From the Walter Reed Army Medical Center,Washington, DC, and Uniformed Services University of the Health Sciences, Bethesda, Maryland.

The views expressed herein are those of the authors only and are not to be construed as those of the Department of the Army or the Department of Defense.

HMG-CoA reductase inhibitors (statins) are well-established agents for secondary prevention in patients with coronary heart disease. Several randomized controlled trials have sought to clarify whether statins have additional benefits if prescribed early and at a high dose in patients with acute coronary syndrome.^1-13 Most trials suggest that there is a benefit to early, intensive statin therapy, although several studies did not achieve statistical significance. One recent meta-analysis suggested that there was no benefit at 4 months of follow-up,¹⁴ but a separate meta-analysis showed a reduction in adverse cardiovascular outcomes after 6 months of treatment.¹⁵ We conducted a meta-analysis to determine the benefits of early intensive statin treatment in subjects with acute coronary syndrome.¹⁶

Subjects and methods

We performed a meta-analysis of 17,963 subjects enrolled in 13 randomized controlled trials who were hospitalized for acute coronary syndrome and were receiving early statin therapy. All included studies compared early, intensive statin therapy with placebo or a less intensive regimen. Early statin therapy was defined as medication starting within 14 days of hospitalization for acute coronary syndrome. Intensive statin therapy was defined as doses higher than those recommended by contemporary National Cholesterol Education Program (NCEP) guidelines. Outcomes were extracted at 1, 4, 6, 12, and 24 months for the primary endpoint from each trial in addition to cardiovascular death, recurrent ischemia, and recurrent nonfatal myocardial infarction (MI). Outcomes for the 13 trials were pooled with meta-analysis using hazard ratios and survival curves.

Results

The mean age of subjects was 60 years, and 76% were men. Nine trials compared a statin with placebo,^1-5,9,11-13 2 trials compared intensive statin therapy with a lower dose control group,^2,4 and 2 trials compared intensive statin therapy with usual care.^3,10 Pravastatin (Pravachol)^1,5-8,13 and atorvastatin (Lipitor)^2,3,10,11 were the medications most commonly studied (6 and 4 trials, respectively); 2 trials used fluvastatin (Lescol),^9,12 and 1 trial used simvastatin (Zocor).⁴ The study duration ranged from 1 to 48 months (median, 6 months). The time to initiation of statin therapy ranged from 1 to 14 days (median, 4 days).

All 13 trials included within their primary end points death, recurrent nonfatal MI, and recurrent ischemia. Nine studies evaluated revascularization by coronary artery bypass graft surgery or percutaneous coronary intervention^1,2,4,5,9-13; 4 studies did not include this outcome.^3,6-8

Within the first 4 months of follow-up, no significant difference was noted between intensive statin therapy and the control group in the risk of any adverse cardiovascular event. By 6 months, however, a statistically significant 24% hazard reduction of adverse cardiovascular events occurred (95% confidence interval [CI], 0.70-0.84; Figure and Table). This reduction remained significant throughout 2 years of follow-up (hazard ratio [HR] = 0.81; 95% CI, 0.77-0.87). Subgroup analysis showed a similar reduction for recurrent ischemia (24-month HR = 0.68; 95% CI, 0.50-0.92) and cardiovascular death (HR = 0.76; 95% CI, 0.66-0.87).

Figure. Pooled survival curves by outcome for: (A) any cardiovascular event; (B) myocardial infarction; (C) ischemia (unstable angina or revascularization); and (D) cardiovascular death. HR indicates hazard ratio; CI, confidence interval.

A review of the safety data from each trial showed that subjects receiving intensive statin therapy had adverse event rates similar to those receiving usual care, although slightly higher rates of asymptomatic aspartate aminotransferase and alanine aminotransferase elevation were noted in 4 trials (an incidence of less than 3.3% in all trials). Three subjects had serious hepatitis within the 8981 patient-years of follow-up. Myositis also occurred at comparable rates, with 3 cases of rhabdomyolysis reported. Intensive statin therapy and usual care had similar rates of discontinuation.

Table. Pooled hazard ratios (HRs) for subgroups over 24 months.

MI indicates myocardial infarction; HR, hazard ratio; CI, confidence interval.

