Patients with acute coronary syndromes (ACSs) still experience high rates of recurrent coronary events, particularly, early in their presentation. Statins yield substantial cardiovascular benefits, but the optimal timing of their administration, before or after percutaneous coronary intervention (PCI), remains unclear. We aimed to perform a meta-analysis of randomized controlled trials of statin administration before or after PCI versus no statin or low-dose statin in patients with ACS. Primary end points were 30-day all-cause mortality and 30-day myocardial infarction (MI) stratified by pre- and post-PCI statin administration. Secondary end points were major adverse cardiac events (MACEs) or major adverse cardiac and cerebrovascular events (MACCEs). Long-term analysis beyond 30 days was also performed. Twenty randomized controlled trials enrolling 8,750 patients were included. At 30 days, the rate of MI was significantly lower in the statin group (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.53 to 0.84, p = 0.0007) with a trend toward reduced mortality (p = 0.06) and significant reductions in MACE and MACCE compared with no or low-dose statin. The 30-day incidence of MI was markedly lower when statins were administered before PCI (OR 0.38, 95% CI 0.24 to 0.59, p <0.0001) rather than after PCI (p = 0.28). The direction and magnitude of the estimates for before and after PCI versus no statin or low-dose statin were sustained at long term, not reaching statistical significance for MI (OR 0.81, 95% CI 0.65 to 1.01, p = 0.06) but with significant reductions in MACE (p = 0.0002). By meta-regression, earlier statin administration correlated significantly with lower risk of MI, MACE, and MACCE at 30 days. In conclusion, the present meta-analysis indicates a time-related impact of statin therapy on clinical outcomes of patients with ACS undergoing PCI: the earlier the administration before PCI, the greater the benefits.
Despite innovation in treatment strategies, patients with acute coronary syndrome (ACS) still experience markedly higher rates of coronary events compared with those with stable coronary artery disease, particularly at the time of percutaneous coronary intervention (PCI) and during the first 30 days after presentation. Statins have been found to be effective in improving the outcome of patients with ACS, owing, at least in part, to their pleiotropic effects, but the optimal timing, before or after coronary intervention, remains unclear. Recent randomized controlled trials (RCTs) suggest that earlier statin treatment after the diagnosis of ACS may yield greater benefits, as reflected in the 2011 American College of Cardiology Foundation/American Heart Association guidelines ; another recent analysis, however, questioned the findings and fueled debate on the real benefits of early statin treatment during ACS. The conflicting results among published studies partly reflect the different timing of statin administration in relation to PCI. To clarify the issue, we aimed to perform the most updated and comprehensive meta-analysis of randomized studies on the impact of statin administration versus no statin or low-dose statin soon after ACS, stratified according to whether randomization occurred before or after coronary intervention; the relation between timing of statin intake and risk of events was further investigated by meta-regression analyses.
Methods
Established methods were used in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement for reporting reviews and meta-analyses in health-care interventions. A search covering the period up to November 2013 was conducted by 2 independent investigators (EPN and MK) using PubMed/MEDLINE, Cochrane/Wiley, Google Scholar, and CINAHL/EBSCO databases, as well as conference proceedings from the American College of Cardiology, American Heart Association, European Society of Cardiology, Transcatheter Cardiovascular Therapeutics, and EuroPCR scientific sessions. The following keywords were applied: “statin,” “acute coronary syndrome,” “unstable angina,” “ST elevation myocardial infarction,” “non–ST elevation myocardial infarction,” “3-hydroxy-3-methylglutaryl coenzyme A reductase,” “atorvastatin,” “fluvastatin,” “pitavastatin,” “pravastatin,” “rosuvastatin,” and “simvastatin.” References of retrieved studies were searched manually for additional trials. No language restrictions were applied. A review protocol was not defined. Data were abstracted on prespecified forms by 2 independent investigators (EPN and MK) not involved in any of the studies retrieved; divergences were resolved by discussion with a third investigator (FA).
