Statins for acute coronary syndrome
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.
PICOs
Plain language 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.
Authors' conclusions
Summary of findings
| Statins compared to control at 4 months (3 to 6 months) for acute coronary syndrome | ||||||
| Patient or population: patients with acute coronary syndrome | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control at 4 months (3 to 6 months) | Statins | |||||
| Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths | 80 per 10001 | 75 per 1000 | RR 0.93 | 9625 | ⊕⊕⊕⊝ | |
| Death from all causes | 28 per 10001 | 25 per 1000 | RR 0.9 | 9733 | ⊕⊕⊕⊝ | |
| Fatal and non‐fatal myocardial infarction or reinfarction | 65 per 10001 | 59 per 1000 | RR 0.91 | 9537 | ⊕⊕⊕⊝ | |
| Fatal and non‐fatal stroke | 10 per 10001 | 7 per 1000 | RR 0.72 | 8536 | ⊕⊕⊕⊝ | |
| Unstable angina | 63 per 10001 | 48 per 1000 | RR 0.76 | 8770 | ⊕⊕⊕⊝ | |
| Acute heart failure | 26 per 10001 | 22 per 1000 | RR 0.86 | 7583 | ⊕⊕⊕⊝ | |
| Rhabdomyolysis | 0 per 10001 | 0 per 1000 | RR 6.9 | 4497 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1The basis of the assumed risk is the average risk of control group patients. | ||||||
Background
Coronary heart disease accounts for 20% of overall mortality in the United States (AHA 2007). Large trials and meta‐analyses have shown that HMG CoA reductase inhibitors (statins) effectively reduce low‐density lipoprotein (LDL) cholesterol and clinical endpoints such as cardiovascular events and overall mortality in a large spectrum of patients at varying risk of cardiovascular disease (4S 1994; HPS 2002; Shepherd 1995; Studer 2005). A limitation of most of the trials in secondary prophylaxis after acute myocardial infarction or unstable angina is, however, that statins have been started three or more months after an acute event. Acute coronary syndrome (ACS) is defined as a broad spectrum of manifestations that are due to insufficient coronary blood supply. These include ST‐segment elevation myocardial infarction, non‐ST‐segment elevation ACS with or without myocardial cell necrosis (unstable angina and/or non‐ST‐segment elevation myocardial infarction), and ST‐segment depression (non‐Q‐wave) myocardial infarction. The early period following an ACS represents a critical stage of coronary heart disease with a high risk of recurrent events and death due to vessel occlusions from vulnerable coronary plaques (Wood 1998). Therefore, strategies to stabilize vulnerable coronary plaques during this high‐risk period are paramount.
Experimental data indicate that statins may have early beneficial effects by improving the endothelial function of arteries (RECIFE 1999), decreasing platelet aggregability and thrombus formation (Rosenson 1998), and reducing vascular inflammation (Ridker 1998). Each of these mechanisms plays an important role in ACS and they are targets for existing or new drugs in the management of the ACS (Kumar 2009). Statins may exert these additional effects beyond their cholesterol‐lowering effect, which makes them amenable to supplementary therapy of ACS (Sposito 2002).
There is controversial evidence from observational studies that statin therapy prior to or at hospital discharge is associated with reducing short‐term mortality among patients after an ACS (Aronow 2001; Fonarow 2005; Newby 2002; Spencer 2004; Stenestrand 2001). Evidence from randomized controlled trials (RCTs) focusing on patients with an ACS indicates that statins may reduce combined endpoints that include recurrent angina, re‐angioplasty, and re‐hospitalization (Cannon 2004b; L‐CAD 2000; MIRACL 2001; Serruys 2002). These endpoints, however, may be less reliable because they depend to a greater extent on clinical judgement and local practices. Therefore information on 'harder' clinical endpoints, such as definite myocardial infarction, stroke, and coronary heart disease‐specific mortality, is important.
Why it is important to do this review
This is an update of a Cochrane review previously published in 2011. Morrissey et al have questioned the Level of Evidence: 1A recommendation of the current American College of Cardiology/American Heart Association (ACC/AHA) guidelines that statin therapy should be initiated in patients before hospital discharge after an episode of ACS regardless of the baseline LDL level because of a mismatch with the underlying evidence (Morrissey 2009). Two previous meta‐analyses on the topic suggested that early treatment with statins does not reduce death, myocardial infarction, or stroke up to four months following an ACS (Briel 2006a; Hulten 2006). Hulten et al used slightly different eligibility criteria (e.g. they allowed for head to head comparisons of statins to be included), did not contact investigators of primary trials for unpublished data, and pooled hazard ratios instead of risk ratios (Hulten 2006). They concluded that early statin therapy reduces the combined endpoint of death, recurrent ischemia, and recurrent myocardial infarction at six months of treatment and thereafter.
The purpose of the present study is to comprehensively update previous systematic reviews and meta‐analyses of RCTs evaluating the effects of early use of statins on relevant clinical endpoints of cardiovascular morbidity and overall mortality during the early stages at one and four months following the onset of ACS (Briel 2006a; Vale 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.
Methods
Criteria for considering studies for this review
Types of studies
We include randomized controlled trials (RCTs) comparing statin to placebo or no treatment in patients with an ACS (myocardial infarction or unstable angina). We excluded trials comparing two different statins without a placebo or no treatment control. We only considered trials with at least 30 days of follow‐up of participants after an ACS, reporting at least one clinical outcome.
Types of participants
Adults with recent ACS, regardless of prior lipid levels and prior lipid‐modifying treatment or diet. ACS is defined as a broad spectrum of manifestations that are due to insufficient coronary blood supply. These include ST‐segment elevation myocardial infarction, non‐ST‐segment elevation ACS with or without myocardial cell necrosis (unstable angina and/or non‐ST‐segment elevation myocardial infarction), and ST‐segment depression (non‐Q‐wave) myocardial infarction. We included patients regardless of previous ACS, percutaneous coronary interventions including stents, or co‐morbidities such as atrial fibrillation with or without antithrombotic treatment.
Types of interventions
Initiation of statin therapy (HMG‐CoA reductase inhibitors such as pravastatin, simvastatin, atorvastatin, fluvastatin, lovastatin, rosuvastatin) administered orally at any dosage within 14 days following the onset of an acute coronary syndrome. We only considered trials using cerivastatin for sensitivity analysis since this compound was withdrawn from the market in 2001 (Staffa 2002).
Types of outcome measures
We assessed the following clinical outcomes at one month, four months (range three to six months), and 12 months of follow‐up.
Primary outcome
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Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and death from all causes
Secondary outcomes
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Death from all causes
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Death from cardiovascular causes
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Fatal and non‐fatal myocardial infarction or reinfarction
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Fatal and non‐fatal stroke
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Revascularization procedures (bypass grafts, angioplasty with or without stenting)
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Unstable angina (recurrent myocardial ischemia requiring emergency hospitalization)
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Acute (new or worsening) heart failure
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Adverse events (rhabdomyolysis, creatinine kinase levels more than 10 times the upper limit of normal values, and liver aminotransferase levels more than three times the upper limit of normal values)
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Patient‐perceived quality of life
We considered outcomes and adverse events irrespective of their putative relation to the treatment. To maximize the statistical power of our primary analysis and to recognize the event hierarchy of fatal and non‐fatal events (occurrence of death precludes any other clinical events), we chose a combined primary endpoint to test the most patient‐relevant 'hard' outcomes: death, myocardial infarction, and stroke. Each of the components is highly patient‐relevant and about equally frequent (Montori 2005).
Search methods for identification of studies
To identify relevant trials we updated the searches from February 2010 by re‐running the searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 3), MEDLINE (Ovid, 1946 to April Week 1 2013), EMBASE Classic and EMBASE (Ovid, 1947 to 2013 Week 14), and CINAHL (EBSCO, 1938 to 12 April 2013) on 12 April 2013.
We did not impose any language restrictions. In addition, we searched previous systematic reviews (Briel 2006a; Hulten 2006), reference lists of identified articles, recently published editorials and narrative reviews on the topic, and trial registries (ISRCTN trials registry: isrctn.org/; US National Institute of Health Clinical Trials Registry: www.clinicaltrials.gov/) for further eligible trials. We contacted specialists in the field for any unpublished studies.
The detailed electronic search strategies developed by NB and MB for MEDLINE, EMBASE, CENTRAL, and CINAHL, which include filters for finding RCTs (modified from Dickersin 1994), are listed in Appendix 1. We updated the electronic searches with the help of the Cochrane Heart Group (Appendix 2). We have added some search terms and updated the RCT filter for MEDLINE and EMBASE (Lefebvre 2011).
Data collection and analysis
Selection of studies
Two authors (NV and AJN) independently assessed trial eligibility using a predefined form. We resolved disagreement by discussion and consensus. We excluded double reports. We applied no language restrictions.
Assessment of risk of bias in included studies
Two authors (NV and AJN) independently assessed the risk of bias in the selected trials according to the Cochrane 'Risk of bias' tool (six domains).
We ranked the risk of selection bias with respect to allocation concealment as:
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low risk (i.e. central randomization; numbered or coded bottles or containers; drugs prepared by the pharmacy; serially numbered, opaque, sealed envelopes; or other description regarding the methods used that warrants a judgement of adequate allocation concealment)
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unclear risk (i.e. unreported)
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high risk (for instance, alternation or reference to case record numbers or to dates of birth)
We resolved disagreements by discussion and consensus. We used our 'Risk of bias' assessment of included trials to explore heterogeneity among trials and to perform subgroup analysis.
Data extraction and management
Two authors (NV and AJN) independently extracted trial data in duplicate using predefined forms. We extracted data on patients' characteristics (age, gender, diabetes, hypertension, current smoker, prior myocardial infarction, lipid values at baseline, myocardial infarction as the index event, concomitant treatment for the index event (fibrinolysis, percutaneous coronary intervention), statin regimen (type of statin, daily dosage, starting time, duration), control group therapy (placebo or conventional treatment), follow‐up duration, and measured outcomes for both study groups (proportion of patients with the outcome) at one, four, and 12 months following the onset of the ACS. We resolved any disagreement between authors by discussion and consensus.
Data synthesis
We calculated risk ratios with 95% confidence intervals for all outcomes in the treatment and control groups and pooled them by conducting a random‐effects model meta‐analysis (DerSimonian 1986). We also calculated Peto odds ratios (fixed‐effect model), which are suggested for rare events (Deeks 1998). We investigated the presence of publication bias by means of funnel plots (Sterne 2001). We tested for heterogeneity with the Cochran Q test and measured inconsistency (I2 statistic: the percentage of total variance across studies that is due to heterogeneity rather than chance) of treatment effects across the primary and secondary outcomes (Higgins 2002; Higgins 2003). We did not include studies without events in either group in the analyses.
Sensitivity analysis
We examined treatment effects according to 'Risk of bias' components (concealed treatment allocation, blinding of patients and caregivers, blinded outcome assessment) for the combined primary outcome death, myocardial infarction, and stroke, for death from all causes, and for unstable angina. We also assessed the effect of time to initiation of statins on the combined primary outcome, and the type of statin on the combined primary outcome. We also conducted a sensitivity analysis by including unpublished data from a trial using cerivastatin on death from all causes, total myocardial infarction, total stroke, and unstable angina (PRINCESS 2004).
Results
Description of studies
The combined search of CENTRAL, MEDLINE, EMBASE, and CINAHL identified 2324 potentially relevant articles, of which we excluded all but 63 because it was clear from the abstract that they were not eligible (Figure 1). Full‐text assessment of the 63 potentially relevant articles resulted in the further exclusion of 39 studies (39 articles) because they were not randomized trials, had a follow‐up of less than one month, treatment was given for less than one month, they were head‐to‐head comparisons of statins, statin therapy was initiated beyond 14 days following the onset of ACS, or no or unclear clinical outcome data were reported. In an update of the electronic search on 12 April 2013 we identified another 2268 potentially relevant articles (Appendix 2). After title and abstract screening we checked 24 full texts but found no new eligible studies for inclusion.
Study flow chart.
For information on the excluded studies please see Characteristics of excluded studies.
Included in the meta‐analysis were 19 RCTs (24 references). One trial using cerivastatin was prematurely stopped because the drug was withdrawn from the market (PRINCESS 2004). We excluded data from the 4.5‐month follow‐up of this trial from the primary analysis, but included the data in a sensitivity analysis. The remaining 18 RCTs enrolled a total of 14,303 patients (7172 treatment, 7131 control). We found no evidence of ongoing eligible trials. Authors of included primary trials contributed additional data relevant for the purpose of this analysis. We were unable to contact the investigators from three trials (LAMIL 1997; Sakamoto 2005; Shal'nev 2007).
