressive LDL-C lowering therapy with a statin, and therapy should be initiated prior to hospital discharge.