Effect of High‐Dose Statin Pretreatment on the Incidence of Periprocedural Myocardial Infarction in Patients Undergoing Percutaneous Coronary Intervention: Grading the Evidence Through a Cumulative Meta‐analysis

ABSTRACT

Background

Previous studies have showed that high‐dose statin pretreatment could reduce the incidence of periprocedural myocardial infarction (PMI) in patients undergoing percutaneous coronary intervention (PCI). However, previous analyses have not performed reliable grading of evidence.

Hypothesis

In previous analyses, it supposed that the high‐dose statin pretreatment was effective in reduction of the rate of PMI. In this analysis, we evaluated the effect of high‐dose statin pretreatment on the reduction of rate of PMI based on a cumulative meta‐analysis and grading of evidence.

Methods

We assembled the relevant published randomized controlled trials that compared the efficacy of high‐dose statin pretreatment prior to PCI. We evaluated the risk of PMI by a cumulative meta‐analysis, with subgroups stratified by clinical classifications and different statin histories, and we conducted explicit grading of evidence.

Results

High‐dose statin pretreatment caused a 55% reduction in PMI through this cumulative meta‐analysis of 23 RCTs (odds ratio [OR]: 0.45, 95% confidence interval [CI]: 0.37‐0.54). The effect of high‐dose statin pretreatment was significant for the stable angina subgroup (OR: 0.42, 95% CI: 0.32‐0.56), ACS subgroup (OR: 0.43, 95% CI: 0.29‐0.64), and the mixed presentation subgroup (OR: 0.50, 95% CI: 0.36‐0.70). In different statin therapy histories, high‐dose statin pretreatment reduced incidence of PMI 55% in the statin‐naive subgroup (OR: 0.45, 95% CI: 0.36‐0.56) and 54% in the low‐dose statin subgroup (OR: 0.46, 95% CI: 0.32‐0.66). The GRADE system indicated that the overall evidence quality was moderate. This finding may strengthen the confidence in any recommendations.

Conclusions

High‐dose statin pretreatment can reduce the rate of PMI, irrespective of either the clinical presentation or previous statin‐treatment history. Importantly, the overall GRADE evidence quality was moderate.

Introduction

Percutaneous coronary intervention (PCI) is established as an important part of treatment for coronary artery disease. Recently, PCI has become a prevalent revascularization strategy based on low rates of severe complications. In the last few years, the number of patients undergoing PCI for coronary artery disease has been increasing rapidly, according to many medical reports from all over the world. However, many studies have demonstrated that periprocedural myocardial infarction (PMI) is a vital and frequent complication for patients undergoing PCI,1 which was assessed by quantitative measurement of myocardial enzymes and elevation of cardiac biomarkers such as troponins and creatine kinase‐myocardial band,2 leading to higher mortality during the perioperative period.3, 4 Cardiologists have indicated that several factors affect the occurrence of PMI, including the formation of distal embolism, side‐branch occlusion, coronary artery dissection, disruption of collateral flow, inflammation, and mixed pathological mechanisms.1, 5

Recently, studies have indicated that high‐dose statin pretreatment may result in a significant reduction in PMI in patients undergoing PCI.6, 7 Patti et al performed a meta‐analysis that demonstrated that high‐dose statin pretreatment is significantly associated with the reduction of PMI, without assessing the relative subgroups.8 Another more comprehensive meta‐analysis in 2014 including 24 randomized controlled trials (RCTs) grouped the patients according to whether or not they had a different history of statin treatment prior to the high‐dose statin pre‐PCI treatment.9 They suggested that the positive effect of high‐dose statin pretreatment on PMI is significant for the previous 2 subgroups. However, the previous studies were not conducted with assessment of the evidence quality levels and recommendations.

Therefore, the aims of the present study are to appraise the evidence from a cumulative meta‐analysis that evaluates the effect of high‐dose statin pretreatment on the incidence of PMI in patients undergoing PCI and to develop GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) based on the recommendations for using a high‐dose statin in patients who are undergoing PCI.

