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Statins decrease cardiac events in patients at high cardiovascular risk, including those with diabetes. Few data exist, however, on the timing and intensity of this therapy as it relates to acute coronary syndrome (ACS).
De Lemos et al. recently reported the results of Phase Z of the A to Z trial.1 This randomized, double-blind international trial consisted of two overlapping phases. Phase A was designed to compare enoxaparin (Lovenox, Sanofi-Aventis) with unfractionated heparin in the acute phase of the hospitalization of ACS patients. Phase Z compared two strategies of therapy with simvastatin (Zocor, Merck) therapy in patients from Phase A who had been stabilized for at least 12 hours within 5 days of symptom onset.
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Each eligible patient was randomized to one of two treatment arms: an early, intensive statin arm (40 mg simvastatin for 30 days and then 80 mg thereafter) or a less intensive arm (placebo for 4 months and 20 mg simvastatin thereafter). Patients were then followed for up to 24 months. Additional dietary, lifestyle, and compliance counseling was provided to those who had LDL >130 mg/dl at month 8. If the LDL remained elevated, the patient could have a bile-acid sequestrant added or the study drug could be stopped and open-label statin therapy prescribed.
The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, or stroke. Secondary end points included individual components of the primary end point, and revascularization for ischemia, all-cause mortality, heart failure, and rehospitalization for cardiovascular cause.
In all, 4,497 patients were enrolled at 322 centers in 41 countries. High rates of concomitant aspirin, beta-blocker, and angiotensin converting enzyme (ACE)-inhibitor therapy were used by each group. In the less intensive group, LDL cholesterol increased by 11% during the placebo phase, but then decreased 31% below baseline 9 months after the initiation of a daily dose of simvastatin 20 mg once a day.
In the more intensive group, after one month of simvastatin 40 mg once a day, the mean LDL cholesterol was reduced by 39%. By month 4, after 3 months on the 80-mg dose, LDL cholesterol was reduced an additional 7%. At the conclusion of the study, the LDL cholesterol concentrations were 81 and 66 mg/dl in the two groups, respectively, a difference of 19%.
OUTCOMES
The composite cardiovascular end point occurred in 16.7% in the placebo/low-dose simvastatin group and in 14.4% in the high-dose simvastatin group. As for secondary end points, data suggested some benefit, but reached statistical significance only for heart failure, with trends toward reduced all-cause mortality and cardiovascular death.
No difference between the treatment groups was observed during the first 4 months of therapy, corresponding to the placebo control period. After 4 months, the primary end point was reduced by 6.8% and 9.3% in the less intensive and more intensive groups, respectively. There were no significant interactions based on subgroup analyses, as defined by demographic characteristics, presence of diabetes, baseline cardiac diagnosis or intervention, and initial lipid levels and C-reactive protein.
DISCUSSION
The main conclusion of the Z phase of the A to Z trial is that ACS patients experienced a nonsignificant 11% relative risk reduction and a 2.3% absolute risk reduction in the predefined composite cardiovascular end point from an earlier and more intensive statin program.
In setting trends for reductions in both the primary composite end point and the individual secondary end points, lack of statistical significance likely was due to several factors. The study ultimately was underpowered to detect a difference in outcomes between the groups, since the clinical benefit was both delayed and smaller than expected. In addition, there were fewer end points than predicted (652 instead of 970), probably due to widespread use of aggressive risk-factor management with aspirin, beta-blockers, and ACE inhibitors. Lastly, there was a high rate (33%) of study-drug discontinuation, mainly unrelated to adverse effects, which would have the tendency to attenuate differences between groups.
Interpretation of this study is challenging, given its somewhat complex initial design. Importantly, both groups in the A to Z trial received statin therapy, with one group receiving it earlier and at higher doses. With these two major differences in the lipid-lowering strategy between the groups, it is difficult to ascribe any benefit to one or the other component (i.e., timing versus intensity).
The post hoc observation of no difference in outcomes during the first 4 months suggests that the timing of statin therapy relative to ACS is not as important as the ultimate LDL cholesterol level and/or the statin dose achieved. These data, while not as impressive, are consistent with recent reports from the PROVE-IT2 and REVERSAL3 trials that indicate improved outcomes with more aggressive lipid lowering with higher-dose statins.
The lack of early benefit was in contrast to the MIRACL study,4 which reported a 16% event rate reduction 4 months following ACS in patients given 80 mg of atorvastatin. Methodological variances between the two studies may at least partially explain this difference.
It should be of little surprise that a modestly greater reduction in LDL cholesterol resulted in a modestly greater reduction in event rates. The A to Z trial would appear to confirm the recent impression from other investigations, including the Heart Protection Study (HPS),5 that when referring to LDL cholesterol, "lower is better." Clearly, however, as demonstrated by the less intensive simvastatin group, most of the benefit appears to be with the initial reductions in LDL cholesterol.
This report, I believe, underscores the importance of treating diabetic ACS
patients aggressively with lipid-lowering therapy with higher-than-usual
starting doses of statins—although the importance of the timing
of this therapy remains unclear. 
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Footnotes
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EDITOR'S NOTE: Dr. Inzucchi has received funding from Merck.
References
2. Cannon CP, Braunwald E, McCabe CH, et al.: Intensive vs. moderate
lipid lowering with statins after acute coronary syndromes. N Engl
J Med 350:1495–1504, 2004.
3. Nissen SE, Tuzcu EM, Schoenhagen P, et al.: Effect of intensive
compared with moderate lipid-lowering therapy on progression of coronary
atherosclerosis: A randomized controlled trial. JAMA 291: 1071–1080, 2004.
4. Schwartz GG, Olssen AG, Ezekowitz DM, et al.: Effects of
atorvastatin on early recurrent ischemic events in acute coronary syndromes;
the MIRACL study: A randomized controlled trial. JAMA 285: 1711–1718, 2001.
5. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomized placebo-controlled trial. Lancet 360:7–22, 2002.[Medline]
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