Seventeen of the 19 included trials investigated four different statins: pravastatin (seven trials; LAMIL 1997; L‐CAD 2000; OACIS‐LIPID 2008; PACT 2004; PAIS 2001; PTT 2002; RECIFE 1999), atorvastatin (four trials; Colivicchi 2002; ESTABLISH 2004; Macin 2005; MIRACL 2001), fluvastatin (three trials; FACS 2010; FLORIDA 2002; LIPS 2002), and simvastatin (three trials; de Lemos 2004; Ren 2009; Shal'nev 2007) (Table 1). One trial allowed any statin to be used in the intervention group (Sakamoto 2005).
| Trial (reference) | Randomized individuals, n | Mean age, years (SD) | Men, n (%) | Diabetes, n (%) | Hypertension, n (%) | Current smoker, n (%) | Prior MI, n (%) | MI as index event, n (%) | Fibrinolysis for index event, n (%) | PCI for index event, n (%) | ||||||||||
| Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | |
| LAMIL 1997 | 36 | 33 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 36 (100) | 33 (100) | NA | NA | NA | NA |
| RECIFE 1999 | 30 | 30 | 55 (2) | 56 (2) | 26 (93) | 22 (81) | 1 (4) | 0 (0) | 5 (18) | 8 (29) | 14 (50) | 17 (63) | 1 (4) | 2 (7) | 11 (39) | 12 (44) | 0 (0) | 0 (0) | 16 (57) | 17 (63) |
| L‐CAD 2000 | 70 | 56 | 55 (10) | 59 (11) | 57 (81) | 44 (79) | 0 (0) | 0 (0) | 22 (31) | 18 (32) | 49 (70) | 36 (64) | 45 (64) | 39 (70) | 32 (46) | 23 (41) | NA | NA | 58 (83) | 50 (89) |
| PAIS 2001 | 50 | 49 | 64 (1) | 63 (2) | 35 (70) | 37 (76) | 8 (16) | 5 (10) | 12 (24) | 16 (33) | 17 (34) | 17 (35) | 14 (28) | 12 (25) | 35 (70) | 31 (63) | 17 (34) | 14 (29) | 0 (0) | 0 (0) |
| PTT 2002 | 79 | 85 | 53 (11) | 52 (10) | 65 (82) | 69 (81) | 14 (18) | 13 (15) | 16 (20) | 21 (25) | 63 (80) | 66 (78) | 0 (0) | 0 (0) | 79 (100) | 85 (100) | 79 (100) | 85 (100) | 0 (0) | 0 (0) |
| PACT 2004 | 1710 | 1698 | 62 (12) | 61 (12) | 1308 (76) | 1285 (76) | 244 (14) | 234 (14) | 700 (41) | 714 (42) | 608 (36) | 575 (34) | 236 (14) | 197 (12) | 1109 (65) | 1111 (65) | 651 (38) | 671 (40) | 414 (24) | 406 (24) |
| LIPS 2002 | 417* | 407* | 61 (10) | 60 (10) | 344 (83) | 336 (83) | 65 (16) | 34 (8) | NA | NA | NA | NA | 184 (44) | 172 (42) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 417 (100) | 407 (100) |
| FLORIDA 2002 | 265 | 275 | 61 (12) | 60 (11) | 214 (81) | 234 (85) | 29 (11) | 31 (11) | 67 (25) | 65 (24) | 140 (53) | 139 (51) | 31 (12) | 31 (11) | 265 (100) | 275 (100) | 137 (52) | 133 (48) | 8 (3) | 10 (4) |
| MIRACL 2001 | 1538 | 1548 | 65 (12) | 65 (12) | 992 (64) | 1020 (66) | 342 (22) | 373 (24) | 843 (55) | 846 (55) | 429 (28) | 430 (28) | 382 (25) | 392 (25) | 812 (53) | 843 (55) | 109 (7) | 137 (9) | 0 (0) | 0 (0) |
| Colivicchi 2002 | 40 | 41 | 69 (14) | 68 (14) | 23 (58) | 24 (59) | 22 (55) | 24 (59) | 35 (88) | 37 (90) | NA | NA | 34 (85) | 35 (85) | NA | NA | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| ESTABLISH 2004 | 35 | 35 | 61 (10) | 63 (11) | 30 (86) | 30 (86) | 12 (34) | 11 (31) | 19 (54) | 19 (54) | 24 (69) | 19 (54) | 5 (14) | 5 (14) | 22 (63) | 26 (74) | 7 (20) | 3 (9) | 35 (100) | 35 (100) |
| A‐to‐Z 2004 | 2265 | 2232 | 60 (11) | 61 (11) | 1716 (76) | 1680 (75) | 529 (23) | 530 (24) | 1131 (50) | 1105 (50) | 926 (41) | 915 (41) | 409 (18) | 355 (16) | 1956 (86) | 1919 (86) | 483 (21) | 472 (21) | 979 (43) | 979 (44) |
| Sakamoto 2005 | 237 | 244 | 63 (11) | 65 (12) | 190 (80) | 193 (79) | 83 (35) | 61 (25) | 149 (63) | 142 (58) | 131 (55) | 130 (53) | 10 (4) | 15 (6) | 208 (88) | 219 (90) | 45 (19) | 50 (20) | 215 (91) | 220 (90) |
| Macin 2005 | 44 | 46 | 59 (13) | 61 (12) | 34 (77) | 33 (72) | 10 (23) | 11 (24) | 29 (65.9) | 31 (67.4) | 18 (41) | 19 (41) | 5 (11) | 7 (15) | 23 (52) | 31 (67) | 7 (15.9) | 8 (17.4) | 0 (0) | 0 (0) |
| Sato 2008 | 176 | 177 | 64 (10) | 63 (11) | 129 (73) | 142 (80) | 52 (30) | 59 (34) | 81 (46) | 87 (49) | 98 (56) | 105 (59) | 16 (9) | 19 (10) | NA | NA | NA | NA | 161 (91) | 161 (91) |
| Shal'nev 2007 | 55 | 55 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| FACS 2005 | 78 | 78 | 61 (12) | 63 (11) | 55 (71) | 51 (65) | 14 (18) | 16 (21) | 40 (51) | 40 (51) | 33 (42) | 39 (50) | 4 (5) | 8 (10) | > 47 (60) | > 54 (69) | 0 (0) | 0 (0) | 68 (87) | 71 (91) |
| Ren 2009 | 43 | 43 | 58 (11) | 59 (10) | 27 (63) | 30 (70) | 12 (28) | 10 (23) | 21 (49) | 18 (42) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
* These individuals make up the subgroup of patients with unstable angina (n=824).
MI: myocardial infarction
NA: not applicable
PCI: percutaneous coronary intervention
SD: standard deviation
In accordance with our eligibility criteria, we only included the subgroup of patients with unstable angina from the Lescol Intervention Prevention Study (LIPS 2002). In the A‐to‐Z trial we only used data from the placebo comparison during the first four months of follow‐up (de Lemos 2004).
Of the 19 included trials, four were international, multicenter trials (de Lemos 2004; LIPS 2002; MIRACL 2001; PRINCESS 2004), three were conducted in Japan (ESTABLISH 2004; OACIS‐LIPID 2008; Sakamoto 2005), two in the Netherlands (FLORIDA 2002; PAIS 2001), and one each were conducted in Germany (L‐CAD 2000), Belgium (LAMIL 1997), Argentina (Macin 2005), Australia (PACT 2004), Turkey (PTT 2002), Canada (RECIFE 1999), China (Ren 2009), the Czech Republic and Slovakia (FACS 2010), and Russia (Shal'nev 2007). The earliest included trial started recruitment in April 1996 (LIPS 2002), with the latest concluding in July 2006 (Ren 2009). However, six trials did not specify the recruitment dates (L‐CAD 2000; LAMIL 1997; PACT 2004; PRINCESS 2004; RECIFE 1999; Shal'nev 2007). Eleven trials were reported to be industry‐sponsored (de Lemos 2004; FLORIDA 2002; L‐CAD 2000; LAMIL 1997; LIPS 2002; MIRACL 2001; PACT 2004; PAIS 2001; PRINCESS 2004; RECIFE 1999; FACS 2010). See Characteristics of included studies.
Study population
The reported mean age of participants in the trials ranged from 53 to 69 years (Table 2). All trials enrolled mostly men (range among trials, 59% to 88%). There was considerable variation in the proportion of cardiovascular risk factors and participants with a myocardial infarction prior to the index event (range, 0% to 85%). Due to different trial protocols the proportion of participants with co‐interventions for the index event such as fibrinolytic therapy or percutaneous coronary interventions (PCI) varied widely among trials (range, 0% to 100%).
| Source | Daily | Control | No. of | Mean initiation | Duration of | No. (%) of | Reported concealed |
| LAMIL 1997 | Pravastatin 10 to 20 mg | Placebo | 69 | 2 | 1 and 3 | 55 (80) | No/yes/yes/no |
| RECIFE 1999 | Pravastatin 40 mg | Placebo | 60 | 10 | 1.5 | 55 (92) | No/yes/yes/no |
| L‐CAD 2000 | Pravastatin 20 to 40 mg* | Usual care† | 126 | 6 | 1, 4, and 6 | 126 (100) | No/no/no/no |
| PAIS 2001 | Pravastatin 40 mg | Placebo | 99 | 2 | 1 and 3 | 97 (98) | No/yes/yes/no |
| PTT 2002 | Pravastatin 40 mg | Usual care† | 164‡ | 1 | 1 and 6‡ | 164 (100) | No/no/no/no |
| PACT 2004 | Pravastatin 20 to 40 mg | Placebo | 3408 | 1 | 1 | 3323 (98) | No/yes/yes/no |
| LIPS 2002 | Fluvastatin 80 mg | Placebo | 824§ | 2 | 1, 4, and 6 | 824 (100) | No/yes/yes/yes |
| FLORIDA 2002 | Fluvastatin 80 mg | Placebo | 540 | 8 | 1, 4, and 6 | 540 (100) | No/yes/yes/yes |
| MIRACL 2001 | Atorvastatin 80 mg | Placebo | 3086 | 3 | 1 and 4 | 3075 (99.6) | Yes/yes/yes/yes |
| Colivicchi 2002 | Atorvastatin 80 mg | Usual care† | 81 | 12 | 1, 3, and 6 | 81 (100) | No/no/no/yes |
| ESTABLISH 2004 | Atorvastatin 20 mg | Usual care† | 70 | 1 | 1, 4, and 6 | 69 (99) | No/no/no/no |
| A‐to‐Z 2004 | Simvastatin 40 to 80 mg | Placebo | 4497 | 4 | 1 and 4|| | 4453 (99) | Yes/yes/yes/yes |
| Sakamoto 2005 | Any statin** | Usual care | 486 | 4 | 12 | 407 (84) | No/No/No/Yes |
| Macin 2005 | Atorvastatin 40 mg | Placebo | 90 | 1 | 1 | 89 (99) | No/Yes/Yes/No |
| Sato 2008 | Pravastatin 10 mg | Usual care† | 353 | 7 | 1 and 12 | 348 (99) | No/No/No/Yes |
| Shal'nev 2007 | Simvastatin 40 mg | Usual care | 110 | 1 | 6 | 108 (98) | No/No/No/No |
| FACS 2005 | Fluvastatin 80 mg | Placebo | 156 | 1 | 1, 3, and 12 | 156 (100) | No/Yes/Yes/No |
| Ren 2009 | Simvastatin 40 mg | Placebo | 86 | 3 | 1 | 86 (100) | No/Yes/Yes/Yes |
* 8 of 70 individuals received additionally cholestyramine or nicotinic acid.
† Individuals in the control group were allowed conventional medical treatment including lipid‐lowering therapy.
‡ All 164 individuals were followed‐up for 1 month, a subgroup of 77 (40/37) individuals with additional coronary angioplasty were followed‐up for 6 months.
§ These 824 individuals represent just the subgroup with unstable angina; the LIPS [Lescol Intervention Prevention Study]‐trial originally included another 853 individuals with stable angina.
|| After 4 months individuals in the control group received simvastatin 20mg.