Methods

Search Strategy

We assembled the relevant published RCTs and PRISMA‐compliant searches of MEDLINE, OVID, Science Direct, Embase, the Cochrane Central database and Google Scholar published through January 2014 that compared the efficacy of high‐dose statin pretreatment with different clinical classifications and statin‐therapy histories prior to PCI. The following search terms were used to maximize the search sensitivity and specificity: percutaneous coronary intervention, PCI, stent, randomized, periprocedural myocardial infarction, PMI, statin, statins, atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and hydroxymethylglutaryl‐CoA.

Inclusion and Exclusion Criteria

Studies were included if they estimated the effect of high‐dose statin pretreatment in patients undergoing PCI. The important focus of our analysis was the susceptibility of PMI, which was determined through the elevation of cardiac biomarkers and myocardial enzymes. Single case reports, review articles, and noncomparable studies were excluded. We restricted our study to RCTs, which are less likely than observational studies to be subject to bias and confounding factors. Studies were eligible for inclusion in the present meta‐analysis if the following criteria were met: (1) study type was RCT; (2) the trial evaluated the effect of high‐dose statin pretreatment in patients undergoing PCI; (3) the study included enough follow‐up time after PCI; and (4) the study reported the incidence of PMI, the primary endpoint of the following outcome.

Study Selection

In the present study, 2 authors independently screened the titles and abstracts of the studies for the eligibility criteria. Furthermore, the full text of the studies that potentially met the inclusion criteria was read and reviewed to determine the final included studies. Disagreements were resolved by consensus reached through discussion.

Date Extraction

The data from all included studies were extracted independently by 2 reviewers (C.N.Z. and Y.Z.) using a standardized data‐extraction protocol. The data included the study title, authors, and design; clinical classification; perioperative statin regime; type of statin; follow‐up duration; and outcome parameters. The corresponding authors of the included studies were contacted to obtain any required information that was missing. The extracted data were verified by H.L.C.

Outcomes

The following items were the outcomes of the present study: the incidence of PMI with statin pretreatment, comparing no statin with low‐dose statin; the incidence of PMI when subgroup analysis was conducted according to different clinical presentation; and the incidence of PMI based on the cumulative meta‐analysis.

Assessment of Methodological Quality

Following the Cochrane Handbook for Systematic Reviews of Interventions 5.3,10 the methodological quality of the included studies was independently assessed by 2 authors (C.N.Z. and Y.Z.). Any disagreements were resolved by discussion. The third author (H.L.C.) was the adjudicator when no consensus could be achieved.

Statistical Analysis

All of the meta‐analyses were performed with the RevMan software, version 5.1 (the Nordic Cochrane Centre, the Cochrane Collaboration, Copenhagen, Denmark). The odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the dichotomous outcomes, such as the incidence of PMI. To combine the separate statistics, the inverse variance and Mantel‐Haenszel techniques were used. The heterogeneity was investigated by the use of the Q statistic, and P values <0.05 was regarded as statistically significant. A fixed‐effects model was used when the effects were assumed to be homogenous (P > 0.05). P < 0.05 was regarded as statistical heterogeneity, and a random‐effects model was used in the above circumstances. In the cumulative meta‐analysis, outcome data for the effect of high‐dose statin pretreatment on the incidence of PMI in patients undergoing PCI from all present studies were calculated sequentially according to the year first used.

Publication bias was evaluated statistically using Begg funnel plots and the Egger bias test using Stata software, version 12.0 (StataCorp LP, College Station, TX). The above methods measured the degree of funnel‐plot asymmetry statistically.11, 12 The Begg adjusted rank correlation test was used to evaluate the relationship between the test accuracy estimates and their variances. The deviation of Spearman ρ values from zero provided an estimate of the funnel‐plot asymmetry. Positive values indicated a trend toward higher levels of test accuracy in studies with smaller sample sizes. The Egger bias test detects funnel‐plot asymmetry by determining whether the intercept deviates significantly from zero in a regression of the standardized effect estimates against their precision values.

