Statins for acute coronary syndrome: Cochrane systematic review

Abstract

Background

The early period following the onset of acute coronary syndrome (ACS) represents a critical stage of coronary heart disease, with a high risk of recurrent events and deaths. The short-term effects of early treatment with statins on patient-relevant outcomes in patients suffering from ACS are unclear. This is an update of a review previously published in 2011.

Objectives

To assess the effects, both harms and benefits, of early administered statins in patients with ACS, in terms of mortality and cardiovascular events.

Search methods

We updated the searches of CENTRAL (2013, Issue 3), MEDLINE (Ovid) (1946 to April Week 1 2013), EMBASE (Ovid) (1947 to 2013 Week 14), and CINAHL (EBSCO) (1938 to 2013) on 12 April 2013. We applied no language restrictions. We supplemented the search by contacting experts in the field, by reviewing the reference lists of reviews and editorials on the topic, and by searching trial registries.

Selection criteria

Randomized controlled trials (RCTs) comparing statins with placebo or usual care, with initiation of statin therapy within 14 days following the onset of ACS, follow-up of at least 30 days, and reporting at least one clinical outcome.

Data collection and analysis

Two authors independently assessed risk of bias and extracted data. We calculated risk ratios (RRs) for all outcomes in the treatment and control groups and pooled data using random-effects models.

Main results

Eighteen studies (14,303 patients) compared early statin treatment versus placebo or no treatment in patients with ACS. The new search did not identify any new studies for inclusion. There were some concerns about risk of bias and imprecision of summary estimates. Based on moderate quality evidence, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction, and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) or four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up when compared to placebo or no treatment. There were no statistically significant risk reductions from statins for total death, total myocardial infarction, total stroke, cardiovascular death, revascularization procedures, and acute heart failure at one month or at four months, although there were favorable trends related to statin use for each of these endpoints. Moderate quality evidence suggests that the incidence of unstable angina was significantly reduced at four months following ACS (RR 0.76, 95% CI 0.59 to 0.96). There were nine individuals with myopathy (elevated creatinine kinase levels more than 10 times the upper limit of normal) in statin-treated patients (0.13%) versus one (0.015%) in the control groups. Serious muscle toxicity was mostly limited to patients treated with simvastatin 80 mg.

Authors' conclusions

Based on moderate quality evidence, due to concerns about risk of bias and imprecision, initiation of statin therapy within 14 days following ACS does not reduce death, myocardial infarction, or stroke up to four months, but reduces the occurrence of unstable angina at four months following ACS. Serious side effects were rare.

Author(s)

Vale Noah, Nordmann Alain J, Schwartz Gregory G, de Lemos James, Colivicchi Furio, den Hartog Frank, Ostadal Petr, Macin Stella M, Liem Anho H, Mills Edward J, Bhatnagar Neera, Bucher Heiner C, Briel Matthias

Summary

Statins for acute coronary syndrome

Long-term therapy with statins (for at least one year) has been shown to reduce the risk of heart attack, stroke, and all-cause mortality in patients with and without established coronary heart disease. The early period following an acute coronary syndrome is a critical stage of coronary heart disease, with a high risk of recurrent events and death. We aimed to determine if early initiation of statins improves patient-relevant outcomes within the first four months following an acute coronary syndrome. This review is an update of a review previously published in 2011 that included 18 studies, enrolling 14,303 patients. The update of this review did not identify any new studies for inclusion. We did not find a significant risk reduction for all-cause mortality, heart attack, or stroke within the first four months. We had some concerns about risk of bias and imprecision of the results. The risk of unstable angina was reduced by about 25% at four months following acute coronary syndrome. Serious side effects from early treatment with statins were rare (0.1%), and serious muscle toxicity was mostly observed with simvastatin 80 mg.

Reviewer's Conclusions

Implications for practice

Statins impact lipid profiles within days (Correia 2002), and in vitro studies show immediate inhibition of smooth muscle cell proliferation and stimulation of re-endothelialization by statins (Walter 2004). These effects seem to translate into a reduction of unstable angina pectoris at four months following ACS, but not to the same extent into a reduction of death, myocardial infarction, or stroke.

In our meta-analysis we considered only endpoint events that occurred during the period of randomized treatment. It is likely that the beneficial effects of statins are cumulative. In most of the landmark trials of statins in patients with chronic coronary heart disease a benefit of treatment was not evident until one to two years after randomization (4S 1994; LIPID Study Group 1998). Similarly, there appeared to be a delayed benefit of more intensive statin treatment, compared to less intensive statin treatment, in the late phase of the A-to-Z trial (de Lemos 2004). Therefore, some of the benefit of statin treatment in the period up to four months after ACS may only become manifest after four months.

This systematic review confirms that early treatment with statins in ACS can, in general, be considered safe and that the highest approved doses of potent statins may be considered in this context (Stone 2013). However, physicians and patients should pay close attention to muscle-related symptoms, especially when maximum available doses - in particular of simvastatin 80 mg - are administered (Ara 2009), or when clinical risk factors for statin myopathy are present (e.g. advanced age, low body mass, impaired renal function).

There are concerns that when administered in clinical practice, long-term adherence to statins among patients with recent onset of ACS is poor (Jackevicius 2002). Evidence from a small randomized trial and from observational studies suggests better adherence to statins when therapy is started in hospital shortly after an acute event (Nordmann 2000; Smith 2005).

In summary, initiation of statin therapy within 14 days following ACS produces favorable trends but does not significantly reduce death, myocardial infarction, or stroke up to four months after the index event. Early initiation of statin therapy does significantly reduce the occurrence of unstable angina at four months following ACS. Serious muscle toxicity was more common with early statin therapy than with placebo, but was rare and mostly limited to treatment with simvastatin 80 mg.

Implications for research

A pooled analysis using individual patient data from eligible trials would be useful since it allows for pooled time-to-event analyses, powerful subgroup analyses, and multivariable regression analyses to clarify further the timing and mechanism by which statins confer cardiovascular benefits.

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