ACS: acute coronary syndrome
Lipid‐lowering effects
The average weighted mean baseline LDL cholesterol level of included participants was 120 mg/dL (3.1 mmol/L) (range, 78 to 178 mg/dL (2.0 to 4.6 mmol/L)) (Table 3). Mean reduction of LDL cholesterol ranged from ‐15% to ‐53% and of total cholesterol from ‐9% to ‐37%, with higher reductions in trials using higher drug doses and/or more potent drugs. The effects on HDL cholesterol and triglycerides were less pronounced and inconsistent among trials (range of average change for HDL cholesterol, ‐9.5% to +13%; and for triglycerides, ‐28% to +10%).
| Trial (reference) | Intervention | Follow‐up* | Total cholesterol | LDL cholesterol | HDL cholesterol | Triglycerides |
| Baseline mean, mg/dL (% mean change in difference between treatment and control groups)† | ||||||
| LAMIL 1997 | Pravastatin 10 to 20 mg | 3 months | 228 (‐13) | 158 (‐23) | 36 (+5.3) | NA |
| RECIFE 1999 | Pravastatin 40 mg | 1.5 months | 247 (‐21) | 164 (‐27) | 42 (+13) | 194 (‐21) |
| L‐CAD 2000‡ | Pravastatin 20 to 40 mg | 1 month | 237 (‐24) | 178 (‐25) | 32 (‐6.0) | 142 (±0) |
| PAIS 2001 | Pravastatin 40 mg | 3 months | 255 (‐23) | 176 (‐24) | 43 (+9.1) | 199 (‐13) |
| PTT 2002‡ | Pravastatin 40 mg | 1 month | 230 (‐12) | 133 (‐25) | 39 (+3.0) | 214 (‐5.8) |
| PACT 2004 | Pravastatin 20 to 40 mg | NA | 219 (NA) | NA | NA | NA |
| LIPS 2002 | Fluvastatin 80 mg | 1.5 months | 201 (‐28) | 131 (‐39) | 39 (‐2.0) | 155 (‐21) |
| FLORIDA 2002 | Fluvastatin 80 mg | 12 months | 207 (‐22) | 137 (‐31) | 46 (+3.3) | 146 (‐22) |
| MIRACL 2001 | Atorvastatin 80 mg | 1.5 months | 206 (‐37) | 124 (‐53) | 47 (±0) | 183 (‐28) |
| Colivicchi 2002‡ | Atorvastatin 80 mg | 2 months | 220 (‐9) | 131 (‐15) | 39 (+1.0) | 167 (‐13) |
| ESTABLISH 2004‡ | Atorvastatin 20 mg | 6 months | 191 (‐28) | 124 (‐41) | 44 (‐8.7) | 109 (+4.9) |
| A‐to‐Z 2004 | Simvastatin 40 to 80 mg | 1 month | 184 (‐33) | 112 (‐49) | 39 (+2.0) | 149 (‐22) |
| Sakamoto 2005 | Any statin | 3 months | 207 (‐12) | 134 (‐23) | 47 (+2.2) | 135 (‐5.2) |
| Macin 2005 | Atorvastatin 40 mg | 1 month | 194 (‐19) | 124 (‐30) | 37 (+11) | 189 (+0.8) |
| Sato 2008‡ | Pravastatin 10 mg | 9 months | 220 (NA) | 49 (NA) | 117 (NA) | 148 (NA) |
| Shal'nev 2007 | Simvastatin 40 mg | 0.5 months | 212 (‐29) | 131 (‐46) | 49 (‐9.5) | 146 (‐15) |
| FACS 2005 | Fluvastatin 80 mg | 1 month | 212 (‐26) | 135 (‐31) | 47 (‐4.1) | 162 (+10) |
| Ren 2009 | Simvastatin 40 mg | 1 month | 228 (‐23%) | 139 (‐31) | 40 (+9.6) | NA |
* Lipid values in individual trials were measured at different time points during follow‐up; we report those closest to the 4 months follow‐up date.
† Baseline lipid levels were defined as the average (mean) before treatment in intervention and control groups. The percentage of change for each trial was calculated as the difference in the mean change in lipid levels from baseline to follow‐up in the intervention and the control groups. To convert from mg/dL to mmol/L, multiply by 0.02586 for cholesterol and by 0.01129 for triglycerides.
‡ Individuals in the control group were allowed conventional medical treatment including lipid‐lowering therapy.
HDL: high‐density lipoprotein
LDL: low‐density lipoprotein
NA: not applicable
Risk of bias in included studies
Risk of bias varied among studies (see 'Risk of bias' summary, Figure 2). Concealed allocation of participants was reported only for three trials (de Lemos 2004; LIPS 2002; MIRACL 2001). Eight trials were reported to have assessed clinical outcomes in a blinded fashion (Colivicchi 2002; de Lemos 2004; FLORIDA 2002; LIPS 2002; MIRACL 2001; OACIS‐LIPID 2008; Sakamoto 2005; Ren 2009), and 11 trials reported blinding of caregivers and patients (de Lemos 2004; FACS 2010; FLORIDA 2002; LAMIL 1997; LIPS 2002; Macin 2005; MIRACL 2001; PACT 2004; PAIS 2001; RECIFE 1999; Ren 2009). Loss to follow‐up was under 2% in all but three studies (RECIFE 1999: 8%, Sakamoto 2005: 16%, LAMIL 1997: 19%). One trial was stopped early for benefit (Colivicchi 2002), with potential overestimation of treatment effects (Bassler 2010).
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Effects of interventions
Statins versus placebo or no treatment
Analyses for publication bias indicated no evidence for such bias (Figure 3; Figure 4; Figure 5). Since there were only minimal differences in the estimates when calculating risk ratios or Peto odds ratios (fixed‐effect model), we reported outcomes as risk ratios (RR) only.
Funnel plot of comparison: 1 Statins versus control at 1 month, outcome: 1.1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Funnel plot of comparison: 2 Statins versus control at 4 months (3 to 6 months), outcome: 2.1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Funnel plot of comparison: 3 Statins versus control at 12 months, outcome: 3.1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and death from all causes
There was no significant difference in the primary combined outcome with early statin treatment in comparison to placebo or no treatment at one month (RR 0.93, 95% confidence interval (CI) 0.80 to 1.08; 13 studies, 13,484 patients) (Analysis 1.1), four months (RR 0.93, 95% CI 0.81 to 1.06; 11 studies, 9625 participants) (Analysis 2.1), or 12 months (RR 0.80, 95% CI 0.58 to 1.11; six studies, 2080 participants) (Analysis 3.1). We found no evidence of relevant heterogeneity among trials at any follow‐up time points (I² = 0%).
In sensitivity analyses, summary estimates of the primary endpoint at four months suggested smaller risk reductions for trials with higher methodological quality compared to trials that lacked a respective quality component. In trials with concealed allocation the summary RR for statins compared to control was 0.96 (95% CI 0.79 to 1.16; three studies, 8407 participants) (Analysis 5.1). For trials without concealed allocation the RR was 0.70 (95% CI 0.44 to 1.14; eight studies, 1218 participants) (Analysis 5.1). For trials with blinded outcome assessment the summary RR was 0.94 (95% CI 0.82 to 1.08; five studies, 9028 participants) (Analysis 5.3). For trials without blinded outcome assessment the RR was 0.60 (95% CI 0.30 to 1.22; six studies, 597 participants) (Analysis 5.3). For trials with blinding of patients and caregivers the summary RR was 0.95 (95% CI 0.82 to 1.09; seven studies, 9271 participants; Analysis 5.2). For trials without blinding of patients and caregivers the RR was 0.46 (95% CI 0.21 to 1.00; four studies, 354 participants) (Analysis 5.2).
We did not find different treatment effects for trials with initiation of statin therapy within three days versus up to 14 days (Analysis 5.14), or for trials using different types of statins (Analysis 5.15). Overall, we found moderate quality evidence that early statins provide no relevant risk reduction for the combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total deaths within the first four months following acute coronary syndrome (ACS) (see summary of findings Table for the main comparison).
Death from all causes
We found no statistically significant difference in death from all causes with early statin therapy compared to placebo or usual care at one month (RR 0.78, 95% CI 0.59 to 1.03; 13 studies, 13,155 patients) (Analysis 1.2), four months (RR 0.90, 95% CI 0.70 to 1.14; 12 studies, 9733 participants) (Analysis 2.2), or 12 months (RR 0.68, 95% CI 0.39 to 1.20; six studies, 2080 participants) (Analysis 3.2). We found no evidence of relevant heterogeneity among trials at any follow‐up time points (I² = 0%).
In sensitivity analyses, summary estimates of the primary endpoint at four months suggested smaller risk reductions for trials with higher methodological quality compared to trials that lacked a respective quality component. For trials with concealed allocation the RR for statins compared to control was 0.94 (95% CI 0.72 to 1.21; three studies, 8407 participants) (Analysis 5.4). For trials without concealed allocation the RR was 0.64 (95% CI 0.31 to 1.31; nine studies, 1326 participants) (Analysis 5.4). For trials with blinded outcome assessment the summary RR was 0.91 (95% CI 0.71 to 1.17; five studies, 9028 participants) (Analysis 5.6). For trials without blinded outcome assessment the RR was 0.77 (95% CI 0.31 to 1.90; seven studies, 705 participants) (Analysis 5.6). For trials with blinding of patients and caregivers the summary RR was 0.93 (95% CI 0.72 to 1.19; seven studies, 9271 participants) (Analysis 5.5). For trials without blinding of patients and caregivers the RR was 0.55 (95% CI 0.21 to 1.44; five studies, 462 participants) (Analysis 5.5). When we additionally included 4.5‐month data from 3605 patients with ACS from the PRINCESS study in a sensitivity analysis (Prevention of Ischemic Events by Early Treatment of Cerivastatin Study, PRINCESS 2004), the summary RR for all‐cause mortality was 0.95 (95% CI 0.78 to 1.17) (Analysis 5.10).
Overall, we found moderate quality evidence that early statins provide no relevant risk reduction for the combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total deaths within the first four months following ACS (see summary of findings Table for the main comparison).
Death from cardiovascular causes
There was no statistically significant difference in deaths from cardiovascular causes with early statin treatment in comparison to placebo or no treatment at one month (RR 0.80, 95% CI 0.60 to 1.07; 10 studies, 12,387 participants) (Analysis 1.3), four months (RR 0.84, 95% CI 0.64 to 1.09; eight studies, 9273 participants) (Analysis 2.3), or 12 months (RR 0.55, 95% CI 0.28 to 1.09; five studies, 1954 participants) (Analysis 3.3). We found no evidence of relevant heterogeneity among trials at any follow‐up time points (I² = 0%).
Fatal and non‐fatal myocardial infarction or reinfarction
We found no statistically significant difference in fatal and non‐fatal myocardial infarctions with early statin treatment in comparison to placebo or usual care at one month (RR 0.98, 95% CI 0.82 to 1.16; 12 studies, 13,074 participants) (Analysis 1.4), four months (RR 0.91, 95% CI 0.77 to 1.06; 10 studies, 9537 participants) (Analysis 2.4), or 12 months (RR 0.94, 95% CI 0.61 to 1.45; five studies, 1954 participants) (Analysis 3.4). We found no evidence of relevant heterogeneity among trials at any follow‐up time points (I² = 0%).
In a sensitivity analysis we included 4.5‐month data from 3605 patients with ACS from the PRINCESS study and found a summary RR for fatal and non‐fatal myocardial infarctions of 0.90 (95% CI 0.78 to 1.03) (Analysis 5.11).
Due to some concerns about risk of bias and imprecision of results we rated the quality of the available evidence that early statins provide no relevant risk reduction for fatal and non‐fatal myocardial infarction within the first four months following ACS as moderate (see summary of findings Table for the main comparison).
Fatal and non‐fatal stroke
There was no statistically significant difference in fatal and non‐fatal strokes with early statin treatment in comparison to placebo or usual care at one month (RR 0.78, 95% CI 0.47 to 1.29; seven studies, 12,147 participants) (Analysis 1.5), four months (RR 0.72, 95% CI 0.45 to 1.16; seven studies, 8536 participants) (Analysis 2.5), or 12 months (RR 0.38, 95% CI 0.13 to 1.10; four studies, 1130 participants) (Analysis 3.5). We found no evidence of relevant heterogeneity among trials at all follow‐up time points (I² = 0%).
In a sensitivity analysis we included 4.5‐month data from 3605 patients with ACS from the PRINCESS study and found a summary RR for fatal and non‐fatal strokes of 0.79 (95% CI 0.52 to 1.18) (Analysis 5.12).
Revascularization procedures
There was no statistically significant difference for revascularization procedures (bypass grafts, angioplasty) with early statin treatment compared to placebo or usual care at one month (RR 1.00, 95% CI 0.86 to 1.16; 10 studies, 9668 participants) (Analysis 1.6), or four months (RR 0.92, 95% CI 0.78 to 1.08; nine studies, 9474 participants) (Analysis 2.6). However, at 12 months we found a reduced risk of revascularization procedures with early statins (RR 0.70, 95% CI 0.52 to 0.93; five studies, 1999 participants) (Analysis 3.6). The heterogeneity among treatment effects was low at one month (I² = 0%) and four months (I² = 21%), but moderate at 12 months (I² = 50%). This may be due to differences in settings and definitions of the endpoint of revascularization procedures among trials (Table 4).