Evidence Synthesis

The evidence grade was determined by the use of the guidelines of the GRADE working group.13 Although the GRADE system acknowledged the primacy of RCTs, it also recognized circumstances in which observational studies generated high‐quality evidence of treatment effects. The GRADE system uses a sequential assessment of the evidence quality that is followed by an assessment of the risk‐benefit balance and a subsequent judgment on the strength of the recommendations. The evidence grades are divided into the following categories: (1) high grade, which indicates that further research is unlikely to change confidence in the effect estimate; (2) moderate grade, which indicates that further research is likely to significantly alter confidence in the effect estimate and may change the estimate; (3) low grade, which indicates that further research is likely to significantly alter confidence in the effect estimate and to change the estimate; and (4) very low grade, which indicates that any effect estimate is uncertain. Uniformity of the estimated effects across studies and the extent to which the patients, interventions, and outcome measures are similar to those of interest may lower or raise the evidence grade.14, 15, 16, 17, 18 The reasons for increasing the quality of evidence include presentation of a dose‐response gradient, a large effect, and plausible confounders that would decrease an apparent treatment effect.19 As recommended by the GRADE working group, the lowest evidence quality for any of the outcomes is used to rate the overall evidence quality. The evidence quality is graded by using GRADE Pro version 3.6 software. The strengths of the recommendations are according to the quality of the evidence.

Results

Search of the Published Literature

We obtained 511 articles during our initial electronic search; after screening abstracts, most were excluded because they had no relevance to our analysis. Fifty‐eight articles were then removed because of small number cases and unusable data. Finally, 23 studies satisfying the eligibility criteria, all of which adopted a RCT design, eventually met the inclusion criteria of our meta‐analysis.20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42

Methodological Quality of Included Studies

The methodological quality of included studies is presented in Figure 1. Judgments about each risk‐of‐bias item are presented as percentages across all included studies in Figure 2.

Figure 1.

Methodological quality of included studies. This risk‐of‐bias tool incorporates assessment of randomization (sequence generation and allocation concealment), blinding (participants, personnel, and outcome assessors), completeness of outcome data, selection of outcomes reported, and other sources of bias. The items were scored with “yes,” “no,” or “unsure.” Abbreviations: ARMYDA, Atorvastatin for Reduction of Myocardial Damage During Angioplasty; ARMYDA‐RECAPTURE, Atorvastatin for Reduction of Myocardial Damage During Angioplasty‐RECAPTURE.

Figure 2.

Risk of bias. Each risk‐of‐bias item is presented as percentages across all included studies, which indicate the proportion of different levels of risk of bias for each item.

Characteristics of Included Studies

A total of 23 RCTs on the effect of high‐dose statin pretreatment in patients undergoing PCI were involved in the present cumulative meta‐analysis, containing 5311 individuals. Table 1 shows the characteristics of the overall individuals included in the trials investigated. Although we tried to contact authors of the original studies, no responses were received.

Table 1.