Discussion

This meta-analysis shows that intensive statin therapy safely reduces adverse cardiovascular outcomes when begun soon after hospitalization for acute coronary syndrome. Significant reductions were found for the combined outcome of adverse cardiovascular events, cardiovascular death, and recurrent ischemia requiring readmission to the hospital or revascularization.

The mechanism for these benefits has not been proven. It has been hypothesized that statins may possess pleiotropic effects, such as plaque and endothelial stabilization, anti-inflammatory effects, and antithrombotic properties, among other possible benefits. It is well established that statins have effects other than reducing low-density lipoprotein (LDL) cholesterol levels, but studies conflict regarding whether such effects bear clinical importance or are simply coincidental with LDL cholesterol reduction.¹⁷ A meta-analysis recently concluded that secondary prevention of cardiovascular events occurs through LDL cholesterol reduction alone without pleiotropic effects.¹⁸

In our meta-analysis, benefits for hazard reduction occurred beyond LDL cholesterol reduction. Using stratified analyses and meta-regression, we were unable to completely explain the beneficial effects on the basis of LDL cholesterol reduction alone. However, Canon and colleagues conducted a similar metaanalysis of 4 randomized trials of intensive statin therapy and noted that LDL cholesterol reductions alone could potentially explain the beneficial effects.¹⁵ Thus, the question of pleiotropic effects remains unanswered. An analysis of individual subject data is currently under way by the Cholesterol Clinical Trials (CCT) group, which will help to clarify this important question.

Our meta-analysis is now the third published study to investigate the theory that early, intensive statin therapy above the doses usually recommended by current NCEP guidelines may have benefits for patients with acute coronary syndrome. Briel and colleagues conducted a similar analysis, but with only a 4-month follow-up period, compared with the 2 years of follow-up in our study.¹⁴ Similar to our meta-analysis, they found no significant risk reduction for early, intensive statin therapy after 4 months, although a reduction in recurrent ischemia was noted. Canon and colleagues performed a meta-analysis of 2 large inpatient studies (Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE-IT] and Aggrastat to Zocor [A to Z]) and 2 large outpatient studies (Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] and Treating New Targets [TNT]).¹⁵ Although their included studies were different from those in our metaanalysis, their risk reductions were also significant and consistent in magnitude with our results.

The safety data noted in this metaanalysis are consistent with the 2 other meta-analyses published in 2006, which also concluded that intensive statin therapy has a risk profile comparable with usual dosing. This is also consistent with another meta-analysis, which found no increased risk of adverse effects with a dose of 80 mg of atorvastatin compared with 10 mg.¹⁹ Studies among stable outpatients with established cardiovascular disease, such as the IDEAL trial, have also shown comparable safety.²⁰

Several ongoing trials continue to evaluate the potential benefits of early, intensive statin therapy for patients with acute coronary syndrome (Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome [JAPAN-ACS], Limiting Under-treatment of Lipids in ACS with Rosuvastatin [LUNAR], and Fluva-statin in the Therapy of Acute Coronary Syndrome [FACS]). The recently published A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) demonstrated that intensive statin therapy is capable of safely achieving a reduction in coronary atherosclerosis by intravascular ultrasound.²¹

In addition to safe, significant risk reduction of adverse cardiovascular outcomes, we also must emphasize that studies have shown the importance of beginning medications while patients are in the hospital to improve compliance.²² Given the high noncompliance rates of post-MI patients (up to one third are noncompliant with medications 1 month after discharge),²³ initiating statin therapy in the hospital is a simple, effective strategy to improve compliance and thereby reduce mortality.

Conclusion

This meta-analysis of early, intensive statin therapy evaluated the cardiovascular outcomes of 17,963 subjects in 13 randomized controlled trials. Significant reductions in adverse cardiovascular outcomes, cardiovascular death, and recurrent ischemia began between 4 and 6 months after initiation of therapy and remained significant for 2 years. Now that several trials and 3 meta-analyses have established safe, significant risk reductions for early, intensive statin therapy, we can expect the NCEP to continue the trend of recommending more aggressive cholesterol reduction that has occurred with each subsequent iteration of the guidelines. A meta-analysis of pooled patient-level data from each of the original randomized trials would help in performing stratified analyses and better quantify any potential pleiotropic benefits of statins.

References

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