| Trial (reference) | Total death, MI, stroke, n (%) * | Total death, n (%) | Cardiovascular death, n (%) | Total MI, n (%) | Total stroke, n (%) | Revascularization (CABG/PCI), n (%) | Unstable angina, n (%) | Adverse events, n (%) | Acute heart failure | QOL | ||||||||||||||
| Rhabdomyolysis | CK > 10x ULN | ALT > 3x ULN | ||||||||||||||||||||||
| Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | |
| LAMIL 1997 | NA | NA | 1 (2.8) | 0 (0) | 1 (2.8) | 0 (0) | 1 (2.8) | 0 (0.0) | NA | NA | NA | NA | NA | NA | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA |
| 3 (8.3) | 3 (9.1) | 1 (2.8) | 0 (0) | 1 (2.8) | 0 (0) | 3 (8.3) | 3 (9.1) | 0 (0) | 0 (0) | 1 (2.8) | 1 (3.0) | NA | NA | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| RECIFE 1999 | 0 (0) | 1 (3.3) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0.0) | 1 (3.3) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (3.3) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (3.3) | NA | NA |
| L‐CAD 2000 | 1 (1.4) | 0 (0) | 1 (1.4) | 0 (0) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 0 (0) | 2 (3.6) | NA | NA | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 1 (1.4) | 1 (1.9) | 1 (1.4) | 1 (1.9) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 2 (2.9) | 9 (16.1) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| 1 (1.4) | 1 (1.9) | 1 (1.4) | 1 (1.9) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 6 (8.6) | 12 (21.4) | 6 (8.6) | 10 (17.9) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| PAIS 2001 | 2 (4.0) | 3 (6.1) | 1 (2.0) | 2 (4.1) | 1 (2.0) | 2 (4.1) | 2 (4.0) | 2 (4.1) | 0 (0) | 1 (2.0) | 4 (8.0) | 2 (4.1) | 16 (32.0) † | 11 (22.4) † | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 4 (8.0) | 4 (8.2) | 2 (4.0) | 2 (4.1) | 2 (4.0) | 2 (4.1) | 4 (8.0) | 2 (4.1) | 0 (0) | 2 (4.1) | 11 (22.0) | 9 (18.4) | 24 (48.0) † | 21 (42.9) † | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| PTT 2002 | 4 (5.1) | 14 (16.5) | 3 (3.8) | 9 (10.6) | 3 (3.8) | 7 (8.2) | 3 (3.8) | 5 (5.9) | 2 (2.5) | 7 (8.2) | 12 (15.2) | 15 (17.6) | 11 (13.9) † | 25 (29.4) † | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 2 (5.0) | 7 (18.9) | 1 (2.5) | 3 (8.1) | 0 (0) | 3 (8.1) | 1 (2.5) | 6 (16.2) | 0 (0) | 1 (2.7) | 11 (27.5) | 16 (43.2) | 12 (30.0) † | 22 (59.4) † | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| PACT 2004 | 86 (5.0) | 96 (5.7) | 27 (1.6) | 39 (2.3) | 26 (1.5) | 34 (2.0) | 67 (3.9) | 70 (4.1) | 8 (0.5) | 10 (0.6) | NA | NA | 123 (7.2) | 126 (7.4) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 7 (0.4) | 5 (0.3) | 28 (1.6) | 31 (1.8) | NA | NA |
| LIPS 2002 | 3 (0.7) | 1 (0.2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 3 (0.7) | 1 (0.2) | 0 (0) || | 0 (0) || | 77 (18.5) | 87 (21.4) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 8 (1.9) | 3 (0.7) | 1 (0.2) | 0 (0) | 1 (0.2) | 0 (0) | 7 (1.7) | 3 (0.7) | 0 (0) || | 0 (0) || | 78 (18.7) | 88 (21.6) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| 11 (2.6) | 10 (2.5) | 3 (0.7) | 4 (1.0) | 2 (0.5) | 3 (0.7) | 8 (1.9) | 6 (1.5) | 0 (0) || | 0 (0) || | 79 (18.9) | 88 (21.6) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| FLORIDA 2002 | 5 (1.9) | 5 (1.8) | 1 (0.4) | 3 (1.1) | 1 (0.4) | 3 (1.1) | 4 (1.5) | 2 (0.7) | 0 (0) | 1 (0.4) | 16 (6.0) | 12 (4.4) | 6 (2.3) ¶ | 5 (1.8) ¶ | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 10 (3.8) | 10 (3.6) | 2 (0.8) | 6 (2.2) | 2 (0.8) | 6 (2.2) | 8 (3.0) | 6 (2.2) | 0 (0) | 1 (0.4) | 30 (11.3) | 32 (11.6) | 11 (4.2) ¶ | 9 (3.3) ¶ | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| 14 (5.3) | 14 (5.1) | 3 (1.1) | 6 (2.2) | 3 (1.1) | 6 (2.2) | 11 (4.2) | 10 (3.6) | 0 (0) | 1 (0.4) | 36 (13.6) | 41 (14.9) | 14 (5.3) ¶ | 14 (5.1) ¶ | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| 28 (10.6) | 28 (10.2) | 7 (2.6) | 11 (4.0) | 6 (2.3) | 11 (4.0) | 21 (7.9) | 16 (5.8) | 2 (0.8) | 5 (1.8) | 46 (17.4) | 51 (18.5) | 16 (6.0)¶ | 18 (6.5)¶ | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| MIRACL 2001 | 101 (6.6) | 96 (6.2) | 32 (2.1) | 30 (1.9) | 27 (1.8) | 21 (1.4) | 80 (5.2) | 67 (4.3) | 7 (0.5) | 10 (0.6) | 162 (10.5) | 147 (9.5) | 72 (4.7) # | 87 (5.6) # | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | NA | NA |
| 162 (10.5) | 183 (11.8) | 64 (4.2) | 68 (4.4) | 51 (3.3) | 60 (3.9) | 118 (7.7) | 131 (8.5) | 12 (0.8) | 24 (1.6) | 254 (16.5) | 250 (16.1) | 95 (6.2) # | 130 (8.4) # | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 38 (2.5) | 9 (0.6) | 43 (2.8) | 40 (2.6) | NA | NA | |
| Colivicchi 2002 | 0 (0) | 3 (7.3) | 0 (0) | 1 (2.4) | 0 (0) | 1 (2.4) | 0 (0.0) | 3 (7.3) | 0 (0) | 0 (0) | 0 (0) ** | 0 (0) ** | 1 (2.5) # | 1 (2.4) # | 0 (0) | 0 (0) | 1 (2.5)## | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 5 (12.5) | 9 (22.0) | 2 (5.0) | 3 (7.3) | 1 (2.5) | 2 (4.9) | 3 (7.5) | 7 (17.1) | 1 (2.5) | 1 (2.4) | 0 (0) ** | 0 (0) ** | 2 (5.0) # | 3 (7.3) # | 0 (0) | 0 (0) | 1 (2.5)## | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| 7 (17.5) | 13 (31.7) | 3 (7.5) | 4 (9.8) | 2 (5.0) | 3 (9.8) | 5 (12.5) | 10 (24.4) | 1 (2.5) | 2 (4.9) | 0 (0) ** | 0 (0) ** | 2 (5.0) # | 6 (14.6) # | 0 (0) | 0 (0) | 1 (2.5)## | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| ESTABLISH 2004 | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 0 (0) | 1 (2.9) | 0 (0) | 1 (2.9) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| 0 (0) | 1 (2.9) | 0 (0) | 1 (2.9) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 8 (22.9) | 8 (22.9) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| A‐to‐Z 2004 | 99 (4.4) | 105 (4.7) | 20 (0.9) | 29 (1.3) | 20 (0.9) | 29 (1.3) | 86 (3.8) | 98 (4.4) | 10 (0.4) | 6 (0.3) | 19 (0.8) †† | 22 (1.0) †† | 27 (1.2) ‡‡ | 30 (1.3) ‡‡ | 3 (0.1) | 0 (0) | 0 (0) | 1 (0.04) | 1 (0.04) | 27 (1.2)§§ | 31 (1.4)§§ | NA | NA | NA |
| 161 (7.1) | 160 (7.2) | 44 (1.9) | 48 (2.2) | 42 (1.9) | 48 (2.2) | 130 (5.7) | 140 (6.3) | 16 (0.7) | 12 (0.5) | 60 (2.6) †† | 60 (2.7) †† | 56 (2.5) ‡‡ | 61 (2.7) ‡‡ | 3 (0.1) | 0 (0) | 7 (0.3) | 1 (0.04) | 13 (5.7) | 45 (2.0)§§ | 55 (2.5)§§ | 98 (5.0) | NA | NA | |
| Sakamoto 2005 | 4 (1.7) | 1 (0.4) | 4 (1.7) | 1 (0.4) | 4 (1.7) | 1 (0.4) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 12 (5.0) | 4 (1.6) | 6 (2.5) | 2 (0.8) | 6 (2.5) | 2 (0.8) | NA | NA | 3 (1.2) | 2 (0.8) | 18 (7.5) | 24 (9.8) | 6 (2.5) | 17 (6.9) | NA | NA | NA | NA | NA | NA | 1 (0.4) | 9 (3.7) | NA | NA | |
| Macin 2005 | 3 (6.8) | 5 (10.9) | 1 (2.3) | 3 (6.5) | 1 (2.3) | 3 (6.5) | 1 (2.3) | 3 (6.5) | 0 (0) | 0 (0) | 8 (18.2)¶ | 8 (17.4)¶ | 7 (1.6) | 8 (1.7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 4 (9.3) | 10 (21.7) | NA | NA |
| Sato 2008 | 0 (0) | 1 (0.6) | 0 | 1 (0.6) | 0 (0) | 1 (0.6) | 0 (0.0) | 0 (0.0) | 0 (0) | 1 (0.6) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA |
| 4 (2.3) | 7 (4.0) | 3 (1.7) | 2 (1.1) | 1 (0.6) | 2 (1.1) | NA | NA | 0 (0) | 2 (1.1) | 22 (12.7) | 36 (20.6) | 5 (2.9) | 5 (2.9) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 5 (2.8) | NA | NA | |
| Shal'nev 2007 | NA | NA | 2 (3.6) | 3 (5.5) | NA | NA | NA | NA | NA | NA | NA | NA | 4 (7.3) | 7 (12.7) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| FACS 2005 | 2 (2.6) | 2 (2.6) | 1 (1.3) | 0 (0) | 0 (0) | 0 (0) | 1 (1.3) | 2 (2.6) | 0 (0) | 0 (0) | 3 (3.8) | 4 (5.1) | 2 (2.6) | 6 (7.7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 2 (2.6) | 4 (5.1) | 1 (1.3) | 0 (0) | 0 (0) | 0 (0) | 1 (1.3) | 3 (3.8) | 0 (0) | 1 (1.3) | 3 (3.8) | 8 (10.3) | 3 (3.8) | 12 (15.4) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| 4 (5.1) | 10 (12.8) | 1 (1.3) | 4 (5.1) | 0 (0) | 2 (2.6) | 2 (2.6) | 5 (6.4) | 1 (1.3) | 3 (3.8) | 6 (7.7) | 15 (19.2) | 6 (7.7) | 16 (20.5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| Ren 2009 | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | NA | NA | 0 (0) | 1 (2.3) | NA | NA | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA |
* Combined primary endpoint; unique patients.
† Patients with “recurrent angina pectoris”.
‡ All 164 individuals were followed‐up for 1 month, a subgroup of 77 individuals with additional coronary angioplasty were followed‐up for 6 months.
§ These 824 individuals represent just the subgroup with unstable angina; the LIPS [Lescol Intervention Prevention Study]‐trial originally included another 853 individuals with stable angina.
|| Fatal strokes only; non‐fatal strokes were not recorded.
¶ Patients with “recurrent ischemia necessitating hospitalization”.
# Patients with “recurrent symptomatic myocardial ischemia with objective evidence and emergency hospitalization”.
** Individuals enrolled into the trial were not amenable for direct revascularization by coronary artery bypass grafting or percutaneous coronary intervention.
†† Revascularization procedures had to be urgent, occur more than 14 days after randomization, and were not allowed to be planned prior to enrollment.
‡‡ Patients with “readmission for acute coronary syndrome”.
§§ Patients with “new onset congestive heart failure requiring admission or initiation of heart failure medications”.
ALT: aminotransferase
CABG: coronary artery bypass grafting
CK: creatin kinase
MI: myocardial infarction
NA: not applicable
PCI: percutaneous coronary intervention
QOL: quality of life
ULN: upper limit of normal values
Unstable angina
The RR for unstable angina with early statin therapy compared to placebo or no treatment at one month was 0.89 (95% CI 0.76 to 1.05; 10 studies, 12,181 participants) (Analysis 1.7), at four months the RR was 0.76 (95% CI 0.59 to 0.96; nine studies, 8770 participants) (Analysis 2.7), and at 12 months the RR was 0.61 (95% CI 0.33 to 1.12; four studies, 1130 participants) (Analysis 3.7). The heterogeneity among treatment effects was low at one month (I² = 0%), but we found moderate heterogeneity at four months (I² = 33%) and at 12 months (I² = 35%). This may be due to differences in the definition of the endpoint of unstable angina among trials (Table 4).
In sensitivity analyses, summary estimates for unstable angina at four months suggested smaller risk reductions for trials with higher methodological quality compared to trials that lacked a respective quality component. In trials with concealed allocation the summary RR for statins compared to control was 0.79 (95% CI 0.64 to 0.97; two studies, 7583 participants) (Analysis 5.7). For trials without concealed allocation the RR was 0.68 (95% CI 0.44 to 1.04; seven studies, 1187 participants) (Analysis 5.7). For trials with blinded outcome assessment the summary RR was 0.81 (95% CI 0.66 to 0.99; four studies, 8204 participants) (Analysis 5.9). For trials without blinded outcome assessment the RR was 0.59 (95% CI 0.35 to 1.00; five studies, 566 participants) (Analysis 5.9). For trials with blinding of patients and caregivers the summary RR was 0.85 (95% CI 0.64 to 1.14; five studies, 8378 participants) (Analysis 5.8). For trials without blinding of patients and caregivers the RR was 0.51 (95% CI 0.34 to 0.79; four studies, 392 participants) (Analysis 5.8).
When we additionally included 4.5‐month data from 3605 patients with ACS from the PRINCESS study in a sensitivity analysis (PRINCESS 2004), the summary RR for unstable angina was 0.78 (95% CI 0.65 to 0.95) (Analysis 5.13).