Characteristics of the Included Studies

Study	Year	Clinical Presentation	High‐Dose Statin, n	Controls, n	Type of Population	Type of Statin	Statin Regime Before PCI	Statin Regime After PCI	Follow‐up
ARMYDA21	2004	Stable angina	76	77	Statin naive	Atorvastatin	7‐d 40‐mg qd before PCI vs placebo	40 mg qd	30 d
Briguori et al20	2004	8% UA; 92% stable angina/ asymptomatic	226	225	Statin naive	29% atorvastatin; 29% pravastatin; 39% simvastatin; 3% fluvastatin	3‐d pretreatment (average 17 d) vs no statin pretreatment	Same statin as before PCI in the statin group; atorvastatin 20 mg qd in control	In‐hospital
ARMYDA‐ACS24	2007	NSTE‐ACS	86	85	Statin naive	Atorvastatin	80 mg 12 h before PCI + 40 mg 2 h before PCI vs placebo before PCI	40 mg qd	30 d
Kinoshita et al23	2007	Stable angina	21	21	Statin naive	Atorvastatin	5–20 mg qd ≥2 wk before PCI to reach LDL‐C <70 mg/dL vs 100 mg/dL	5–20 mg qd	6 mo
Bozbas et al22	2007	Stable angina	29	64	Statin naive	Pravastatin	1‐wk pretreatment with 10 mg qd vs 40 mg qd before PCI vs no statin pretreatment	10–40 mg qd	In‐hospital
NAPLES II25	2009	98% stable angina/ asymptomatic; 2% UA	338	330	Statin naive	Atorvastatin	80 mg within 24 h before PCI vs no statin pretreatment	20 mg qd	In‐hospital
ARMYDA‐ RECAPTURE26	2009	53% stable angina and 47% NSTE‐ACS	192	191	Statin treated	Atorvastatin	80 mg 12 h before PCI + 40 mg 2 h before PCI vs placebo	40 mg qd	30 d
Jia et al27	2009	70.6% NSTE‐ACS; 29.4% STE‐ACS	113	115	Statin naive	Simvastatin	7‐day pretreatment with 80 mg qd before PCI vs 20 mg qd before PCI	20 mg qd	In‐hospital
Cay et al28	2010	Stable angina	153	146	Statin naive	Rosuvastatin	40 mg 24 h before PCI vs no statin pretreatment	10 mg to 40 mg qd	In‐hospital
Toso et al30	2011	Stable angina	77	84	Statin naive	Atorvastatin	80 mg within 48 h before PCI vs placebo within 48 h before PCI	NA	In‐hospital
Yun et al33	2011	NSTE‐ACS	225	220	Statin naive	Rosuvastatin	40 mg within 7–25 h before PCI vs no statin treatment before PCI	10 mg qd	12 mo
Veselka et al31	2011	Stable angina	100	100	Statin naive	Atorvastatin	2‐day pretreatment with 80 mg qd before PCI vs no statin pretreatment	20 mg to 80 mg qd	45 mo
Fujii et al29	2011	Stable angina	40	40	Statin naive	Pravastatin	4‐week pretreatment with 20 mg qd before PCI vs no statin pretreatment	NA	In‐hospital
Yu et al32	2011	NSTE‐ACS	41	40	Statin naive	Atorvastatin	80 mg 12 h before PCI + 40 mg before PCI vs placebo	20 mg qd	30 d
Gao et al34	2012	NSTE‐ACS	59	58	Statin naive	Rosuvastatin	20 mg 12 h before PCI + 10 mg 2 h before PCI vs no statin treatment	10 mg qd	6 mo
Jang et al42	2013	NSTE‐ACS	163	172	Statin naive	Atorvastatin	80 mg 12 h and 40 mg 2 h before PCI vs no statin pretreatment	40 mg qd	30 d
Zemanek et al41	2013	Stable angina	100	102	Statin‐treated	Atorvastatin	7‐d pretreatment with 80 mg qd vs no statin pretreatment	NA	In‐hospital
ROMA II38	2013	Stable angina	350	100	Statin‐treated	Atorvastatin, rosuvastatin	Rosuvastatin 40 mg qd or atorvastatin 80 mg 24 h before PCI vs no statin pretreatment	Rosuvastatin 20 mg qd; atorvastatin 40 mg qd	12 mo
Nafasi et al35	2013	Stable angina and recent MI	95	95	Statin‐treated	Atorvastatin	80 mg within 24 h before PCI vs placebo within 24 h before PCI	NA	In‐hospital
ROMA37	2013	Stable angina	80	80	Statin naive	Rosuvastatin	Rosuvastatin 40 mg within 24 h before PCI vs no statin treatment	20 mg qd	12 mo
Takano et al39	2013	Stable angina	104	106	Statin treated and statin naive	Rosuvastatin	5–7‐d pretreatment with 20 mg qd before PCI vs 5–7‐d pretreatment with 2.5 mg before PCI	10 mg qd and 2.5 mg qd	In‐hospital
Wang et al40	2013	NSTE‐ACS	62	63	Statin naive	Rosuvastatin	20 mg 2–4 h before PCI vs placebo before PCI	10 mg qd	30 d
Luo et al36	2013	NSTE‐ACS	31	36	Statin naive	Rosuvastatin	20 mg 12 h before PCI + 20 mg 2 h before PCI vs no statin pretreatment	10 mg qd	30 d

Abbreviations: ARMYDA, Atorvastatin for Reduction of Myocardial Damage During Angioplasty; LDL‐C, low‐density lipoprotein cholesterol; MI, myocardial infarction; NA, not available; NAPLES II, Novel Approaches for Preventing or Limiting Events II; NSTE‐ACS, non–ST‐segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; qd, every day; ROMA, Rosuvastatin pretreatment in patients undergoing elective PCI to reduce the incidence of myocardial periprocedural necrosis; UA, unstable angina.

