Statin use in acute coronary syndromes: The sooner, the better?

Recent randomized clinical trials have provided solid evidence that intensive HMG-CoA reductase inhibitor (statin) therapy is effective for secondary prevention for patients with acute coronary syndromes (ACS).1-3 In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, 3,086 ACS patients with non—ST-segment elevation myocardial infarction (MI) were randomly assigned to receive high-dose atorva-statin (Lipitor) 80 mg/day, or placebo.1 At the, 4-month follow-up, the combined end point of death, nonfatal MI, cardiac arrest, or recurrent ischemia was reduced by 16% (relative risk [RR], 0.84; 95% confidence interval [CI], 0.70–1.00;

P = .05). This benefit was primarily driven by lower recurrent ischemia. MIRACL did not incorporate all current ACS therapies. Patients with percutaneous coronary intervention (PCI) were excluded, and there was low use of glycoprotein IIb/IIIa receptor inhibitors and clopidogrel (Plavix). The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trial compared two statin regimens in over 4,000 ACS patients, contrasting moderate lipid lowering with pravastatin (Pravachol), 40 mg/day, versus intensive therapy with atorva-statin, 80 mg/day.2 Drugs were initiated around the time of discharge. After 2 years of follow-up, the intensive-treatment arm had a lower rate for the combined primary end point of death, nonfatal MI, unstable angina, and stroke compared with the moderate-treatment arm (reduced hazard ratio [HR], 16%; 95% CI, 0.05—0.26; P = .005). In contrast to the MIRACL trial, 69% of PROVE IT patients had revascularization before randomization. In the recent A to Z trial, nearly 4,500 ACS patients were randomly assigned to receive early intensive statin treatment (simvastatin [Zocor], 40 mg/day, for 30 days, followed by 80 mg/day) versus a delayed, less intensive statin regimen (placebo for 4 months, followed by simvastatin, 20 mg).3 Although there was no difference in the primary end point (cardiovascular death, nonfatal MI, stroke, or readmission for ACS) at 4 months, improved outcome was noted in the early intensive-dose statin group in the 4- to 24-month follow-up period (HR, 0.75; 95% CI, 0.60–0.95; P = .02). Concomitant therapy

in the A to Z trial was different from the

MIRACL and PROVE IT studies. A to Z and PROVE IT had high use of glycoprotein IIb/IIIa receptor blockers, but in A to Z, only 44% of patients had PCI before randomization.

These data strongly suggest that early intensive statin treatment should be routinely administered to high-risk ACS patients. This therapy appears effective when started after stabilization with antiplatelet agents, glycoprotein IIb/IIIa receptor blockers, and revascularization. Unknown from these trials, however, is the optimal timing for initiation of statin therapy in the setting of ACS (eg, immediately after hospital admission versus at discharge). In the MIRACL trial, the drug was started 24 to 96 hours (mean, 63 hours) after admission. In the PROVE IT trial, statins were begun at a median of 7 days after onset of ACS. In the A to Z study, the drug was started after initial stabilization for at least 12 hours but no longer than after 5 days (mean, 3.7 days).

Initiating very early statin treatment immediately on diagnosis of ACS may provide the added benefit. In an animal model of MI, pretreatment with a statin resulted in reduced ischemic injury.4 In the article by Kondapaneni and Spencer (page 35), results of the Global Registry of Acute Coronary Events (GRACE) study suggest an advantage to very early administration (within 48 hours) of statins in ACS patients. The GRACE registry tracked 19,537 ACS patients from 94 hospitals in 14 countries. Using a cohort study design, this observational study compared the effect of prehospital and in-hospital use of statins on short-term outcome for four groups of ACS patients: (1) patients taking statins prehospitalization who were continued on statins in the hospital, (2) patients taking statins prehospitalization who had statins discontinued after admission, (3) patients first started on statins in the hospital, and (4) patients who did not receive statins either before or during hospitalization. GRACE results showed that patients on statins both before and during hospitalization had less ST-segment elevation and fewer MIs. Furthermore, patients given statins in the hospital, with or without prehospital statin use, had less mortality compared with patients who never received statins before discharge (odds ratio [OR], 0.66; 95% CI, 0.56—0.77). In contrast, patients taking statins prehospitalization who had statins discontinued on admission had mortality rates similar to those who did not receive statins before or during hospitalization. Most important, patients started on statins in the hospital had less mortality and fewer combined adverse events (death, in-hospital MI, or stroke) compared with patients who did not receive statins before discharge (OR, 0.38; 95% CI, 0.30–0.48, and OR, 0.87; 95% CI, 0.78–0.97, respectively). These benefits were marginal, however, after adjustment for hospital of admission (OR, 0.81; 95% CI, 0.65–1.1).

The mechanisms by which prehospital and in-hospital statin treatment may benefit ACS patients may be the result of effects other than low-density lipoprotein (LDL) (pleiotropic) effects of this class of medications.5 Protective actions of statins may include enhanced endothelial function (upregulation of endothelial nitric oxide synthase, lower vascular cell adhesion molecule [VCAM], and intracellular adhesion molecule [ICAM]), anti-inflammatory effects (lower cytokine, interleukin [IL]-6, fi-brinogen, and C-reactive protein levels), lower metallomatrix proteinases, and reduced tissue factor expression. Thus far, however, clinical trials have not substantiated the non-LDL action of statins in the first few days of initiation of therapy. Patients in the Prevention of Ischemic Events by Early Treatment of Cerivastatin (PRINCESS) trial were randomly assigned to receive very early (within 48 hours) or late (after 3 months) statin therapy. The early statin treatment group failed to show reductions in fibrinogen, ICAM-1, VCAM-1, and IL-6 after 2 weeks.6 In the A to Z study, similar to the PRINCESS trial, the C-reactive protein levels did not differ in the early simvastatin (40 mg/day) group versus the placebo group at 30 days.

Because GRACE was a nonrandomized observational study, it is possible that the outcomes were the result of nonmeasured clinical variables or clinical differences that could not be accurately adjusted by standard statistical methods. The observation that patients taking statins prehospitalization had less ST-segment elevation MI may be because these patients were attuned to possible cardiac events and came to the hospital earlier and for more minor events. Better outcome for these ACS patients on statins prehospitalization may have been the result of faster diagnosis and treatment. Other potential confounding factors in GRACE include the intensity of

early medical and invasive strategies for ST-segment elevation MI and non—ST-segment elevation MI, as well as the intensity of risk reduction strategies following hospital discharge (treatment with antiplatelet agents, beta blocking agents, etc). Finally, not starting or discontinuing statins in the hospital may have been a marker for less intense care of ACS in general with a poorer outcome, whereas continuing or initiating statins may have been a marker for more intensive ACS care and a better outcome.

Clinical trials have established that intensive, high-dose statin therapy is beneficial after ACS (MIRACL and PROVE IT). Although the benefits of very early use of statins in the hospital for ACS patients have not been determined, their use appears to be safe. Even though the precise timing of initiation has not been established, it is clear that intensive statin therapy should be the standard of care before or at hospital discharge.