Overall, we found moderate quality evidence that early statin therapy leads to a relevant risk reduction of unstable angina within the first four months following ACS (see summary of findings Table for the main comparison).
Acute heart failure
There was no statistically significant difference for acute (new or worsening) heart failure with early statin treatment compared to placebo or no treatment at one month (RR 0.85, 95% CI 0.63 to 1.14; five studies, 11,141 participants) (Analysis 1.8), four months (RR 0.86, 95% CI 0.65 to 1.15; two studies, 7583 participants) (Analysis 2.8), or at 12 months (RR 0.09, 95% CI 0.01 to 1.64; one study, 353 participants) (Analysis 3.8). The heterogeneity among treatment effects was low at one month (I² = 0%) and four months (I² = 0%); at 12 months there was only one study.
Adverse events
Among all included trials, only three incidents of rhabdomyolysis were reported in patients treated with statins (0.04%); all occurred in the A‐to‐Z trial (RR 6.90, 95% CI 0.36 to 133.47; 4497 participants) (Analysis 4.1). There were nine individuals with myopathy (elevated creatinine kinase levels more than 10 times the upper limit of normal) in the statin groups versus one in the control groups (0.13% versus 0.015%); the summary RR for myopathy was significantly higher with statins than with control (RR 4.69, 95% CI 1.01 to 21.67; three studies, 4677 participants) (Analysis 4.2). All nine cases occurred beyond the first month of statin treatment and seven of the nine patients were treated with high‐dose simvastatin (80 mg/day). None of the nine patients died. The risk of elevated liver aminotransferase levels (ALT more than three times the upper limit of normal) was significantly higher in the early statin groups than the control groups (RR 2.49, 95% CI 1.16 to 5.32; five studies, 11,914 participants) (Analysis 4.3). The heterogeneity in the effects on elevated liver aminotransferase levels was moderate (I² = 48%). This may be due to differences in trial settings and included patients (Table 4). Due to serious concerns about the imprecision of the rhabdomyolysis results, we rated the available evidence as low quality (see summary of findings Table for the main comparison).
Patient‐perceived quality of life
None of the included trials reported patient‐perceived quality of life.
Discussion
Key findings
This systematic review of randomized controlled trials in over 14,000 patients with acute coronary syndrome (ACS) investigated whether early statin therapy compared to placebo or no treatment improves patient‐relevant outcomes shortly after ACS. The results of our meta‐analysis did not show a statistically significant reduction of the composite primary endpoint (death, myocardial infarction, or stroke) for patients treated early with statins at one month, four months, and 12 months following ACS. There was, however, a non‐significant trend towards risk reduction and this trend increased with time. There were non‐significant trends towards risk reductions for the secondary outcomes of total death, total myocardial infarction, total stroke, cardiovascular death, and acute heart failure at one month, four months, and 12 months following ACS. The only significant relative risk reductions were in unstable angina at four months (estimated relative risk reduction of 24%) and revascularization procedures at 12 months (estimated relative risk reduction of 30%) following ACS. There were few data available from included trials at 12 months. However, the vulnerable coronary situation following ACS usually stabilizes within three to four months and other studies have already shown significant risk reductions for hard clinical outcomes such as myocardial infarction, stroke, or death in patients with stable coronary heart disease (4S 1994; Briel 2004; LIPID Study Group 1998; Studer 2005). Our results at 12 months are compatible with these findings.
In terms of adverse events we found that the risk of elevated liver aminotransferase levels (ALT more than three times the upper limit of normal) was significantly higher in the early statin groups than the control groups, but serious events such as myopathy or rhabdomyolysis were rare (three reported incidents of rhabdomyolysis in patients treated early with simvastatin 80 mg (0.04%) and nine individuals with myopathy (elevated creatinine kinase levels more than 10 times the upper limit of normal) in statin‐treated patients (0.13%); seven of these nine individuals took simvastatin 80 mg).
Overall we rated the quality of evidence for all outcomes as moderate due to some concerns about risk of bias and imprecision of results (see summary of findings Table for the main comparison), except for rhabdomyolysis for which we only found low quality evidence due to serious concerns about imprecision of results.
Why should effects on unstable angina be stronger than effects on myocardial infarction?
One could argue that statins might ameliorate coronary vascular endothelial function, but that doing so does not directly influence atherothrombosis. One might also posit that there actually are concordant effects on all of these endpoints (trends are all in a favorable direction with statins), but that the composite sample size and duration of observation in this group of trials are inadequate to ascertain an effect with sufficiently low type I error rate. Another important point is the biomarker methods used for ascertainment of myocardial infarction in many of these studies. In the late 1990s or even early 2000s, many sites continued to use CK‐MB or even total CK as the biomarker to detect myocardial injury. Multicenter trials generally do not specify one biomarker to define myocardial injury in endpoint events. Thus many endpoint events that would be associated with a small rise in troponin and today be categorized as acute myocardial infarction according to the current International Definition of Myocardial Infarction (Thygesen 2007), were likely to have been considered biomarker‐negative and categorized as unstable angina using the older and less sensitive biomarker methods prevalent during the conduct of the trials in question. Therefore, one might reasonably expect that had contemporary diagnostic criteria and methods been applied to the events in these trials, there might have been more events categorized as acute myocardial infarction (and fewer as unstable angina), affording greater power to detect an effect of early statin therapy on acute myocardial infarction.
Strengths and weaknesses
We have conducted an extensive literature search to retrieve all relevant eligible trials and collaborated with the investigators of the primary trials. This collaboration with experts in the field should minimize potential publication bias. In addition, formal testing indicated little evidence for such bias. In searching trial registries we found no evidence of ongoing eligible trials, which means that the trials gathered in this review may constitute the totality of the available evidence on the topic.
We were unable to include one small trial with 151 randomized individuals because the original investigators failed to clarify outcome events (Pedersen 2000). Two other trials including 3468 patients had a follow‐up of only one month (PACT 2004) and 1.5 months (RECIFE 1999). As a consequence, the power of our analysis at four months was compromised.
It may well be that early use of statins in ACS is associated with a beneficial effect on hard clinical outcomes such as total mortality, myocardial infarction, and stroke in the short term; summary estimates for all efficacy outcomes show a trend towards risk reduction with early statin therapy, but this meta‐analysis may lack the power to detect a significant risk reduction for hard outcomes. However, our sensitivity analyses indicated even smaller treatment effects when restricting the analysis to trials of adequate methodological quality, or when we additionally included secondary endpoint data from a large, prematurely terminated trial using cerivastatin in 3605 patients (PRINCESS 2004). To rule out effects of 10% risk reduction or less on our combined primary endpoint (death, myocardial infarction, and stroke), more than 34,000 patients with ACS would need to be randomized (Lachin 2000).
As expected, statins lowered low‐density lipoprotein (LDL) cholesterol levels more efficiently than placebo or usual care, and there were larger reductions in LDL cholesterol in trials using higher doses of statins. However, available data precluded adequate exploration of an association between clinical outcomes and the lipid‐lowering potency of different statin types and doses. It remains an open question whether potent statins at top doses provide clinical benefit that is not achieved with lower‐intensity statin therapy, since the only individual trials that have shown significant clinical benefit of statins in the early period following ACS are those that compared atorvastatin 80 mg with placebo (MIRACL 2001) or pravastatin 40 mg (Cannon 2004b). The possibility that high‐intensity, but not moderate‐intensity statin therapy is beneficial in the early period after ACS is supported by data from a meta‐analysis of five randomized controlled trials that compared high‐intensity with moderate‐intensity statin treatment in a total of 39,612 patients with coronary heart disease (Baigent 2010). Two of the five trials (A‐to‐Z (de Lemos 2004) and PROVE‐IT (Cannon 2004b)) included only ACS patients; two other included trials (SEARCH (Armitage 2010) and IDEAL (Pedersen 2005)) included some patients with recent ACS. The risk ratio (RR) for major vascular events among those treated with a high‐intensity regimen was 0.85 (95% confidence interval (CI) 0.82 to 0.89). In part, this finding led to the recent recommendation in the 2013 AHA/ACC Guideline for the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults that most patients with established coronary heart disease should be treated with an intensive statin regimen (Stone 2013).
Finally, this systematic review cannot address the benefit of the use of early statins in patients with ACS undergoing early percutaneous coronary intervention (PCI) of culprit lesions, since only a minority of patients in the included trials underwent PCI. Finally, as only one trial specified that it was unfunded (PTT 2002), and 11 trials specified direct industry sponsorship (de Lemos 2004; FACS 2010; FLORIDA 2002; L‐CAD 2000; LAMIL 1997; LIPS 2002; MIRACL 2001; PACT 2004; PAIS 2001; PRINCESS 2004; RECIFE 1999), the reader should be cautioned of a potential bias of interpretation of trial results (Als‐Nielsen 2003).
Comparison with other studies
Our findings contrast with results from published observational studies on the topic that suggest a lower risk of mortality with early statin therapy within one month following ACS (odds ratios as low as 0.4) (Aronow 2001; Fonarow 2005; Spencer 2004; Stenestrand 2001). Results from these observational studies, however, may be prone to bias due to survivor treatment selection (Glesby 1996), competing medical issues (Redelmeier 1998), or differences in unknown confounders between comparison groups (Laupacis 2004). Another large observational study that found no benefit of early statin initiation in a propensity and covariate‐adjusted analysis might have better captured potentially important confounders (Newby 2002). Our meta‐analysis of randomized controlled trials demonstrates that observational studies with insufficient control of confounders greatly overestimate the magnitude of effect from early statin therapy in ACS.
On first sight, our findings might appear to contrast with results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE‐IT) trial that randomized patients with ACS to atorvastatin 80 mg/day or pravastatin 40 mg/day (Cannon 2004a). In fact, however, there is no obvious discordance. In PROVE‐IT, Kaplan‐Meier curves of the primary composite endpoint appear to diverge as early as 30 days after ACS in favor of patients treated with atorvastatin, but the difference did not reach statistical significance until six months. It is important to note that the primary composite endpoint of PROVE‐IT comprised not only death, myocardial infarction, and stroke, but also recurrent unstable angina requiring re‐hospitalization and revascularization. If the more limited composite of death, myocardial infarction, and stroke is considered, there was no significant difference between the two treatment arms of PROVE‐IT. Unstable angina and revascularization were the most frequent events in PROVE‐IT and appeared to have driven the primary composite endpoint. Similarly, our meta‐analysis indicates that statins reduce the risk of unstable angina following ACS at four months. Although endpoints such as unstable angina depend at least in part on clinicians' judgment or action, and therefore may be less reliable (Freemantle 2003), our finding of a risk reduction for unstable angina of 19% (95% CI 1% to 34%) at four months in trials with blinded outcome assessment supports the validity of this result.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Funnel plot of comparison: 1 Statins versus control at 1 month, outcome: 1.1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Funnel plot of comparison: 2 Statins versus control at 4 months (3 to 6 months), outcome: 2.1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Funnel plot of comparison: 3 Statins versus control at 12 months, outcome: 3.1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Comparison 1 Statins versus control at 1 month, Outcome 1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Comparison 1 Statins versus control at 1 month, Outcome 2 Death from all causes.
Comparison 1 Statins versus control at 1 month, Outcome 3 Death from cardiovascular causes.
Comparison 1 Statins versus control at 1 month, Outcome 4 Fatal and non‐fatal myocardial infarction or reinfarction.
Comparison 1 Statins versus control at 1 month, Outcome 5 Fatal and non‐fatal stroke.
Comparison 1 Statins versus control at 1 month, Outcome 6 Revascularization procedures (bypass grafts, angioplasty).
Comparison 1 Statins versus control at 1 month, Outcome 7 Unstable angina.
Comparison 1 Statins versus control at 1 month, Outcome 8 Acute heart failure.
Comparison 2 Statins versus control at 4 months (3 to 6 months), Outcome 1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Comparison 2 Statins versus control at 4 months (3 to 6 months), Outcome 2 Death from all causes.
Comparison 2 Statins versus control at 4 months (3 to 6 months), Outcome 3 Death from cardiovascular causes.
Comparison 2 Statins versus control at 4 months (3 to 6 months), Outcome 4 Fatal and non‐fatal myocardial infarction or reinfarction.
Comparison 2 Statins versus control at 4 months (3 to 6 months), Outcome 5 Fatal and non‐fatal stroke.
Comparison 2 Statins versus control at 4 months (3 to 6 months), Outcome 6 Revascularization procedures (bypass grafts, angioplasty).
Comparison 2 Statins versus control at 4 months (3 to 6 months), Outcome 7 Unstable angina.
Comparison 2 Statins versus control at 4 months (3 to 6 months), Outcome 8 Acute heart failure.
Comparison 3 Statins versus control at 12 months, Outcome 1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Comparison 3 Statins versus control at 12 months, Outcome 2 Death from all causes.
Comparison 3 Statins versus control at 12 months, Outcome 3 Death from cardiovascular causes.
Comparison 3 Statins versus control at 12 months, Outcome 4 Fatal and non‐fatal myocardial infarction or reinfarction.
Comparison 3 Statins versus control at 12 months, Outcome 5 Fatal and non‐fatal stroke.
Comparison 3 Statins versus control at 12 months, Outcome 6 Revascularization procedures (bypass grafts, angioplasty).