Citations were screened at title and/or abstract level and retrieved as full reports. Inclusion criteria were human studies; randomized trials; studies comparing clinical outcomes of statin versus no statin or low-dose statin; studies conducted in statin-naive patients only, to examine the net effect of statin administration; and studies conducted in patients with ACS undergoing or amenable to PCI. Exclusion criteria were studies not reporting clinical outcomes; non-RCTs; head-to-head comparisons of different statins; studies with a follow-up of <30 days; studies without PCI as a part of the protocol; studies with planned revascularization as an exclusion criterion; fibrinolysis as the only reperfusion treatment; and unavailable data on patients undergoing coronary intervention. The internal validity of each study was appraised by 2 unblinded investigators according to proper allocation sequence or concealment, patient blinding, investigator blinding, and complete outcome data or full reporting. We chose to analyze pre- and post-PCI statin administration versus no or low-dose statin for the primary end points, because coronary intervention itself, although providing overall clinical benefits compared with optimal medical therapy in patients with ACS, is burdened by an increased incidence of periprocedural events, partly related to prothrombotic activation, distal embolization, reperfusion injury, microvascular dysfunction, and contrast-induced nephropathy, toward which statins may have protective effects.
Primary end points were 30-day all-cause mortality and 30-day myocardial infarction (MI), stratified by pre- and post-PCI statin administration. Secondary end points were 30-day incidence of major adverse cardiac events (MACEs), classified as the composite of cardiovascular death, MI, and target vessel revascularization, and 30-day incidence of major adverse cardiac and cerebrovascular events (MACCEs), classified as the composite of death, nonfatal MI, and nonfatal stroke. Follow-up data beyond 30 days were extracted from the initial published studies, from subsequent publications, or from congress presentations.
Data were analyzed according to the intention-to-treat principle. Odds ratio (OR) and 95% confidence intervals (CIs) were used as summary statistics. Heterogeneity was assessed by Cochran Q test. The statistical inconsistency test I 2 = [(Q − df)/Q] × 100%, where Q is the chi-square statistic and df its degrees of freedom, was also used to overcome the low statistical power of Cochran Q test. Pooled ORs were calculated using a fixed-effects model with the Mantel-Haenszel method. The DerSimonian and Laird random-effects model was used in case of significant heterogeneity and/or moderate or significant inconsistency (>50%) across studies. For the primary outcomes (mortality and MI), potential publication bias was examined by constructing a “funnel plot” in which the standard error of the log OR was plotted against the OR. The asymmetry of the plot was estimated both visually and by a linear regression approach. Random-effects meta-regression analyses accounting for within- and between-study variations were conducted to evaluate linear correlations between log OR for specific outcomes and time from PCI to randomization, with the sample size as weight. To better quantify the contribution of very early timing of administration, regression analyses were restricted to studies in which randomization to statins occurred within 3 days after ACS. Finally, we addressed the influence of each study and potential publication bias by testing whether deleting each study in turn would have changed significantly the pooled results of the meta-analysis (sensitivity analysis). Review Manager 5.1 (The Nordic Cochrane Center, Købehvn, Denmark) and Comprehensive Meta-Analysis, version 2 (Biostat, Englewood, New Jersey), were used for statistical computations. p-Values are reported as 2-sided.
Results
A Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart, describing the process of publication screening and the reasons for exclusion, is shown in Figure 1 . From 872 potentially relevant reports retrieved for scrutiny, 805 were excluded based on abstract content during secondary screening. The remaining 67 underwent thorough assessment based on prespecified eligibility criteria. A total of 29 RCTs were included for data abstraction ( Supplementary References 1–32 ). Nine studies were further excluded because of lack of PCI data or because PCI was not a part of the protocol ( Supplementary References 24–32 ). All studies were available as full text. Clinical outcomes beyond 30 days were available as separate reports for 3 studies ( Supplementary References 5, 9 and 15 ). The characteristics of each study are listed in Table 1 .