Cumulative Meta‐analysis Outcomes in Overall Studies

The fixed‐effects model to analyze data of 23 RCTs performed for cumulative meta‐analysis indicated that high‐dose statin pretreatment caused a 55% reduction in PMI (OR: 0.45, 95% CI: 0.37‐0.54), without evidence of statistical heterogeneity (I² = 0.0 %; Figure 3). These results indicated that there was statistical significance for the effect of high‐dose statin pretreatment in patients undergoing PCI.

Figure 3.

Odds ratio estimate for PMI based on cumulative meta‐analysis. Abbreviations: CI, confidence interval; OR, odds ratio; PMI, periprocedural myocardial infarction.

Meta‐analysis Outcomes in Subgroup Analysis With Different Clinical Presentations

Regarding subgroups with different clinical presentation, the meta‐analysis with 11 studies indicated that high‐dose statin pretreatment caused a 58% reduction in PMI (OR: 0.42, 95% CI: 0.32‐0.56) for the stable angina subgroup in the fixed‐effects model, and the result showed no statistical heterogeneity (I² = 28.8%). The meta‐analysis with 5 studies reported high‐dose statin pretreatment caused a 50% reduction in the mixed presentation subgroup; we used a fixed‐effects model analysis because there was no heterogeneity among these studies (I² = 0.0%), which demonstrated statistical significance (OR: 0.50, 95% CI: 0.36‐0.70). The other 7 studies indicated that high‐dose statin pretreatment was associated with a 57% relative reduction in PMI for the acute coronary syndromes subgroup (OR: 0.43, 95% CI: 0.29‐0.64). These outcomes were also based on the fixed‐effects model, because there was no evidence of significant heterogeneity among the 7 studies (I² = 0.0%).

Meta‐analysis Outcomes in Subgroups Analysis With Statin‐Naive and Low‐Dose Statin Therapy

Regarding different statin‐therapy histories prior to PCI, the meta‐analysis with 19 studies of statin‐naive patients indicated high‐dose statin pretreatment caused a 55% reduction in PMI (OR: 0.45, 95% CI: 0.36‐0.56). We used a fixed‐effects model analysis because there was no heterogeneity among these studies (I² = 0.0%). The other subgroup meta‐analysis with 5 studies of low‐dose statin‐therapy‐history prior to PCI showed high‐dose statin pretreatment was associated with 54% relative reduction in PMI (OR: 0.46, 95% CI: 0.32‐0.66). This outcome was also based on the fixed‐effects model, because there was no evidence of significant heterogeneity among these studies (I² = 49.4%).

Quality of the Evidence and Recommendation Strengths

The present outcomes in this cumulative meta‐analysis were evaluated using the GRADE system. The evidence quality for 6 outcomes showed that quality of evidence for the subgroup with PMI incidence in low‐dose statin was moderate. The evidence quality for the total combined outcome and the other 4 subgroup outcomes was high (Table 2). Therefore, we considered that the overall evidence quality was moderate. This finding may strengthen the confidence in any recommendations.

Table 2.

