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. 2013 Aug 27;36(12):E41–E48. doi: 10.1002/clc.22198

Efficacy of Short‐Term High‐Dose Atorvastatin Pretreatment in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: A Meta‐analysis of Nine Randomized Controlled Trials

Yangchun Liu 1, Qiang Su 1, Lang Li 1,✉
PMCID: PMC6649596  PMID: 24038054

Abstract

Background

The efficacy of short‐term high‐dose atorvastatin pretreatment in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) remains unclear. This meta‐analysis was undertaken to assess the efficacy of short‐term high‐dose atorvastatin pretreatment in patients with ACS undergoing PCI.

Hypothesis

Short‐term high‐dose atorvastatin pretreatment may be beneficial in reducing major adverse cardiac events (MACEs) and improving myocardial blood flow in patients with ACS undergoing PCI.

Methods

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically reviewed for randomized controlled trials (RCTs) published up to March 2013, in which short‐term high‐dose atorvastatin pretreatment was compared with control for patients with ACS undergoing PCI. The primary outcome measure was the incidence of MACEs at 30 days. The meta‐analysis was performed with the fixed effect model or random‐effects model according to the heterogeneity. Meta‐analysis was performed by RevMan 5.0 software (Cochrane Collaboration, Copenhagen, Denmark).

Results

Nine RCTs incorporating 952 patients met the inclusion criteria and were included in this meta‐analysis. Short‐term high‐dose atorvastatin pretreatment significantly reduced the incidence of MACEs at 30‐day follow‐up (risk ratio [RR] 0.39, 95% confidence interval [Cl]: 0.25 to 0.61, P < 0.001) and improved the final Thrombolysis in Myocardial Infarction (TIMI) flow grade (RR 1.08, 95% Cl: 1.02 to 1.14, P = 0.01) compared with controls. There were no significant differences in peak creatine kinase‐myocardial band and high‐sensitivity C‐reactive protein level post‐PCI between the 2 groups, though there were favorable trends related to statin use. As to the safety end points, no significant difference was observed in elevated liver aminotransferase level between short‐term high‐dose atorvastatin pretreatment and control groups (RR 1.36, 95% Cl: 0.67 to 2.74).

Conclusions

The use of short‐term high‐dose atorvastatin pretreatment is safe and significantly improves the final TIMI flow grade as well as reduces the 30‐day MACEs in ACS patients post‐PCI. This finding encourages the use of short‐term high‐dose atorvastatin pretreatment as an alternative for ACS patients undergoing PCI, but more high‐quality randomized clinical trials are still needed to confirm the long‐term efficacy and safety.

Introduction

Percutaneous coronary intervention (PCI) is considered to be the preferred reperfusion strategy for acute coronary syndrome (ACS).1 Despite optimal evidence‐based PCI, periprocedural myocardial injury (PMI) and myocardial no‐reflow phenomenon can still occur and is associated with a worse in‐hospital and long‐term prognosis.2, 3 As the processes for no‐reflow and PMI are multifactorial, various therapeutic strategies are required in different situations. Current pharmacological management involves the use of antiplatelet agents, vasodilators, and statins.3, 4

Atorvastatin, the most widely used statin, in addition to its beneficial lipid modulation effects, exerts a variety of several so‐called pleiotropic actions such as inhibiting inflammation, antiventricular remodeling, improving vascular endothelial function, and antioxidant effects.5 Because of the multiple functions, atorvastatin therapy is associated with a significant reduction in cardiovascular morbidity and mortality both in primary and secondary prevention.6, 7 Several meta‐analyses of randomized controlled trials (RCTs) have also provided convincing evidence that statins reduce the risk for myocardial infarction and overall mortality in patients with coronary heart disease as well as patients without coronary heart disease but at high risk for it.8, 9

A previous meta‐analysis of statin therapy in reducing myocardial infarction following elective percutaneous coronary intervention was published in 2007.10 The analysis showed that statin therapy initiated at the time of elective PCI significantly reduces myocardial infarction. Another updated meta‐analysis11 evaluating the effects of early statin therapy for ACS shows that initiation of statin therapy within 14 days following ACS resulted in directionally favorable but nonsignificant reduction in death, myocardial infarction, or stroke, with a significant reduction in the occurrence of unstable angina. However, this meta‐analysis included studies that enrolled mostly patients treated with a conservative strategy without early coronary intervention.