Comparison 3 Statins versus control at 12 months, Outcome 7 Unstable angina.
Comparison 3 Statins versus control at 12 months, Outcome 8 Acute heart failure.
Comparison 4 Statins versus control: adverse events, Outcome 1 Rhabdomyolysis.
Comparison 4 Statins versus control: adverse events, Outcome 2 Elevated CK > 10x upper‐limit of normal.
Comparison 4 Statins versus control: adverse events, Outcome 3 Elevated ALT > 3x upper‐limit of normal.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 1 Allocation concealment ‐ combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 2 Blinded patients and caregivers ‐ combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 3 Blinded assessment ‐ combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 4 Allocation concealment ‐ death from all causes.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 5 Blinded patients and caregivers ‐ death from all causes.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 6 Blinded assessment ‐ death from all causes.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 7 Allocation concealment ‐ unstable angina.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 8 Blinded patients and caregivers ‐ unstable angina.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 9 Blinded assessment ‐ unstable angina.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 10 Death from all causes including PRINCESS.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 11 Fatal and non‐fatal myocardial infarction or reinfarction including PRINCESS.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 12 Fatal and non‐fatal stroke including PRINCESS.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 13 Unstable angina including PRINCESS.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 14 Initiation of statins.
Comparison 5 Statins versus control at 4 months: sensitivity analyses, Outcome 15 Types of statins.
| Statins compared to control at 4 months (3 to 6 months) for acute coronary syndrome | ||||||
| Patient or population: patients with acute coronary syndrome | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control at 4 months (3 to 6 months) | Statins | |||||
| Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths | 80 per 10001 | 75 per 1000 | RR 0.93 | 9625 | ⊕⊕⊕⊝ | |
| Death from all causes | 28 per 10001 | 25 per 1000 | RR 0.9 | 9733 | ⊕⊕⊕⊝ | |
| Fatal and non‐fatal myocardial infarction or reinfarction | 65 per 10001 | 59 per 1000 | RR 0.91 | 9537 | ⊕⊕⊕⊝ | |
| Fatal and non‐fatal stroke | 10 per 10001 | 7 per 1000 | RR 0.72 | 8536 | ⊕⊕⊕⊝ | |
| Unstable angina | 63 per 10001 | 48 per 1000 | RR 0.76 | 8770 | ⊕⊕⊕⊝ | |
| Acute heart failure | 26 per 10001 | 22 per 1000 | RR 0.86 | 7583 | ⊕⊕⊕⊝ | |
| Rhabdomyolysis | 0 per 10001 | 0 per 1000 | RR 6.9 | 4497 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1The basis of the assumed risk is the average risk of control group patients. | ||||||
| Trial (reference) | Randomized individuals, n | Mean age, years (SD) | Men, n (%) | Diabetes, n (%) | Hypertension, n (%) | Current smoker, n (%) | Prior MI, n (%) | MI as index event, n (%) | Fibrinolysis for index event, n (%) | PCI for index event, n (%) | ||||||||||
| Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | |
| LAMIL 1997 | 36 | 33 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 36 (100) | 33 (100) | NA | NA | NA | NA |
| RECIFE 1999 | 30 | 30 | 55 (2) | 56 (2) | 26 (93) | 22 (81) | 1 (4) | 0 (0) | 5 (18) | 8 (29) | 14 (50) | 17 (63) | 1 (4) | 2 (7) | 11 (39) | 12 (44) | 0 (0) | 0 (0) | 16 (57) | 17 (63) |
| L‐CAD 2000 | 70 | 56 | 55 (10) | 59 (11) | 57 (81) | 44 (79) | 0 (0) | 0 (0) | 22 (31) | 18 (32) | 49 (70) | 36 (64) | 45 (64) | 39 (70) | 32 (46) | 23 (41) | NA | NA | 58 (83) | 50 (89) |
| PAIS 2001 | 50 | 49 | 64 (1) | 63 (2) | 35 (70) | 37 (76) | 8 (16) | 5 (10) | 12 (24) | 16 (33) | 17 (34) | 17 (35) | 14 (28) | 12 (25) | 35 (70) | 31 (63) | 17 (34) | 14 (29) | 0 (0) | 0 (0) |
| PTT 2002 | 79 | 85 | 53 (11) | 52 (10) | 65 (82) | 69 (81) | 14 (18) | 13 (15) | 16 (20) | 21 (25) | 63 (80) | 66 (78) | 0 (0) | 0 (0) | 79 (100) | 85 (100) | 79 (100) | 85 (100) | 0 (0) | 0 (0) |
| PACT 2004 | 1710 | 1698 | 62 (12) | 61 (12) | 1308 (76) | 1285 (76) | 244 (14) | 234 (14) | 700 (41) | 714 (42) | 608 (36) | 575 (34) | 236 (14) | 197 (12) | 1109 (65) | 1111 (65) | 651 (38) | 671 (40) | 414 (24) | 406 (24) |
| LIPS 2002 | 417* | 407* | 61 (10) | 60 (10) | 344 (83) | 336 (83) | 65 (16) | 34 (8) | NA | NA | NA | NA | 184 (44) | 172 (42) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 417 (100) | 407 (100) |
| FLORIDA 2002 | 265 | 275 | 61 (12) | 60 (11) | 214 (81) | 234 (85) | 29 (11) | 31 (11) | 67 (25) | 65 (24) | 140 (53) | 139 (51) | 31 (12) | 31 (11) | 265 (100) | 275 (100) | 137 (52) | 133 (48) | 8 (3) | 10 (4) |
| MIRACL 2001 | 1538 | 1548 | 65 (12) | 65 (12) | 992 (64) | 1020 (66) | 342 (22) | 373 (24) | 843 (55) | 846 (55) | 429 (28) | 430 (28) | 382 (25) | 392 (25) | 812 (53) | 843 (55) | 109 (7) | 137 (9) | 0 (0) | 0 (0) |
| Colivicchi 2002 | 40 | 41 | 69 (14) | 68 (14) | 23 (58) | 24 (59) | 22 (55) | 24 (59) | 35 (88) | 37 (90) | NA | NA | 34 (85) | 35 (85) | NA | NA | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| ESTABLISH 2004 | 35 | 35 | 61 (10) | 63 (11) | 30 (86) | 30 (86) | 12 (34) | 11 (31) | 19 (54) | 19 (54) | 24 (69) | 19 (54) | 5 (14) | 5 (14) | 22 (63) | 26 (74) | 7 (20) | 3 (9) | 35 (100) | 35 (100) |
| A‐to‐Z 2004 | 2265 | 2232 | 60 (11) | 61 (11) | 1716 (76) | 1680 (75) | 529 (23) | 530 (24) | 1131 (50) | 1105 (50) | 926 (41) | 915 (41) | 409 (18) | 355 (16) | 1956 (86) | 1919 (86) | 483 (21) | 472 (21) | 979 (43) | 979 (44) |
| Sakamoto 2005 | 237 | 244 | 63 (11) | 65 (12) | 190 (80) | 193 (79) | 83 (35) | 61 (25) | 149 (63) | 142 (58) | 131 (55) | 130 (53) | 10 (4) | 15 (6) | 208 (88) | 219 (90) | 45 (19) | 50 (20) | 215 (91) | 220 (90) |
| Macin 2005 | 44 | 46 | 59 (13) | 61 (12) | 34 (77) | 33 (72) | 10 (23) | 11 (24) | 29 (65.9) | 31 (67.4) | 18 (41) | 19 (41) | 5 (11) | 7 (15) | 23 (52) | 31 (67) | 7 (15.9) | 8 (17.4) | 0 (0) | 0 (0) |
| Sato 2008 | 176 | 177 | 64 (10) | 63 (11) | 129 (73) | 142 (80) | 52 (30) | 59 (34) | 81 (46) | 87 (49) | 98 (56) | 105 (59) | 16 (9) | 19 (10) | NA | NA | NA | NA | 161 (91) | 161 (91) |
| Shal'nev 2007 | 55 | 55 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| FACS 2005 | 78 | 78 | 61 (12) | 63 (11) | 55 (71) | 51 (65) | 14 (18) | 16 (21) | 40 (51) | 40 (51) | 33 (42) | 39 (50) | 4 (5) | 8 (10) | > 47 (60) | > 54 (69) | 0 (0) | 0 (0) | 68 (87) | 71 (91) |
| Ren 2009 | 43 | 43 | 58 (11) | 59 (10) | 27 (63) | 30 (70) | 12 (28) | 10 (23) | 21 (49) | 18 (42) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| * These individuals make up the subgroup of patients with unstable angina (n=824). MI: myocardial infarction | ||||||||||||||||||||
| Source | Daily | Control | No. of | Mean initiation | Duration of | No. (%) of | Reported concealed |
| LAMIL 1997 | Pravastatin 10 to 20 mg | Placebo | 69 | 2 | 1 and 3 | 55 (80) | No/yes/yes/no |
| RECIFE 1999 | Pravastatin 40 mg | Placebo | 60 | 10 | 1.5 | 55 (92) | No/yes/yes/no |
| L‐CAD 2000 | Pravastatin 20 to 40 mg* | Usual care† | 126 | 6 | 1, 4, and 6 | 126 (100) | No/no/no/no |
| PAIS 2001 | Pravastatin 40 mg | Placebo | 99 | 2 | 1 and 3 | 97 (98) | No/yes/yes/no |
| PTT 2002 | Pravastatin 40 mg | Usual care† | 164‡ | 1 | 1 and 6‡ | 164 (100) | No/no/no/no |
| PACT 2004 | Pravastatin 20 to 40 mg | Placebo | 3408 | 1 | 1 | 3323 (98) | No/yes/yes/no |
| LIPS 2002 | Fluvastatin 80 mg | Placebo | 824§ | 2 | 1, 4, and 6 | 824 (100) | No/yes/yes/yes |
| FLORIDA 2002 | Fluvastatin 80 mg | Placebo | 540 | 8 | 1, 4, and 6 | 540 (100) | No/yes/yes/yes |
| MIRACL 2001 | Atorvastatin 80 mg | Placebo | 3086 | 3 | 1 and 4 | 3075 (99.6) | Yes/yes/yes/yes |
| Colivicchi 2002 | Atorvastatin 80 mg | Usual care† | 81 | 12 | 1, 3, and 6 | 81 (100) | No/no/no/yes |
| ESTABLISH 2004 | Atorvastatin 20 mg | Usual care† | 70 | 1 | 1, 4, and 6 | 69 (99) | No/no/no/no |
| A‐to‐Z 2004 | Simvastatin 40 to 80 mg | Placebo | 4497 | 4 | 1 and 4|| | 4453 (99) | Yes/yes/yes/yes |
| Sakamoto 2005 | Any statin** | Usual care | 486 | 4 | 12 | 407 (84) | No/No/No/Yes |
| Macin 2005 | Atorvastatin 40 mg | Placebo | 90 | 1 | 1 | 89 (99) | No/Yes/Yes/No |
| Sato 2008 | Pravastatin 10 mg | Usual care† | 353 | 7 | 1 and 12 | 348 (99) | No/No/No/Yes |
| Shal'nev 2007 | Simvastatin 40 mg | Usual care | 110 | 1 | 6 | 108 (98) | No/No/No/No |
| FACS 2005 | Fluvastatin 80 mg | Placebo | 156 | 1 | 1, 3, and 12 | 156 (100) | No/Yes/Yes/No |
| Ren 2009 | Simvastatin 40 mg | Placebo | 86 | 3 | 1 | 86 (100) | No/Yes/Yes/Yes |
| * 8 of 70 individuals received additionally cholestyramine or nicotinic acid. † Individuals in the control group were allowed conventional medical treatment including lipid‐lowering therapy. ‡ All 164 individuals were followed‐up for 1 month, a subgroup of 77 (40/37) individuals with additional coronary angioplasty were followed‐up for 6 months. § These 824 individuals represent just the subgroup with unstable angina; the LIPS [Lescol Intervention Prevention Study]‐trial originally included another 853 individuals with stable angina. || After 4 months individuals in the control group received simvastatin 20mg. ACS: acute coronary syndrome | |||||||
| Trial (reference) | Intervention | Follow‐up* | Total cholesterol | LDL cholesterol | HDL cholesterol | Triglycerides |
| Baseline mean, mg/dL (% mean change in difference between treatment and control groups)† | ||||||
| LAMIL 1997 | Pravastatin 10 to 20 mg | 3 months | 228 (‐13) | 158 (‐23) | 36 (+5.3) | NA |
| RECIFE 1999 | Pravastatin 40 mg | 1.5 months | 247 (‐21) | 164 (‐27) | 42 (+13) | 194 (‐21) |