| Study | No. of Patients | ACS | Statin Daily Dose | Control | ACS to Statin (Days) ∗ | Primary End Point | Composite End Point | Follow-up Available | Time from PCI to Statin (Median) |
|---|---|---|---|---|---|---|---|---|---|
| RECIFE ( Supplementary Reference 1 ) | 60 | STEMI/NSTEMI | Pravastatin 40 mg | Placebo | 10 | Brachial artery flow | Death, nonfatal MI, nonfatal stroke | 1.5 months | 249.6 h after PCI |
| L-CAD ( Supplementary Reference 2 ) | 126 | NSTEMI | Pravastatin 20–40 mg | No statin † | 6 | MACCE | Death, nonfatal MI, nonfatal stroke | 30 days and 4, 6, 12, and 24 months | 144 h after PCI |
| LIPS ( Supplementary Reference 3 ) | 824 | STEMI/NSTEMI | Fluvastatin 80 mg | Placebo | 2 | MACE | Cardiac death, nonfatal MI, TVR | 30 days and 4 and 12 months | 64.8 h after PCI |
| PTT ( Supplementary References 4 and 5 ) | 164 | STEMI | Pravastatin 40 mg | No statin | 1 | MACCE | Death, nonfatal MI, nonfatal stroke | 30 days and 6 months ‡ | 6 h after PCI |
| A to Z ( Supplementary Reference 6 ) | 4,497 | STEMI/NSTEMI | Simvastatin 40–80 mg | Placebo | 4 | MACCE | Cardiovascular death, nonfatal MI, readmission for ACS, stroke | 30 days and 6 and 24 months | 89 h after PCI |
| ESTABLISH ( Supplementary Reference 7 ) | 70 | STEMI/NSTEMI | Atorvastatin 20 mg | No statin | 1 | MACCE | All-cause death, recurrent ACS, stroke | 30 days and 4 and 6 months | 24 h after PCI |
| FACS ( Supplementary References 8 and 9 ) | 156 | STEMI/NSTEMI | Fluvastatin 80 mg | Placebo | 1 | Levels of CRP, IL-6, and PAPP-A/proMBP | Death, nonfatal MI, nonfatal stroke | 30 days and 3 and 12 months | 1 h after PCI |
| Sakamoto et al ( Supplementary Reference 10 ) | 486 | STEMI/NSTEMI | Any statin § | No statin | <4 | MACCE | Cardiac death, nonfatal AMI, recurrent ischemia, heart failure, nonfatal stroke | 30 days and 24 months | 6 h after PCI |
| ARMYDA-ACS ( Supplementary Reference 11 ) | 171 | NSTEMI | Atorvastatin 80 mg | Placebo | 1 | MACE | Death, nonfatal MI, TVR | 30 days | 12 h before PCI |
| OACIS LIPID ( Supplementary Reference 12 ) | 353 | STEMI/NSTEMI | Atorvastatin 10 mg | Placebo | 7 | MACCE | Death, nonfatal MI, nonfatal stroke, unstable angina, TVR | 30 days and 9 months | 209 h after PCI |
| ARMYDA-RECAPTURE ( Supplementary Reference 13 ) | 383 ‖ | NSTEMI | Atorvastatin 80 mg | Placebo | 1 | MACE | Cardiac death, MI, TVR | 30 days | 12 h before PCI |
| Yun et al ( Supplementary References 14 and 15 ) | 445 | NSTEMI | Rosuvastatin 40 mg | No statin | 1 | MACCE | Cardiac death, nonfatal MI, nonfatal stroke, TVR | 30 days and 12 months | 16 h before PCI |
| Extended-ESTABLISH ( Supplementary Reference 16 ) ¶ | 180 | STEMI/NSTEMI | Atorvastatin 20 mg | No statin | 1 | MACCE | All-cause death, recurrent ACS, stroke | 6 and 12 months | 24 h after PCI |
| Hahn et al ( Supplementary Reference 17 ) | 173 | STEMI | Atorvastatin 80 mg | Atorvastatin 10 mg | 1 | Infarct size at SPECT | Death, new-onset hypotension or heart failure, readmission for LV dysfunction | 30 days and 6 months | 1.5 h before PCI |
| Yu et al ( Supplementary Reference 18 ) | 81 | NSTEMI | Atorvastatin 80 mg | Placebo | 1 | MACE | Cardiac death, nonfatal MI, TVR | 30 days | 12 h before PCI |
| STATIN STEMI ( Supplementary Reference 19 ) | 171 # | STEMI | Atorvastatin 80 mg | Atorvastatin 10 mg | 1 | MACE | Death, nonfatal MI, TVR | 30 days and 9 months | 1.3 h before PCI |
| REPERATOR ( Supplementary Reference 20 ) | 55 | STEMI | Atorvastatin 80 mg | Placebo | 1 | ESVI at 3 months | NA | 3 months | 0.5 h before PCI |
| Gao et al ( Supplementary Reference 21 ) | 117 | NSTEMI | Rosuvastatin 20 mg | Placebo | 1 | MACE | Cardiac death, nonfatal MI, TVR | 3 and 6 months | 12 h before PCI |
| Wang et al ( Supplementary Reference 22 ) | 125 | NSTEMI | Rosuvastatin 20 mg | Placebo | 1 | MACE | Cardiac death, nonfatal MI, TVR | 30 days | 3 h before PCI |
| PRATO-ACS ( Supplementary Reference 23 ) | 504 | NSTEMI | Rosuvastatin 40 mg | No statin | 1 | Contrast-induced acute kidney injury | Death, nonfatal MI | 30 days and 6 months | 22.5 h before PCI |
∗ Mean time between onset of ACS symptoms and statin initiation.