GRADE Evidence Quality of Each Outcome

Quality Assessment							No. of Patients		Effect		Quality	Importance
No. of Studies	Design	Risk of Bias	Inconsistency	Indirectness	Imprecision	Other Considerations	MI	Control	Relative (95% CI)	Absolute
PMI incidence
23	Randomized trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	Strong association reduced effect for RR >> 1 or RR << 1	190/2761 (6.9%)	373/2550 (14.6%)	OR: 0.41 (0.34‐0.49)	81 fewer per 1000 (from 69 fewer to 91 fewer)	High	Critical
								15.6%		86 fewer per 1000 (from 73 fewer to 97 fewer)
PMI incidence in low‐dose statin
5	Randomized trials	Serious	No serious inconsistency	No serious indirectness	No serious imprecision	Reporting bias reduced effect for RR >> 1 or RR << 1	60/803 (7.5%)	78/594 (13.1%)	OR: 0.44 (0.3‐0.64)	69 fewer per 1000 (from 43 fewer to 88 fewer)	Moderate	Critical
								10.5%		56 fewer per 1000 (from 35 fewer to 71 fewer)
PMI incidence in statin naive
19	Randomized trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	Strong association reduced effect for RR >> 1 or RR << 1	135/2024 (6.7%)	303/2062 (14.7%)	OR: 0.41 (0.33‐0.5)	81 fewer per 1000 (from 68 fewer to 93 fewer)	High	Critical
							15.8%			87 fewer per 1000 (from 72 fewer to 100 fewer)
PMI incidence in stable
11	Randomized trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	Strong association increased effect for RR ∼ 1	91/1130 (8.1%)	163/920 (17.7%)	OR: 0.37 (0.28‐0.49)	103 fewer per 1000 (from 82 fewer to 120 fewer)	High	Important
								18.9%		110 fewer per 1000 (from 87 fewer to 128 fewer)
PMI incidence in ACS
7	Randomized trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	38/667center (5.7%)	91/674center (13.5%)	OR: 0.39 (0.26‐0.58)	78 fewer per 1000 (from 52 fewer to 96 fewer)	High	Critical
								15.3%		87 fewer per 1000 (from 58 fewer to 108 fewer)
PMI incidence in mixed presentation
5	Randomized trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	Strong association	61/964center (6.3%)	119/956 (12.4%)	OR: 0.47 (0.34‐0.65)	62 fewer per 1000 (from 40 fewer to 78 fewer)	High	Important
								10.5%		53 fewer per 1000 (from 34 fewer to 67 fewer)

Abbreviations: ACS, acute coronary syndromes; MI, myocardial infarction; CI, confidence interval; GRADE, Grading of Recommendations, Assessment, Development, and Evaluation; OR, odds ratio; PMI, periprocedural myocardial infarction; RR, relative risk.

Publication Bias

The publication bias test was performed for overall studies. A significant publication bias was shown for overall studies by the Begg rank‐correlation method (P = 0.010) and the Egger weighted‐regression method (P = 0.026).

Discussion

Various studies have demonstrated that PMI is a severe complication in patients after elective PCI. The studies have shown that PMI is associated with high mortality.4 The occurrence of PMI, even without relative clinical symptoms, also seriously affected the prognosis and overall survival rate in patients undergoing PCI.43 The pathophysiological mechanism of PMI and how to reduce the incidence of PMI was a critical topic among medical research. The cardiac protection provided by high‐dose statin pretreatment was highly advocated in the periprocedural period. This protective effect was especially based on the anti‐inflammatory effect of statins, because high‐dose statin therapy was thought to reduced high‐sensitivity C‐reactive protein levels over the early 24‐hour period after PCI,44 which may be a critical mechanism that decreased the probability of periprocedural myocardial damage. The outcomes of many observational and randomized trials in recent years indicate that a high‐dose statin regimen could effectively reduce the rate of PMI. In view of the above research, some studies8, 9 had performed meta‐analysis to evaluate the efficacy of high‐dose statin pretreatment in patients undergoing elective PCI. However, the previous meta‐analyses were not included the explicit GRADE evidence classification. The main goal of the present study was to conduct a cumulative meta‐analysis by collecting the published RCTs and performing reliable grading of evidence.

Meta‐analysis is used as a method in the research article about interventional effects. It has higher accuracy and reliability than that in regression analysis or original articles. Meta‐analysis can promote statistical power and amplify sample size via the combination of original studies, which could provide more stable evidence. Moreover, cumulative meta‐analysis is defined as a method conducted by calculation in sequence according to the year in which they first published. Thus, we conducted a cumulative meta‐analysis to evaluate the evidence from relevant studies that evaluate the effect of high‐dose statin pretreatment on the incidence of PMI after PCI.

