Evaluation of early versus delayed initiation of simvastatin in patients who receive guideline based treatment for acute coronary syndrome - A to Z, Phase Z

Description:

The goal of the trial was to evaluate the safety and efficacy of early initiation of high-dose statin therapy with a more conservative, delayed low-dose statin strategy in high-risk patients with acute coronary syndrome (ACS).

Hypothesis:

Early initiation of high-dose statin therapy will be associated with a reduction in long-term cardiac events compared with a more conservative, delayed low-dose statin strategy in high-risk patients with ACS.

Study Design

Patients Enrolled: 4,497
Mean Follow Up: Two years
Mean Patient Age: Median age 61 years
Female: 25

Patient Populations:

Age 21-80 years, treatment with optimal guideline recommended ACS therapy, total cholesterol <250 mg/dl, and at least one additional risk factor

Exclusions:

Patients not stable within 120 hours, current treatment with statin therapy, no coronary artery disease on catheterization, planned CABG, or serum creatinine >2.0 mg/dl

Primary Endpoints:

Composite of cardiovascular death, myocardial infarction, stroke, or readmission of an ACS

Secondary Endpoints:

Individual components of the primary endpoint, revascularization due to documented ischemia, all-cause mortality, new-onset congestive heart failure (requiring admission or initiation of heart failure medications), and cardiovascular rehospitalization

Drug/Procedures Used:

A total of 4,497 patients with a recent ACS event were enrolled in the A to Z trial. The A phase of the trial, which has been previously published, randomized patients to either unfractionated heparin or enoxaparin, and all patients were treated with tirofiban. In the Z phase, patients were randomized to either intensive statin therapy strategy (n=2,265) with simvastatin 40 mg from enrollment to one month, followed by simvastatin 80 mg through two years or the conservative statin therapy strategy (n=2,232), with placebo for four months followed by simvastatin 20 mg through two years.

Principal Findings:

Per the inclusion criteria, the majority of patients were on optimal therapy for ACS management, including aspirin (98%), beta-blocker (90%), and ACE inhibitor (75%). Percutaneous coronary intervention was performed in 44% of patients. Low-density lipoprotein (LDL) at four months was lower in the simvastatin 40/80 mg group compared with the placebo/simvastatin 20 mg group (1.8 vs. 3.2 mmol/l, p<0.001), a difference that was smaller but remained at the 24-month follow-up (1.7 vs. 2.1 mmol/l, p<0.001). C-reactive protein did not differ at one month (2.4 vs. 2.5 mg/l, p=NS), but was also lower in the simvastatin 40/80 mg group at the four-month timepoint (1.7 vs. 2.3 mg/l, p<0.001) and the eight-month timepoint (1.5 vs. 1.8 mg/l, p<0.001).

The difference in the primary composite endpoint did not differ significantly by treatment strategy (14.4% for simvastatin 40/80 mg vs. 16.7% for placebo/simvastatin 20 mg, hazard ratio [HR] 0.89, p=0.14). Cardiovascular mortality was lower in the simvastatin 40/80 group (4.1% vs. 5.4%, HR 0.75, p=0.05), but there were no differences in cardiac events including myocardial infarction (7.1% vs. 7.4%, p=0.74), readmission for ACS (4.9% vs. 5.0%, p=0.97), or coronary revascularization due to ischemia (5.9% vs. 6.2%, p=0.60). Congestive heart failure was lower in the simvastatin 40/80 group (3.7% vs. 5.0%, HR 0.72, p=0.04).

The event-free survival curves for the primary endpoint began to diverge after four months when the 80 mg dose of simvastatin was initiated in the intensive strategy. In a post-hoc analysis evaluating events after four months, the primary composite endpoint was lower in the intensive group compared with the simvastatin 20 mg group (6.8% vs. 9.3%, HR 0.75, p=0.02).

Discontinuation of study medication for AST or ALT elevation >3x the upper limit of normal was 0.9% in the simvastatin 40/80 group and 0.4% in the placebo/simvastatin 20 group (p=0.05). Myopathy, while rare, occurred more frequently in the simvastatin 40/80 group (0.4% vs. 0.04%, p=0.02). Three of the nine cases of myopathy met the criteria for rhabdomyolysis.

Interpretation:

Among high-risk patients with ACS, treatment with early initiation of high-dose statin therapy was not associated with a significant reduction in the primary composite endpoint of cardiovascular events compared with a more conservative, delayed low-dose statin strategy, despite an early and sustained reduction in LDL. However, a post-hoc analysis of events beyond four months when all patients were on simvastatin, but at different doses demonstrated a reduction in the primary endpoint in the high-dose group.

At the time the study was designed, there were no data on the safety of high-dose statin therapy during the early time after an ACS event, which led the trial investigators to select a 40 mg dose for the first month after the index event. Trials reported after this study was designed, such as PROVE IT-TIMI 22, demonstrated that early aggressive lipid lowering was associated with a reduction in cardiovascular events.

The present trial, while trending in favor of an early aggressive strategy, was underpowered to detect a difference because there were only 652 events, lower than the expected 970 events. Given the higher rate of myopathy and the small number, but serious cases of rhabdomyolysis in the simvastatin 80 mg group, patients should be carefully monitored when receiving this dose.

References:

de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004;292:1307-16.

Blazing, MA. Z phase of the A to Z trial: evaluation of early versus delayed initiation of simvastatin in patients who receive guideline based treatment for acute coronary syndrome. Paper presented at the European Society of Cardiology Congress 2004, 29 August-1 September, Munich, Germany.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, ACS and Cardiac Biomarkers, Anticoagulation Management and ACS, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and ACS

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Heparin, Coronary Disease, Simvastatin, Tyrosine, Percutaneous Coronary Intervention, Rhabdomyolysis, Lipoproteins, LDL, Cholesterol, C-Reactive Protein, Enoxaparin, Heart Failure


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