Long‐term administration of statins has been clearly shown to improve cardiovascular outcomes among those with cardiovascular disease, yet it is less clear whether short‐term high‐dose atorvastatin pretreatment provides a benefit in ACS patients undergoing PCI.12 Recently, an increasing number of studies13, 14, 15, 16, 17, 18, 19, 20, 21 on the efficacy of short‐term high‐dose atorvastatin pretreatment in patients with ACS undergoing PCI have been published, but all of them are underpowered to detect the differences in terms of hard clinical outcomes, and controversy remains. We therefore conducted a meta‐analysis based on relevant and available RCTs to assess the efficacy of short‐term high‐dose atorvastatin pretreatment in patients with ACS undergoing PCI.

Methods

Search Strategy

We performed an electronic search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from their inception to March 2013. Search terms included: atorvastatin, percutaneous coronary intervention, and randomized controlled trials. We also screened the reference lists of included studies and related publications to identify additional randomized trials. To ensure that no clinical trials were missed, we also conducted an extensive search of a citation database (ISI Web of Science) using cross‐references from eligible articles. No language restrictions were used. This search strategy was performed iteratively until no new potential citations could be found on review of the reference lists of retrieved articles. The results were hand searched for eligible trials.

Inclusion Criteria

Trials were included if (1) they enrolled patients with a diagnosis of ACS regardless of unstable angina pectoris, non–ST‐segment elevation ACS, or ST‐segment elevation myocardial infarction; (2) they were studies that randomly allocated patients to short‐term high‐dose atorvastatin pretreatment (80 mg immediate or 12 hours before PCI) or control (blank/placebo/10 mg) groups; and (3) they reported information on Thrombolysis in Myocardial Infarction (TIMI) classification, peak creatine kinase‐myocardial band (CK‐MB) and high‐sensitivity C‐reactive protein (hs‐CRP) level post‐PCI, major adverse cardiac events (MACEs) (eg, all‐cause death, target vessel revascularization, recurrent angina, or myocardial infarction, and sever heart failure), and incidence of elevated alanine transaminase (ALT) after PCI. Exclusion criteria included: (1) follow‐up data in <90% of patients, (2) duplicate reports failing to report additional or extended clinical outcomes, (3) nonrandom treatment allocation, and (4) patients with previous or current use of statins.

Data Extraction and Quality Assessment

Two investigators (Y.C.L. and Q.S.) independently extracted the following information from each study: the first author's name, year of publication, participants' characteristics, study design (randomized, blinded or not), total number of individuals, mean age, percentage of males in each trial, regimen of atorvastatin, type of controls (blank, placebo, or 10 mg atorvastatin), prespecified clinical outcomes, and status of illness (unstable angina pectoris, non–ST‐segment elevation ACS or ST‐segment elevation myocardial infarction). Disagreements were discussed between the authors, and if the authors could not reach a consensus, disagreements were resolved by the third author (L.L.).

The bias risk of trials was assessed with the components recommended by the Cochrane Collaboration,22 including sequence generation of the allocation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias.

The primary end point was 30‐day MACEs. Secondary end points were final TIMI flow grade, peak CK‐MB and hs‐CRP post‐PCI, and the incidence of elevated ALT post‐PCI was set as safety end point. MACEs indicated major adverse cardiac events and was defined as composite of death, myocardial infarction, and target vessel revascularization. The level of CK‐MB and hs‐CRP post‐PCI were set to assess myocardial injury and inflammatory response after PCI.