† Subjects in the control group were allowed conventional medical treatment including lipid-lowering therapy at the discretion of the family physician.
‡ Only a subgroup of 77 patients (40 in intervention and 37 in control groups undergoing PCI) were followed up for 6 months.
§ Pravastatin, atorvastatin, rosuvastatin, simvastatin, or pitavastatin; statin and dose at the discretion of treating physician and could be switched or adjusted at any time, but subjects were prohibited from using any other lipid-lowering agent.
‖ Total number of patients enrolled from both NSTEMI and stable angina populations; NSTEMI n = 163.
¶ Continuation of ESTABLISH trial, with extended number of randomized patients and follow-up.
The 20 RCTs included in the meta-analysis involved 8,750 patients ( Supplementary References 1–23 ). Four studies ( Supplementary References 4, 5, 17, 19, and 20 ) enrolled only patients with ST elevation myocardial infarction, whereas 8 were restricted to non–ST elevation myocardial infarction ( Supplementary References 2, 11, 13–15, 18, and 21–23 ). The remaining 8 studies enrolled patients with any type of MI presentation and/or unstable angina. In 3 studies ( Supplementary References 2, 17, and 19 ) the control group comprised usual or standard care instead of placebo, allowing for low-dose lipid-lowering therapy. The mean timing of statin administration after ACS was 1.43 days (3.2 SD), whereas the mean timing before and after PCI was 0.53 ± 0.42 and 3.18 ± 3.56 days, respectively ( Table 1 ). The risk of publication bias is depicted in Supplementary Figure 1 available online.
Ten studies were included in the 30-day mortality analysis, with an overall incidence of 0.91% (32 of 3,513) in the statin group and 1.41% (49 of 3,470) in the no or low-dose statin group. There was a nonsignificant trend toward mortality reduction in the statin group (OR 0.66, 95% CI 0.43 to 1.02, p = 0.06; Figure 2 ). The 9 studies included in the beyond 30-day mortality analysis showed a modest nonsignificant benefit in mortality reduction in the statin group ( Figure 2 ). Patients receiving either pre- or post-PCI statin administration did not show significant mortality differences versus no or low-dose statin, either at 30 days or beyond. The funnel plots for mortality at 30 days and beyond did not show asymmetry on visual inspection ( Supplementary Figure 1 ), and this was confirmed by Egger’s test, which was not significant (p = 0.806).
Eleven studies were included in the 30-day analysis of MI with an overall incidence of 3.40% (123 of 3,621) in the statin group and 5% (179 of 3,577) in the no or low-dose statin group. Statin treatment significantly reduced the odds of MI by 33%, with OR 0.67, 95% CI 0.53 to 0.84, p = 0.0007. Analysis of studies stratified by pre- and post-PCI administration revealed a remarkable benefit in favor of pre-PCI statin treatment onset versus no statin or low-dose statin, with OR 0.38, 95% CI 0.24 to 0.59, p <0.0001, compared with OR 0.85, 95% CI 0.64 to 1.13, p = 0.28, for post-PCI statin treatment onset versus controls (p = 0.002 for interaction test between the 2 sets of treatments; Figure 3 ). Nine studies were included in the longer term analysis, with a trend in favor of statin treatment given at any time (either before or after PCI) versus no or low-dose statin (p = 0.06; Figure 3 ). Meta-regression analysis revealed a strong linear correlation between log OR of 30-day MI and time from PCI to statin randomization, with early initiation of statins associated with significantly better outcomes (p <0.0001; Figure 4 ). There was no evidence of publication bias either by visual inspection ( Supplementary Figure 1 ) or by Egger’s test (p = 0.069) from the funnel plots for 30-day and beyond 30-day MI incidence.