| L‐CAD 2000‡ | Pravastatin 20 to 40 mg | 1 month | 237 (‐24) | 178 (‐25) | 32 (‐6.0) | 142 (±0) |
| PAIS 2001 | Pravastatin 40 mg | 3 months | 255 (‐23) | 176 (‐24) | 43 (+9.1) | 199 (‐13) |
| PTT 2002‡ | Pravastatin 40 mg | 1 month | 230 (‐12) | 133 (‐25) | 39 (+3.0) | 214 (‐5.8) |
| PACT 2004 | Pravastatin 20 to 40 mg | NA | 219 (NA) | NA | NA | NA |
| LIPS 2002 | Fluvastatin 80 mg | 1.5 months | 201 (‐28) | 131 (‐39) | 39 (‐2.0) | 155 (‐21) |
| FLORIDA 2002 | Fluvastatin 80 mg | 12 months | 207 (‐22) | 137 (‐31) | 46 (+3.3) | 146 (‐22) |
| MIRACL 2001 | Atorvastatin 80 mg | 1.5 months | 206 (‐37) | 124 (‐53) | 47 (±0) | 183 (‐28) |
| Colivicchi 2002‡ | Atorvastatin 80 mg | 2 months | 220 (‐9) | 131 (‐15) | 39 (+1.0) | 167 (‐13) |
| ESTABLISH 2004‡ | Atorvastatin 20 mg | 6 months | 191 (‐28) | 124 (‐41) | 44 (‐8.7) | 109 (+4.9) |
| A‐to‐Z 2004 | Simvastatin 40 to 80 mg | 1 month | 184 (‐33) | 112 (‐49) | 39 (+2.0) | 149 (‐22) |
| Sakamoto 2005 | Any statin | 3 months | 207 (‐12) | 134 (‐23) | 47 (+2.2) | 135 (‐5.2) |
| Macin 2005 | Atorvastatin 40 mg | 1 month | 194 (‐19) | 124 (‐30) | 37 (+11) | 189 (+0.8) |
| Sato 2008‡ | Pravastatin 10 mg | 9 months | 220 (NA) | 49 (NA) | 117 (NA) | 148 (NA) |
| Shal'nev 2007 | Simvastatin 40 mg | 0.5 months | 212 (‐29) | 131 (‐46) | 49 (‐9.5) | 146 (‐15) |
| FACS 2005 | Fluvastatin 80 mg | 1 month | 212 (‐26) | 135 (‐31) | 47 (‐4.1) | 162 (+10) |
| Ren 2009 | Simvastatin 40 mg | 1 month | 228 (‐23%) | 139 (‐31) | 40 (+9.6) | NA |
| * Lipid values in individual trials were measured at different time points during follow‐up; we report those closest to the 4 months follow‐up date. † Baseline lipid levels were defined as the average (mean) before treatment in intervention and control groups. The percentage of change for each trial was calculated as the difference in the mean change in lipid levels from baseline to follow‐up in the intervention and the control groups. To convert from mg/dL to mmol/L, multiply by 0.02586 for cholesterol and by 0.01129 for triglycerides. ‡ Individuals in the control group were allowed conventional medical treatment including lipid‐lowering therapy. HDL: high‐density lipoprotein | ||||||
| Trial (reference) | Total death, MI, stroke, n (%) * | Total death, n (%) | Cardiovascular death, n (%) | Total MI, n (%) | Total stroke, n (%) | Revascularization (CABG/PCI), n (%) | Unstable angina, n (%) | Adverse events, n (%) | Acute heart failure | QOL | ||||||||||||||
| Rhabdomyolysis | CK > 10x ULN | ALT > 3x ULN | ||||||||||||||||||||||
| Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | Statin | Control | |
| LAMIL 1997 | NA | NA | 1 (2.8) | 0 (0) | 1 (2.8) | 0 (0) | 1 (2.8) | 0 (0.0) | NA | NA | NA | NA | NA | NA | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA |
| 3 (8.3) | 3 (9.1) | 1 (2.8) | 0 (0) | 1 (2.8) | 0 (0) | 3 (8.3) | 3 (9.1) | 0 (0) | 0 (0) | 1 (2.8) | 1 (3.0) | NA | NA | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| RECIFE 1999 | 0 (0) | 1 (3.3) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0.0) | 1 (3.3) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (3.3) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (3.3) | NA | NA |
| L‐CAD 2000 | 1 (1.4) | 0 (0) | 1 (1.4) | 0 (0) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 0 (0) | 2 (3.6) | NA | NA | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 1 (1.4) | 1 (1.9) | 1 (1.4) | 1 (1.9) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 2 (2.9) | 9 (16.1) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| 1 (1.4) | 1 (1.9) | 1 (1.4) | 1 (1.9) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 6 (8.6) | 12 (21.4) | 6 (8.6) | 10 (17.9) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| PAIS 2001 | 2 (4.0) | 3 (6.1) | 1 (2.0) | 2 (4.1) | 1 (2.0) | 2 (4.1) | 2 (4.0) | 2 (4.1) | 0 (0) | 1 (2.0) | 4 (8.0) | 2 (4.1) | 16 (32.0) † | 11 (22.4) † | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 4 (8.0) | 4 (8.2) | 2 (4.0) | 2 (4.1) | 2 (4.0) | 2 (4.1) | 4 (8.0) | 2 (4.1) | 0 (0) | 2 (4.1) | 11 (22.0) | 9 (18.4) | 24 (48.0) † | 21 (42.9) † | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| PTT 2002 | 4 (5.1) | 14 (16.5) | 3 (3.8) | 9 (10.6) | 3 (3.8) | 7 (8.2) | 3 (3.8) | 5 (5.9) | 2 (2.5) | 7 (8.2) | 12 (15.2) | 15 (17.6) | 11 (13.9) † | 25 (29.4) † | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 2 (5.0) | 7 (18.9) | 1 (2.5) | 3 (8.1) | 0 (0) | 3 (8.1) | 1 (2.5) | 6 (16.2) | 0 (0) | 1 (2.7) | 11 (27.5) | 16 (43.2) | 12 (30.0) † | 22 (59.4) † | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| PACT 2004 | 86 (5.0) | 96 (5.7) | 27 (1.6) | 39 (2.3) | 26 (1.5) | 34 (2.0) | 67 (3.9) | 70 (4.1) | 8 (0.5) | 10 (0.6) | NA | NA | 123 (7.2) | 126 (7.4) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 7 (0.4) | 5 (0.3) | 28 (1.6) | 31 (1.8) | NA | NA |
| LIPS 2002 | 3 (0.7) | 1 (0.2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 3 (0.7) | 1 (0.2) | 0 (0) || | 0 (0) || | 77 (18.5) | 87 (21.4) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 8 (1.9) | 3 (0.7) | 1 (0.2) | 0 (0) | 1 (0.2) | 0 (0) | 7 (1.7) | 3 (0.7) | 0 (0) || | 0 (0) || | 78 (18.7) | 88 (21.6) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| 11 (2.6) | 10 (2.5) | 3 (0.7) | 4 (1.0) | 2 (0.5) | 3 (0.7) | 8 (1.9) | 6 (1.5) | 0 (0) || | 0 (0) || | 79 (18.9) | 88 (21.6) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| FLORIDA 2002 | 5 (1.9) | 5 (1.8) | 1 (0.4) | 3 (1.1) | 1 (0.4) | 3 (1.1) | 4 (1.5) | 2 (0.7) | 0 (0) | 1 (0.4) | 16 (6.0) | 12 (4.4) | 6 (2.3) ¶ | 5 (1.8) ¶ | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 10 (3.8) | 10 (3.6) | 2 (0.8) | 6 (2.2) | 2 (0.8) | 6 (2.2) | 8 (3.0) | 6 (2.2) | 0 (0) | 1 (0.4) | 30 (11.3) | 32 (11.6) | 11 (4.2) ¶ | 9 (3.3) ¶ | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| 14 (5.3) | 14 (5.1) | 3 (1.1) | 6 (2.2) | 3 (1.1) | 6 (2.2) | 11 (4.2) | 10 (3.6) | 0 (0) | 1 (0.4) | 36 (13.6) | 41 (14.9) | 14 (5.3) ¶ | 14 (5.1) ¶ | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| 28 (10.6) | 28 (10.2) | 7 (2.6) | 11 (4.0) | 6 (2.3) | 11 (4.0) | 21 (7.9) | 16 (5.8) | 2 (0.8) | 5 (1.8) | 46 (17.4) | 51 (18.5) | 16 (6.0)¶ | 18 (6.5)¶ | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| MIRACL 2001 | 101 (6.6) | 96 (6.2) | 32 (2.1) | 30 (1.9) | 27 (1.8) | 21 (1.4) | 80 (5.2) | 67 (4.3) | 7 (0.5) | 10 (0.6) | 162 (10.5) | 147 (9.5) | 72 (4.7) # | 87 (5.6) # | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | NA | NA |
| 162 (10.5) | 183 (11.8) | 64 (4.2) | 68 (4.4) | 51 (3.3) | 60 (3.9) | 118 (7.7) | 131 (8.5) | 12 (0.8) | 24 (1.6) | 254 (16.5) | 250 (16.1) | 95 (6.2) # | 130 (8.4) # | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 38 (2.5) | 9 (0.6) | 43 (2.8) | 40 (2.6) | NA | NA | |
| Colivicchi 2002 | 0 (0) | 3 (7.3) | 0 (0) | 1 (2.4) | 0 (0) | 1 (2.4) | 0 (0.0) | 3 (7.3) | 0 (0) | 0 (0) | 0 (0) ** | 0 (0) ** | 1 (2.5) # | 1 (2.4) # | 0 (0) | 0 (0) | 1 (2.5)## | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 5 (12.5) | 9 (22.0) | 2 (5.0) | 3 (7.3) | 1 (2.5) | 2 (4.9) | 3 (7.5) | 7 (17.1) | 1 (2.5) | 1 (2.4) | 0 (0) ** | 0 (0) ** | 2 (5.0) # | 3 (7.3) # | 0 (0) | 0 (0) | 1 (2.5)## | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| 7 (17.5) | 13 (31.7) | 3 (7.5) | 4 (9.8) | 2 (5.0) | 3 (9.8) | 5 (12.5) | 10 (24.4) | 1 (2.5) | 2 (4.9) | 0 (0) ** | 0 (0) ** | 2 (5.0) # | 6 (14.6) # | 0 (0) | 0 (0) | 1 (2.5)## | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| ESTABLISH 2004 | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 0 (0) | 1 (2.9) | 0 (0) | 1 (2.9) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| 0 (0) | 1 (2.9) | 0 (0) | 1 (2.9) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | 0 (0) | 0 (0) | 8 (22.9) | 8 (22.9) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| A‐to‐Z 2004 | 99 (4.4) | 105 (4.7) | 20 (0.9) | 29 (1.3) | 20 (0.9) | 29 (1.3) | 86 (3.8) | 98 (4.4) | 10 (0.4) | 6 (0.3) | 19 (0.8) †† | 22 (1.0) †† | 27 (1.2) ‡‡ | 30 (1.3) ‡‡ | 3 (0.1) | 0 (0) | 0 (0) | 1 (0.04) | 1 (0.04) | 27 (1.2)§§ | 31 (1.4)§§ | NA | NA | NA |
| 161 (7.1) | 160 (7.2) | 44 (1.9) | 48 (2.2) | 42 (1.9) | 48 (2.2) | 130 (5.7) | 140 (6.3) | 16 (0.7) | 12 (0.5) | 60 (2.6) †† | 60 (2.7) †† | 56 (2.5) ‡‡ | 61 (2.7) ‡‡ | 3 (0.1) | 0 (0) | 7 (0.3) | 1 (0.04) | 13 (5.7) | 45 (2.0)§§ | 55 (2.5)§§ | 98 (5.0) | NA | NA | |
| Sakamoto 2005 | 4 (1.7) | 1 (0.4) | 4 (1.7) | 1 (0.4) | 4 (1.7) | 1 (0.4) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| 12 (5.0) | 4 (1.6) | 6 (2.5) | 2 (0.8) | 6 (2.5) | 2 (0.8) | NA | NA | 3 (1.2) | 2 (0.8) | 18 (7.5) | 24 (9.8) | 6 (2.5) | 17 (6.9) | NA | NA | NA | NA | NA | NA | 1 (0.4) | 9 (3.7) | NA | NA | |
| Macin 2005 | 3 (6.8) | 5 (10.9) | 1 (2.3) | 3 (6.5) | 1 (2.3) | 3 (6.5) | 1 (2.3) | 3 (6.5) | 0 (0) | 0 (0) | 8 (18.2)¶ | 8 (17.4)¶ | 7 (1.6) | 8 (1.7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 4 (9.3) | 10 (21.7) | NA | NA |
| Sato 2008 | 0 (0) | 1 (0.6) | 0 | 1 (0.6) | 0 (0) | 1 (0.6) | 0 (0.0) | 0 (0.0) | 0 (0) | 1 (0.6) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA |
| 4 (2.3) | 7 (4.0) | 3 (1.7) | 2 (1.1) | 1 (0.6) | 2 (1.1) | NA | NA | 0 (0) | 2 (1.1) | 22 (12.7) | 36 (20.6) | 5 (2.9) | 5 (2.9) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 5 (2.8) | NA | NA | |
| Shal'nev 2007 | NA | NA | 2 (3.6) | 3 (5.5) | NA | NA | NA | NA | NA | NA | NA | NA | 4 (7.3) | 7 (12.7) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| FACS 2005 | 2 (2.6) | 2 (2.6) | 1 (1.3) | 0 (0) | 0 (0) | 0 (0) | 1 (1.3) | 2 (2.6) | 0 (0) | 0 (0) | 3 (3.8) | 4 (5.1) | 2 (2.6) | 6 (7.7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA |
| 2 (2.6) | 4 (5.1) | 1 (1.3) | 0 (0) | 0 (0) | 0 (0) | 1 (1.3) | 3 (3.8) | 0 (0) | 1 (1.3) | 3 (3.8) | 8 (10.3) | 3 (3.8) | 12 (15.4) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| 4 (5.1) | 10 (12.8) | 1 (1.3) | 4 (5.1) | 0 (0) | 2 (2.6) | 2 (2.6) | 5 (6.4) | 1 (1.3) | 3 (3.8) | 6 (7.7) | 15 (19.2) | 6 (7.7) | 16 (20.5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA | NA | NA | |
| Ren 2009 | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0.0) | 0 (0.0) | NA | NA | 0 (0) | 1 (2.3) | NA | NA | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | NA | NA |
| * Combined primary endpoint; unique patients. † Patients with “recurrent angina pectoris”. ‡ All 164 individuals were followed‐up for 1 month, a subgroup of 77 individuals with additional coronary angioplasty were followed‐up for 6 months. § These 824 individuals represent just the subgroup with unstable angina; the LIPS [Lescol Intervention Prevention Study]‐trial originally included another 853 individuals with stable angina. || Fatal strokes only; non‐fatal strokes were not recorded. ¶ Patients with “recurrent ischemia necessitating hospitalization”. # Patients with “recurrent symptomatic myocardial ischemia with objective evidence and emergency hospitalization”. ** Individuals enrolled into the trial were not amenable for direct revascularization by coronary artery bypass grafting or percutaneous coronary intervention. †† Revascularization procedures had to be urgent, occur more than 14 days after randomization, and were not allowed to be planned prior to enrollment. ‡‡ Patients with “readmission for acute coronary syndrome”. §§ Patients with “new onset congestive heart failure requiring admission or initiation of heart failure medications”. ALT: aminotransferase CK: creatin kinase ULN: upper limit of normal values | ||||||||||||||||||||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths Show forest plot | 13 | 13484 | Risk Ratio (IV, Random, 95% CI) | 0.93 [0.80, 1.08] |
| 2 Death from all causes Show forest plot | 13 | 13155 | Risk Ratio (IV, Random, 95% CI) | 0.78 [0.59, 1.03] |
| 3 Death from cardiovascular causes Show forest plot | 10 | 12387 | Risk Ratio (IV, Random, 95% CI) | 0.80 [0.60, 1.07] |
| 4 Fatal and non‐fatal myocardial infarction or reinfarction Show forest plot | 12 | 13074 | Risk Ratio (IV, Random, 95% CI) | 0.98 [0.82, 1.16] |
| 5 Fatal and non‐fatal stroke Show forest plot | 7 | 12147 | Risk Ratio (IV, Random, 95% CI) | 0.78 [0.47, 1.29] |
| 6 Revascularization procedures (bypass grafts, angioplasty) Show forest plot | 10 | 9668 | Risk Ratio (IV, Random, 95% CI) | 1.00 [0.86, 1.16] |
| 7 Unstable angina Show forest plot | 10 | 12181 | Risk Ratio (IV, Random, 95% CI) | 0.89 [0.76, 1.05] |
| 8 Acute heart failure Show forest plot | 5 | 11141 | Risk Ratio (IV, Random, 95% CI) | 0.85 [0.63, 1.14] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths Show forest plot | 11 | 9625 | Risk Ratio (IV, Random, 95% CI) | 0.93 [0.81, 1.06] |
| 2 Death from all causes Show forest plot | 12 | 9733 | Risk Ratio (IV, Random, 95% CI) | 0.90 [0.70, 1.14] |
| 3 Death from cardiovascular causes Show forest plot | 8 | 9273 | Risk Ratio (IV, Random, 95% CI) | 0.84 [0.64, 1.09] |
| 4 Fatal and non‐fatal myocardial infarction or reinfarction Show forest plot | 10 | 9537 | Risk Ratio (IV, Random, 95% CI) | 0.91 [0.77, 1.06] |
| 5 Fatal and non‐fatal stroke Show forest plot | 7 | 8536 | Risk Ratio (IV, Random, 95% CI) | 0.72 [0.45, 1.16] |
| 6 Revascularization procedures (bypass grafts, angioplasty) Show forest plot | 9 | 9474 | Risk Ratio (IV, Random, 95% CI) | 0.92 [0.78, 1.08] |
| 7 Unstable angina Show forest plot | 9 | 8770 | Risk Ratio (IV, Random, 95% CI) | 0.76 [0.59, 0.96] |
| 8 Acute heart failure Show forest plot | 2 | 7583 | Risk Ratio (IV, Random, 95% CI) | 0.86 [0.65, 1.15] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths Show forest plot | 6 | 2080 | Risk Ratio (IV, Random, 95% CI) | 0.80 [0.58, 1.11] |
| 2 Death from all causes Show forest plot | 6 | 2080 | Risk Ratio (IV, Random, 95% CI) | 0.68 [0.39, 1.20] |
| 3 Death from cardiovascular causes Show forest plot | 5 | 1954 | Risk Ratio (IV, Random, 95% CI) | 0.55 [0.28, 1.09] |
| 4 Fatal and non‐fatal myocardial infarction or reinfarction Show forest plot | 5 | 1954 | Risk Ratio (IV, Random, 95% CI) | 0.94 [0.61, 1.45] |
| 5 Fatal and non‐fatal stroke Show forest plot | 4 | 1130 | Risk Ratio (IV, Random, 95% CI) | 0.38 [0.13, 1.10] |
| 6 Revascularization procedures (bypass grafts, angioplasty) Show forest plot | 5 | 1999 | Risk Ratio (IV, Random, 95% CI) | 0.70 [0.52, 0.93] |
| 7 Unstable angina Show forest plot | 4 | 1130 | Risk Ratio (IV, Random, 95% CI) | 0.61 [0.33, 1.12] |
| 8 Acute heart failure Show forest plot | 1 | 353 | Risk Ratio (IV, Random, 95% CI) | 0.09 [0.01, 1.64] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Rhabdomyolysis Show forest plot | 1 | 4497 | Risk Ratio (IV, Random, 95% CI) | 6.90 [0.36, 133.47] |
| 2 Elevated CK > 10x upper‐limit of normal Show forest plot | 3 | 4677 | Risk Ratio (IV, Random, 95% CI) | 4.69 [1.01, 21.67] |
| 3 Elevated ALT > 3x upper‐limit of normal Show forest plot | 5 | 11914 | Risk Ratio (IV, Random, 95% CI) | 2.49 [1.16, 5.32] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Allocation concealment ‐ combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths Show forest plot | 11 | 9625 | Risk Ratio (IV, Random, 95% CI) | 0.93 [0.81, 1.06] |
| 1.1 Reported allocation concealment | 3 | 8407 | Risk Ratio (IV, Random, 95% CI) | 0.96 [0.79, 1.16] |
| 1.2 No reported allocation concealment | 8 | 1218 | Risk Ratio (IV, Random, 95% CI) | 0.70 [0.44, 1.14] |
| 2 Blinded patients and caregivers ‐ combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths Show forest plot | 11 | 9625 | Risk Ratio (IV, Random, 95% CI) | 0.93 [0.81, 1.06] |
| 2.1 Blinded patients and caregivers | 7 | 9271 | Risk Ratio (IV, Random, 95% CI) | 0.95 [0.82, 1.09] |
| 2.2 No blinded patients and caregivers | 4 | 354 | Risk Ratio (IV, Random, 95% CI) | 0.46 [0.21, 1.00] |
| 3 Blinded assessment ‐ combined outcome of non‐fatal myocardial infarction, non‐fatal stroke, and total number of deaths Show forest plot | 11 | 9625 | Risk Ratio (IV, Random, 95% CI) | 0.93 [0.81, 1.06] |
| 3.1 Blinded outcome assessors | 5 | 9028 | Risk Ratio (IV, Random, 95% CI) | 0.94 [0.82, 1.08] |
| 3.2 No blinded outcome assessors | 6 | 597 | Risk Ratio (IV, Random, 95% CI) | 0.60 [0.30, 1.22] |
| 4 Allocation concealment ‐ death from all causes Show forest plot | 12 | 9733 | Risk Ratio (IV, Random, 95% CI) | 0.90 [0.70, 1.14] |
| 4.1 Reported allocation concealment | 3 | 8407 | Risk Ratio (IV, Random, 95% CI) | 0.94 [0.72, 1.21] |
| 4.2 No reported allocation concealment | 9 | 1326 | Risk Ratio (IV, Random, 95% CI) | 0.64 [0.31, 1.31] |
| 5 Blinded patients and caregivers ‐ death from all causes Show forest plot | 12 | 9733 | Risk Ratio (IV, Random, 95% CI) | 0.90 [0.70, 1.14] |
| 5.1 Blinded patients and caregivers | 7 | 9271 | Risk Ratio (IV, Random, 95% CI) | 0.93 [0.72, 1.19] |
| 5.2 No blinded patients and caregivers | 5 | 462 | Risk Ratio (IV, Random, 95% CI) | 0.55 [0.21, 1.44] |
| 6 Blinded assessment ‐ death from all causes Show forest plot | 12 | 9733 | Risk Ratio (IV, Random, 95% CI) | 0.90 [0.70, 1.14] |
| 6.1 Blinded outcome assessors | 5 | 9028 | Risk Ratio (IV, Random, 95% CI) | 0.91 [0.71, 1.17] |
| 6.2 No blinded outcome assessors | 7 | 705 | Risk Ratio (IV, Random, 95% CI) | 0.77 [0.31, 1.90] |
| 7 Allocation concealment ‐ unstable angina Show forest plot | 9 | 8770 | Risk Ratio (IV, Random, 95% CI) | 0.76 [0.59, 0.96] |
| 7.1 Reported allocation concealment | 2 | 7583 | Risk Ratio (IV, Random, 95% CI) | 0.79 [0.64, 0.97] |
| 7.2 No reported allocation concealment | 7 | 1187 | Risk Ratio (IV, Random, 95% CI) | 0.68 [0.44, 1.04] |
| 8 Blinded patients and caregivers ‐ unstable angina Show forest plot | 9 | 8770 | Risk Ratio (IV, Random, 95% CI) | 0.76 [0.59, 0.96] |
| 8.1 Blinded patients and caregivers | 5 | 8378 | Risk Ratio (IV, Random, 95% CI) | 0.85 [0.64, 1.14] |
| 8.2 No blinded patients and caregivers | 4 | 392 | Risk Ratio (IV, Random, 95% CI) | 0.51 [0.34, 0.79] |
| 9 Blinded assessment ‐ unstable angina Show forest plot | 9 | 8770 | Risk Ratio (IV, Random, 95% CI) | 0.76 [0.59, 0.96] |
| 9.1 Blinded outcome assessors | 4 | 8204 | Risk Ratio (IV, Random, 95% CI) | 0.81 [0.66, 0.99] |
| 9.2 No blinded outcome assessors | 5 | 566 | Risk Ratio (IV, Random, 95% CI) | 0.59 [0.35, 1.00] |
| 10 Death from all causes including PRINCESS Show forest plot | 13 | 13338 | Risk Ratio (IV, Random, 95% CI) | 0.95 [0.78, 1.17] |
| 11 Fatal and non‐fatal myocardial infarction or reinfarction including PRINCESS Show forest plot | 11 | 13142 | Risk Ratio (IV, Random, 95% CI) | 0.90 [0.78, 1.03] |
| 12 Fatal and non‐fatal stroke including PRINCESS Show forest plot | 8 | 12141 | Risk Ratio (IV, Random, 95% CI) | 0.79 [0.52, 1.18] |
| 13 Unstable angina including PRINCESS Show forest plot | 10 | 12375 | Risk Ratio (IV, Random, 95% CI) | 0.78 [0.65, 0.95] |
| 14 Initiation of statins Show forest plot | 11 | 9625 | Risk Ratio (IV, Random, 95% CI) | 0.93 [0.81, 1.06] |
| 14.1 Statin initiated within 3 days | 6 | 1295 | Risk Ratio (IV, Random, 95% CI) | 0.82 [0.41, 1.64] |
| 14.2 Initiation of statins up to 14 days | 5 | 8330 | Risk Ratio (IV, Random, 95% CI) | 0.93 [0.81, 1.07] |
| 15 Types of statins Show forest plot | 11 | 9625 | Risk Ratio (IV, Random, 95% CI) | 0.93 [0.81, 1.06] |
| 15.1 Pravastatin | 4 | 371 | Risk Ratio (IV, Random, 95% CI) | 0.65 [0.29, 1.45] |
| 15.2 Fluvastatin | 3 | 1520 | Risk Ratio (IV, Random, 95% CI) | 1.17 [0.54, 2.53] |
| 15.3 Atorvastatin | 3 | 3237 | Risk Ratio (IV, Random, 95% CI) | 0.87 [0.72, 1.06] |
| 15.4 Simvastatin | 1 | 4497 | Risk Ratio (IV, Random, 95% CI) | 0.99 [0.80, 1.22] |