Data Analysis

Risk ratio (RR) with 95% confidence interval (CI) was used to express the pooled effect on discontinuous variables. The summary estimates of continuous variables were presented as weighted mean differences (WMD) with 95% CI. Heterogeneity was quantified using the I 2 statistic, where I 2 > 50% represented between‐study inconsistency. Fixed‐effects meta‐analyses were conducted to pool these outcomes across the included trials when there was no between‐study inconsistency, whereas the random‐effects model was used if heterogeneity existed. Publication bias was evaluated using a funnel plot. Results were considered statistically significant at P < 0.05. The pooled analyses were performed with RevMan 5.0 software (Cochrane Collaboration, Copenhagen, Denmark).

Results

Selected Studies and Baseline Characteristics

Figure 1 shows the flow of the process for identifying potentially eligible trials and reasons for exclusion. Of the 295 potentially relevant articles initially screened, a total of 9 RCTs13, 14, 15, 16, 17, 18, 19, 20, 21 consisting of 952 individuals (476 for atorvastatin and 476 as the control) were included. Table 1 summarizes the baseline characteristics of the included studies.

Figure 1.

Figure 1

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Flow diagram of the systematic overview process. RCTs, randomized controlled trials.

Table 1.

Baseline Characteristics of Patients From the Included Studies

Study Participants, Expt/Ctrl Age, y, Expt/Ctrl Male, n (%), Expt/Ctrl Condition Dyslipidemia, Expt/Ctrl Diabetes Mellitus, Expt/Ctrl Treatment Outcomes
Hahn 2011 89/84 55.5 ± 12.1/59.7 ± 12.8 76(85.4)/69(82.1) STEMI 45(50.6)/43(51.2) 25(28.1)/18(21.4) 80 mg before PCI vs no statin Final TIMI flow grade, peak CK‐MB, ALT elevation
Patti 2007 86/85 64 ± 11/67 ± 10 68(79)/67(79) ACS 27(31)/28(33) 25(29)/28(33) 80 mg 12 hours + 40 mg 2 hours before PCI vs placebo MACEs at 30 days, hs‐CRP level
Liu 2011 46/40 59 ± 10/58 ± 9 25(54.3)/21(52.5) STEMI 18(39.1)/13(32.5) 80 mg before PCI vs no statin Final TIMI flow grade, MACEs at 30 days
Liu 2013 32/32 59.3 ± 10/61.2 ± 12 26(81.2)/24(75) STEMI 8(25)/14(43.7) 4(12.5)/2(6.25) 80 mg before PCI vs no statin Final TIMI flow grade, peak CK‐MB
Wang 2013 40/39 52.5 ± 7.6/54.3 ± 7.2 25(62.5)/24(61.5) UAP 80 mg before PCI vs no statin MACEs at 30 days, ALT elevation, hs‐CRP level
Post 2012 20/22 57.5 ± 7.7/64.6 ± 10.3 13(65)/19(86) STEMI 6(30)/4(19) 1(5)/5(23) 80 mg before PCI vs no statin Final TIMI flow grade, peak CK‐MB, MACEs at 30 days
Ren 2012 36/49 61 ± 12.8/63 ± 12 27(75)/38(77.6) STEMI 3(8.3)/5(10.2) 7(19.4)/12(24.5) 80 mg 1–2 hours before PCI vs no statin Final TIMI flow grade, MACEs at 30 days, peak CK‐MB
Kim 2010 86/85 61 ± 11/59 ± 11 66(76.7)/66(85) STEMI 34 (39.5)/32(38.1) 21(24.5)/16(18.9) 80 mg vs 10 mg before PCI Final TIMI flow grade, peak CK‐MB, hs‐CRP level, MACEs at 30 days
Yu 2011 41/40 63.3 ± 10.5/64.4 ± 11.6 25(61)/23(58) ACS 20(49)/19(48) 14(34)/15(38) 80 mg before PCI vs placebo MACEs at 30 days, ALT elevation, hs‐CRP level
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Abbreviations: ACS, acute coronary syndrome; ALT, alanine aminotransferase; CK‐MB, creatine kinase‐myocardial band; Ctrl, control; Expt, experimental; hs‐CRP, high‐sensitivity C‐reactive protein; MACEs, major adverse cardiac events; PCI, percutaneous coronary intervention; STEMI, ST‐segment elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction; UAP, unstable angina pectoris.