This collaborative meta‐analysis indicated that high‐dose statin pretreatment can result in a significant reduction of the risk of PMI in patients undergoing PCI. A study by Patti et al8 demonstrated that high‐dose statin pretreatment prior to PCI had a positive effect in patients undergoing elective PCI, and that this strategy should be widely recommended before PCI, irrespective of overall clinical presentation and patients who had previously received statin treatment, whereas this study was not treated as exhaustive because of no consequence of subgroups receiving chronic statin therapy. Wang et al9 conducted an elaborate and comprehensive meta‐analysis indicating that high‐dose statin pretreatment could reduce the incidence of PMI through the analytical study of subgroups among statin‐naive and previous low‐dose statin‐therapy patients. They also showed that the positive effect of high‐dose statin pretreatment on PMI is observably significant for patients with acute coronary syndromes by analyzing the subgroups among clinical classifications. However, these previous studies did not give a specific level of evidence. Thus, our result is in according with previous meta‐analyses.8, 9, 45 In addition, a cumulative meta‐analysis was performed in the present analysis. Furthermore, there was no guideline or recommendation for the effects of high‐dose statin pretreatment in preventing PMI after PCI in previous studies. It is necessary to have an evidence base to help physicians make clinical decisions and develop effective PCI treatments. As far as we know, the present study is the first meta‐analysis that uses the GRADE system to appraise the quality of the evidence involving the effect of high‐dose statin pretreatment on the incidence of PMI in patients undergoing PCI.

The methodological quality assessment identified several deficiencies in methodological quality assessment: (1) Only 7 of the included studies used sealed envelopes for allocation concealment. Six of the included studies reported blinding of the participants and personnel, but 3 used dual‐blinding, allowing for assessor and expectation bias and the potential for type II statistical errors regarding these outcomes. The efficacy of the statistics could be improved in the future by including high‐quality RCTs. The studies with a high risk of bias included in this meta‐analysis would overestimate the treatment effects. (2) The long‐term follow‐up results may change the current conclusions. (3) Clinical heterogeneity may be caused by the preexisting conditions of the patients, various indications for PCI, the experience level of physicians, medical comorbidities, and smoking. The above confounding factors might have an impact on the present outcomes. (4) Meta‐analyses are subject to bias and provide inappropriate estimates for the effect of treatment when compared with successive large RCTs.46

Some degree of clinical heterogeneity was induced by the different PCI technologies used, transfemoral/transradial intervention, medical comorbidities, nutritional status of patients, duration of ischemia, admission to the hospital from a health care facility, conditions of ischemia‐reperfusion injury, pre‐PCI medical status, follow‐up times, physician experience, and diagnostic criteria for indication. Heterogeneity may have been caused by study design. Because of limited information obtained from original studies, heterogeneity cannot be completely resolved. Accordingly, although the results of the meta‐analysis should be considered appropriately, methodological quality defects and clinical heterogeneity should be considered when interpreting the findings.

The present study showed that the evidence quality of outcome in the low‐dose statin subgroup was moderate and the other 5 outcomes were high. Therefore, we considered that the overall evidence quality was moderate. This finding may strengthen the confidence in any recommendations. However, moderate evidence quality may imply that conditional status of individual patients should be referred to when making clinical decisions.

A number of strengths were identified to the current evidence base. (1) The majority of the RCTs had sufficient information on the randomization methods. The efficacy of the overall statistic was realized by including a relatively large number of RCTs. (2) The cumulative meta‐analysis presented and combined results with more stability, which was shown by the narrow confidence interval. (3) The GRADE system was performed in the present study, providing objective evidence level based on the results of meta‐analysis. Despite the above strengths, the primary limitations of this meta‐analysis include the following: (1) The statistical efficacy could be improved by including more studies. Owing to the finite of included studies, subgroup analysis cannot be performed on kinds of comorbidities. It may exert instability on consistency of outcomes. (2) Individual studies with varied methodological quality and potential language bias were more likely to give rise to various types of bias. (3) To some extent, clinical heterogeneity cannot be resolved completely, such as dose of statin, clinical presentation, statin regimen, duration of follow‐up, and surgical experience. (4) The overall GRADE quality of evidence was high, which increased confidence in any subsequent recommendations. Although the GRADE system was used to evaluate the evidence quality and recommendation strengths, actual judgments are still required based on clinical practice.

Conclusion

From this cumulative meta‐analysis and grading of the evidence, the present study offers available conclusions and demonstrates that high‐dose statin pretreatment can reduce the rate of PMI for patients undergoing PCI, irrespective of either the clinical presentation or previous history of statin treatment. The strategy of high‐dose statin pretreatment should be generally applied in patients undergoing PCI. Moreover, the overall GRADE evidence quality was moderate, which will improve our confidence in recommendations strengths. Nevertheless, further high‐quality studies are still constantly required to confirm the results because of the several primary limitations of current studies.