While the PROVE IT-TIMI 22 trial supported a specified dosing strategy for statin use following ACS, Phase Z of the A-to-Z trial was designed to evaluate the early initiation of intensive lipid lowering following ACS, as compared to a delayed and less-intensive strategy.5,6 Investigators randomized 4,497 patients (a mean of 3.7 days following either NSTEMI or STEMI) to receive either placebo for four months followed by simvastatin 20 mg/d or simvastatin 40 mg/d for one month followed by simvastatin 80 mg/d. They followed patients for 24 months for the primary end points of cardiovascular death, MI, readmission for ACS, or stroke. The primary end point occurred in 16.7% of the delayed, lower-intensity treatment group and in 14.4% of the early, higher-intensity treatment group (95% CI 0.76-1.04; p=0.14). Despite the lack of a significant difference in the composite primary end point between the two treatment arms, a significant reduction in the secondary end points of cardiovascular mortality (absolute risk reduction (ARR 1.3%; P=0.05) and congestive heart failure (ARR 1.3%; P=0.04) was evident favoring the early, intensive treatment strategy. These differences were not evident until at least four months after randomization. The A-to-Z trial investigators offered several possible explanations for the delay in evident clinical benefits in their trial when compared against the strong trend toward clinical benefit seen with 30 days following the early initiation of high-dose atorvastatin following ACS in the PROVE IT-TIMI 22 trial. In the PROVE IT trial, patients were enrolled an average of seven days after their index event, and as a result, 69% had undergone revascularization by this time. In the A-to-Z trial, patients were enrolled an average of three to four days earlier, and, therefore, were less likely to have undergone a revascularization procedure by the time of enrollment—and may have continued on with active thrombotic processes relatively less responsive to statin therapy.6 Another notable difference between PROVE IT and A-to-Z subjects was the C-reactive protein (CRP) concentrations in the A-to-Z subjects did not differ between treatment groups within 30 days despite significant differences in their LDL levels.16 This lack of a concurrent, pleiotropic, anti-inflammatory effect in the A-to-Z trial aggressive treatment arm may also have contributed to the delayed treatment effect.
In conclusion, the A-to-Z investigators suggest more intensive statin therapy (than the 40 mg Simvastatin in their intensive treatment arm) may be required to derive the most rapid and maximal clinical benefits during the highest risk period immediately following ACS.
Following stroke: Although there is more robust data supporting the benefits of early, intensive, statin therapy following ACS, there also is established and emerging data supporting similar treatment approaches following stroke.
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial was designed to determine whether or not atorvastatin 80 mg daily would reduce the risk of stroke in patients without known coronary heart disease who had suffered a TIA or stroke within the preceding six months.8 Patients who experienced a hemorrhagic or ischemic TIA or stroke between one to six months before study entry were randomized to receive either atorvastatin 80 mg/d or placebo.
Investigators followed patients for a mean period of 4.9 years for the primary end point of time to non-fatal or fatal stroke. Secondary composite end points included stroke or TIA, and any coronary or peripheral arterial event, including death from cardiac causes, non-fatal MI, ACS, revascularization (coronary, carotid, peripheral), and death from any cause. No difference in mean baseline LDL levels was witnessed between the treatment and placebo arms (132.7 and 133.7 mg/dL, respectively). Atorvastatin was associated with a 16% relative reduction in the risk of stroke—hazard ratio, 0.84; 95% CI 0.71–0.99; p=0.03. This was found despite an increase in hemorrhagic stroke in the atorvastatin group—a finding that supports an epidemiologic association between low cholesterol levels and brain hemorrhage. The risk of cardiovascular events also was significantly reduced, however, no significant difference in overall mortality was observed between the two groups.