Of the 9 studies, patients in 7 studies13, 14, 15, 17, 18, 19, 21 were preprocedurally treated with aspirin and clopidogrel, and among those, patients in 3 studies13, 14, 17 were given a loading dose of 600 mg of clopidogrel. Although in 1 study16 the use of aspirin and clopidogrel was not mentioned, and patients in another study20 were pretreated with aspirin only. Glycoprotein IIb/IIIa inhibitors were used at the operator's discretion in 6 studies,13, 14, 15, 17, 18, 19 whereas in the rest of the studies16, 20, 21 the use of glycoprotein IIb/IIIa inhibitors was not mentioned. Postintervention antiplatelet therapy consisted of aspirin and thienopyridines if stents were planted.

Table 2 shows the design characteristics of the included studies. Among the 9 studies, 6 studies13, 14, 15, 16, 17, 21 reported the specific random methods that were used. In 3 studies,13, 14, 16 a block random approach was used, and in other 3 studies,15, 17, 21 a random numbers table was used. In 7 studies, blinded methods were used, and of those, 6 studies13, 14, 15, 16, 17, 18 used a double‐blind approach, and 1 study19 used a single‐blind approach. None of the studies described the allocation concealments in detail or had a loss to follow‐up and missing data.

Table 2.

Assessment of Methodological Quality of Included Studies

Study Randomized Method Allocation Concealment Blinded Withdrawals and Lost to Follow‐up Intent‐to‐Treat Analysis
Hahn 2011 Randomized block design Unclear Double blind No No
Patti 2007 Randomized block design Unclear Double blind No No
Liu 2011 Randomized unclear Unclear Single blind No No
Liu 2013 Randomized number table Unclear Double blind No No
Wang 2013 Randomized unclear Unclear Unclear No No
Post 2012 Randomized block design Unclear Double blind No No
Ren 2012 Randomized number table Unclear Unclear No No
Kim 2010 Randomized number table Unclear Double blind No No
Yu 2011 Randomized unclear Unclear Double blind No No
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Effects on Final TIMI Flow Grade

The data of final TIMI flow grade 3 were available in 6 studies.13, 15, 16, 17, 19, 21 No significant heterogeneity was found between the 2 groups (I 2 = 0%, P = 0.58). The fixed‐effects model was used, and the pooled RR was 1.02 (95% Cl: 1.02 to 1.14, P = 0.01; Figure 2), suggesting that short‐term high‐dose atorvastatin pretreatment significantly improved TIMI myocardial perfusion grade in patients with ACS undergoing PCI.

Figure 2.

Figure 2

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Pooled risk ratio of atorvastatin pretreatment vs control for final Thrombolysis in Myocardial Infarction flow grade 3 after percutaneous coronary intervention. Abbreviations: CI, confidence interval; M‐H, Mantel‐Haenszel.

Effects on Peak CK‐MB and hs‐CRP

The data of peak CK‐MB after PCI were available in 5 studies.13, 15, 16, 17, 21 There was a statistical heterogeneity between the 2 groups (I 2 = 72%, P = 0.007). The random‐effects model was used, and the results showed no difference in peak CK‐MB between the 2 groups (WMD = −25.13, 95% Cl: − 80.62 to 30.36, P = 0. 37; Figure 3). As to the level of hs‐CRP after PCI, the pooling analysis also showed that short‐term high‐dose atorvastatin did not provide an additional reduction in hs‐CRP (WMD = −5.97, 95% Cl: −15.46 to 3.53, P = 0.22; heterogeneity I 2 = 98%, P < 0.001; Figure 4).

Figure 3.

Figure 3

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Pooled mean difference of atorvastatin pretreatment vs control for peak creatine kinase‐myocardial band after percutaneous coronary intervention. Abbreviations: CI, confidence interval; IV, inverse variance; SD, standard deviation.

