Hospitalists frequently manage patients in the stages immediately following ACS and stroke. Based on the large and evolving volume of data regarding the use of statins following these events, when and how should a statin be started in the hospital?
Review of the Data
Following Acute Coronary Syndrome: Death and recurrent ischemic events following ACS are most likely to occur in the early phase of recovery. Based on this observation and evidence supporting the early (in some cases within hours of administration) ‘pleiotropic’ or non-cholesterol lowering effects of statins, including improvement in endothelial function and decreases in platelet aggregation, thrombus deposition, and vascular inflammation, the MIRACL study was designed to answer the question of whether the initiation of treatment with a statin within 24 to 96 hours following ACS would reduce the occurrence of death and recurrent ischemia.4,7,14 Investigators randomized 3,086 patients within 24-96 hours (mean 63 hours) following admission for non-ST segment myocardial infarction (NSTEMI) or unstable angina (UA) to receive either atorvastatin 80 mg/d or placebo.
Investigators monitored patients for the primary end points of ischemic events (death, non-fatal MI, cardiac arrest with resuscitation, symptomatic myocardial ischemia with objective evidence) during a 16-week period. In the treatment arm, the risk of the primary combined end point was significantly reduced—relative risk (RR) 0.84; 95% confidence interval (CI), 0.70-1.00; p=0.048. (See Figure 1, pg. 39)
No significant differences were found between atorvastatin and placebo in the risk of death, non-fatal MI, or cardiac arrest with resuscitation. There was, however, a significantly lower risk of recurrent symptomatic myocardial ischemia with objective evidence requiring emergent re-hospitalization in the treatment arm (RR, 0.74; 95% CI, 0.57-0.95; p=0.02). The mean baseline LDL level in the treatment arm was 124 mg/dL, a value that may represent, in part, suppression of the LDL level in the setting of acute ACS. This is a phenomenon previously described in an analysis of the LUNAR trial.15
Suppression of LDL level after ACS appeared to be minimal, however, and is unlikely to be clinically significant. The benefits of atorvastatin in the MIRACL trial did not appear to depend on baseline LDL level—suggesting the decision to initiate statin therapy after ACS should not be influenced by LDL level at the time of the event.
Only one dose of statin was used in the MIRACL trial, and the investigators commented they were unable to determine if a lower dose of atorvastatin or a gradual dose titration to a predetermined LDL target would have achieved similar benefits. The PROVE IT-TIMI 22 trial was designed to compare the reductions in death and major cardiovascular events following ACS between LDL lowering to approximately 100 mg/dL using 40 mg/d of pravastatin, and more intensive LDL lowering to approximately 70 mg/dL using 80 mg/d of atorvastatin.5 Investigators enrolled 4,162 patients for a median of seven days following ACS (STEMI, NSTEMI, or UA) to the two treatment arms. Investigators observed patients for a period of 18 to 36 months for the primary end points of death, MI, UA, revascularization, and stroke. The median LDL level at the time of enrollment was 106 mg/dL in both treatment arms. During follow up, the median LDL levels achieved were 95 mg/dL in the pravastatin group and 62 mg/dL in the atorvastatin group. After two years, a 16% reduction in the hazard ratio for any primary end point was seen favoring 80 mg/d of atorvastatin—p=0.005; 95% CI=5-26%. (See Figure 2, pg. 39) The benefit of high-dose atorvastatin was seen as early as 30 days after randomization and was sustained throughout the trial.
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Figure 1: PROVE IT-TIMI 22 trial