Figure 4.

Figure 4

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Pooled mean difference of atorvastatin pretreatment vs control for high‐sensitivity C‐reactive protein after percutaneous coronary intervention. Abbreviations: CI, confidence interval; IV, inverse variance; SD, standard deviation.

Effects on Clinical Outcomes

The data of 30‐day MACEs were available in 7 studies.14, 16, 17, 18, 19, 20, 21 No significant heterogeneity was found between the 2 groups (I 2 = 0%, P = 0.57). The fixed‐effects model was used, and the pooled RR was 0.33 (95% Cl: 0.20 to 0.55, P < 0.0001; Figure 5), revealing that short‐term high‐dose atorvastatin pretreatment was associated with a reduced risk of MACEs in 30‐day follow‐up.

Figure 5.

Figure 5

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Pooled risk ratio of atorvastatin pretreatment vs control for 30‐day major adverse cardiac events after percutaneous coronary intervention. Abbreviations: CI, confidence interval; M‐H, Mantel‐Haenszel.

Adverse Events

Three studies13, 18, 20 reported the data of elevated liver alanine aminotransferase (ALT) level. The pooling analysis using a fixed‐effects model showed that atorvastatin pretreatment did not increase the incidence of elevated liver ALT (RR = 1.36, 95% Cl: 0.67 to 2.74, P = 0.39; heterogeneity I 2 = 0%, P = 0.92; Figure 6).

Figure 6.

Figure 6

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Pooled risk ratio of atorvastatin pretreatment vs control for elevated alanine aminotransferase after percutaneous coronary intervention. Abbreviations: CI, confidence interval; M‐H, Mantel‐Haenszel.

Publication Bias

Based on a visual inspection of the funnel plots, there was no evidence of publication bias among the included studies (Figure 7).

Figure 7.

Figure 7

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Funnel plot assessing publication bias of the included studies. Abbreviations: RR, risk ratio; SE, standard error.

Discussion

The main finding of this meta‐analysis was that short‐term high‐dose atorvastatin pretreatment could significantly reduced the incidence of 30‐day MACEs in patients with ACS undergoing PCI. In addition, the procedure significantly improved TIMI myocardial perfusion grade compared to the control. However, atorvastatin pretreatment did not have a beneficial effect for reducing the peak CK‐MB or hs‐CRP level post‐PCI.

PMI is characterized by a postprocedural increase of cardiac markers (eg, CK‐MB, cardiac troponin I) without symptoms, occurs in 10% to 40% of patients after PCI, and is associated with high long‐term mortality.23 Several prospective trials have proven that higher elevation of myocardial necrosis markers after PCI are clinically relevant.24, 25 A large meta‐analysis that compared patients with normal and elevated post‐procedural CK‐MB was published in 2003, and the results showed a dose‐response relationship of progressively higher mortality for increasing levels of CK‐MB, with even a minor increase of CK‐MB conferring a relative risk of death of 1.5.26 The pathogenetic mechanisms of PMI include no‐reflow phenomenon, distal microembolization, and enhanced inflammation.27 On the other hand, myocardial no‐reflow is associated with worse contractile dysfunction and is an independent predictor of death and myocardial infarction.28 It has been demonstrated that the mechanisms of no‐reflow consist of distal embolization, endothelial dysfunction, or microvascular obstruction.29, 30 According to the pathogenesis mentioned above, different strategies have been proposed and tested to prevent PMI and no‐reflow, such as intracoronary glycoprotein IIb/IIIa inhibitors31 and adenosine.32 Distal protection devices also play an important role in preventing distal embolization and reducing no‐reflow or PMI,33 but none of the above strategies is enough for ideal clinical outcomes.

By inhibiting hepatic 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A reductase, atorvastatin exerts a number of protective effects, including lipid lowering, improvement of endothelial function, stabilization of atherosclerotic plaque, inhibition of platelet adhesion and thrombosis, and reduction of inflammation.34, 35 Therefore, the pleiotropic effects all mainly, or at least partially, explain the beneficial effects of statins on PMI and myocardial no‐reflow after PCI. There is significant evidence suggesting that the cardiovascular protective effects of statins are directly linked to their ability to lower low‐density lipoprotein cholesterol.9 Takarada et al36 found that treatment with statins could reduce fibrous‐cap thickness of lipid‐rich plaques, and this might explain why patients receiving chronic statin treatment present less PMI during PCI. Early and intensive statin therapy has also been shown to halt, and in some cases reverse, the progression of atherosclerosis in those with established coronary artery disease and ACS.37

However, it is hard to believe the benefit of short‐term high‐dose atorvastatin pretreatment on myocardial protection is due to its cholesterol‐lowering effect or halting the progression of atherosclerosis. Statins are effective through different mechanisms other than lipid lowering or halting the progression of atherosclerosis.38 Previous animal studies have demonstrated that early statin pretreatment can improve coronary circulation and reduce myocardial infarction size via a mechanism of activating the endothelial nitric oxide synthase activity,27, 39 indicating that statins may reverse endothelial dysfunction and then exert a number of vasoprotective effects. It had been demonstrated that the acute protective effects of statins were due to their anti‐inflammation effect and the activation of a prosurvival pathway.27 Jia et al40 also found significant inhibition of hs‐CRP, P‐selectin, and intercellular adhesion molecule in a statin group compared with controls, and these effects of statin pretreatment were associated with better clinical outcomes. Moreover, statins can reduce the inflammatory cells in atherosclerotic lesions.41 Statins can also interfere with the process of the rupture of atherosclerotic plaques by diminishing the expression of the major procoagulant tissue factor in macrophages and endothelial cells, and promoting fibrinolytic activity as well as enhancing tissue plasminogen activator.42 In addition, statin pretreatment could attenuate platelet activity,43 stimulate endothelial progenitor cells,44 and preserve microvascular integrity,45, 46 leading to better recovery. Therefore, short‐term high‐dose atorvastatin pretreatment may play a vital role in myocardial protection in ACS patients undergoing PCI through the effects of anti‐inflammation, improvement of endothelial function, as well as the inhibition of platelet adhesion and thrombosis.

Our analysis failed to show the benefits of atorvastatin pretreatment in terms of peak CK‐MB and hs‐CRP post‐PCI, though there were favorable trends related to statin use for those items. This may have been due to (1) the initiated time not being enough, (2) the small number of patients involved in the analysis making it hard to identify the difference, and (3) the short time of the administration of atorvastatin before PCI not being enough to prevent the enhanced inflammation induced by PCI. Therefore, more high‐quality randomized clinical trials are still needed to explore the anti‐inflammatory effects of atorvastatin pretreatment in patients with ACS undergoing PCI.

Current guidelines for ACS and PCI recommend statins for secondary prevention of cardiac events through risk‐factor modification. However, none of these guidelines specifically recommend short‐term high‐dose atorvastatin pretreatment in patients with ACS undergoing PCI for reducing myocardial injury and MACEs after PCI. Our analysis can add strength to current recommendations and potential expanded use of atorvastatin before PCI.47, 48

Study Limitations

Some limitations of the present study deserve special consideration. First, the follow‐up period of the 9 assessed trials was not enough. Therefore, more high‐quality RCTs are still needed to confirm the long‐term efficacy and safety of short‐term high‐dose atorvastatin pretreatment in patients with ACS undergoing PCI. Second, due to the limited study numbers and population sizes, the power of the analysis might be restricted. Another limitation for the meta‐analysis is the potential heterogeneity among studies in terms of protocols, patients, and sample sizes, and the unavailability of patient‐level data, which might lead to inaccurate conclusions.

Conclusion

Short‐term high‐dose atorvastatin pretreatment is safe and beneficial in improving myocardial reperfusion as well as reducing 30‐day MACEs in ACS patients undergoing PCI. However, more high‐quality randomized clinical trials are still needed to confirm long‐term efficacy and safety.

The authors have no funding, financial relationships, or conflicts of interest to disclose.

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