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Timing of percutaneous coronary intervention in non-ST elevation acute coronary syndrome - Meta-analysis and systematic review of literature
Journal Pre-proof Timing of Percutaneous coronary intervention in non-ST elevation acute coronary syndrome- Meta-analysis and systematic review of literature
Ahmad Awan, Richard Ogunti, Urooj Fatima, Hilda Gonzalez, Niteesha Ganta, Muhammad Rizwan, Ankit Mahajan, Isaac Opoku-Asare PII:
S1553-8389(19)30653-0
DOI:
https://doi.org/10.1016/j.carrev.2019.10.004
Reference:
CARREV 1718
To appear in:
Cardiovascular Revascularization Medicine
Received date:
27 July 2019
Revised date:
18 September 2019
Accepted date:
2 October 2019
Please cite this article as: A. Awan, R. Ogunti, U. Fatima, et al., Timing of Percutaneous coronary intervention in non-ST elevation acute coronary syndrome- Meta-analysis and systematic review of literature, Cardiovascular Revascularization Medicine(2019), https://doi.org/10.1016/j.carrev.2019.10.004
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© 2019 Published by Elsevier.
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Timing of Percutaneous Coronary Intervention in Non-ST Elevation Acute Coronary Syndrome- Meta-Analysis and Systematic Review of literature Keywords:
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Authors
Ahmad Awan MD1, Richard Ogunti MD2, Urooj Fatima, MD1, Hilda Gonzalez MD1, Niteesha Ganta MD2, Muhammad Rizwan MD2, Ankit Mahajan MD1, Isaac Opoku-Asare MD1.
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1. Department of Cardiology, Howard University Hospital, Washington DC. 2. Department of Internal Medicine, Howard University Hospital, Washington, DC. Corresponding Author: Ahmad Awan, MD [email protected] Cardiology Fellow Howard University Hospital, 2041 Georgia Avenue, NW Washington, DC. 20060. Disclosures: None Word Count: 4292
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ABSTRACT Background: Percutaneous coronary intervention (PCI) is the standard procedure of care for most patients with Non-ST elevation acute coronary syndrome (NSTE-ACS). However, the timing of PCI remains unclear. We performed this meta-analysis with available
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Randomized Controlled Trials (RCTs) to compare early versus late coronary intervention in patients with NSTE-ACS.
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Method: A total of 13 RCTs were selected through PubMed/MEDLINE via OVID, EMBASE via OVID and Cochrane Central Register of Controlled Trials (inception to October 2018) search. Outcomes were analyzed using the relative risk (RR) and 95% CI.
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Pooled RRs were determined using M-H random-effects model, which can account for between study heterogeneity.
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Results: We included 13 RCTs with 11972 patients were included. There were 7101 patients were randomized into early invasive
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group and 4871 in late invasive group. There was a significant decrease in myocardial infarction with long-term follow up in early
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invasive group compared to the delayed invasive group (RR 0.847 [95% CI 0.74-0.95], p=0.009) with no difference in mortality between early and late invasive group (5.41% vs 6.49%, RR 0.882 [95% CI, 0.76-1.02]). On subgroup analysis, data was available
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from 6 RCTs for GRACE (Global Registry of Acute Coronary Events) score and 8 RCTs for elevated troponin. Early intervention led to decrease in adverse events in patients with elevated GRACE score>140, (Mantel-Haenszel pooled RR 0.88 [95% CI 0.82-0.95], pvalue 0.002 but no difference was seen in patients with elevated troponin.
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Conclusion- It can be postulated from these results that early invasive strategy leads to decrease in myocardial infarction but without significant decrease in mortality. In patients with elevated GRACE score (>140), early intervention did show a trend towards decrease in major adverse cardiac events, whereas in patients with elevated troponin alone, similar association was not observed. However,
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adequately powered randomized controlled trial is necessary to validate these findings.
Keywords: PCI, Coronary intervention, time factors.
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Abbreviations
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NSTE-ACS: Non-ST elevated Acute Coronary Syndrome GRACE: Global Registry of Acute Coronary Events RCT: Randomized Controlled Trials RR: Relative Risk
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M-H: Mantel-Haenszel
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PCI: Percutaneous coronary intervention MACE: Major adverse cardiac events CI: Confidence Interval
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INTRODUCTION:
The incidence of hospitalization for Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS) has steadily increased in United
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States over the last several years (1,2). Prior studies have demonstrated decrease in 30-day mortality and recurrent ischemic events
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following STEMI, however similar reduction in mortality has not been demonstrated for patients with NSTE-ACS that collectively incorporates patients admitted with Non-ST elevation MI and unstable angina (2). While there is consensus on the immediate primary
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Percutaneous Coronary Intervention (PCI) in STEMI, ambiguity remains regarding the optimum timing of coronary intervention
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following NSTE-ACS. Multiple prior randomized controlled studies have shown that an invasive strategy following NSTE-ACS has
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superior outcomes when compared to non-invasive approach (4-7), however the optimal timing of PCI remains a conundrum.
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Current ACC/AHA guidelines recommend urgent coronary intervention for patients with hemodynamic instability or refractory chest pain, whereas early invasive strategy (within <24 hours) and delayed approach (within 25-72 hours) for clinically stable patients is
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considered optimal (8). In a previous meta-analysis by Navarese et al, no difference in early versus late intervention was observed in patients with NSTE-ACS (9). In another meta-analysis, Jobs et al, found that early invasive strategy was superior to late invasive approach in high risk patients with elevated troponin, GRACE (Global Registry of Acute Coronary Events) Score >140, diabetes mellitus and age >75 years (10). Since these meta-analyses, recently several randomized trials have also looked into the timing of PCI and its impact on outcomes in patients with NSTE-ACS.
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TAO (Treatment of Acute Coronary Syndrome with Otamixaban) trial demonstrated that in high risk patients with NSTE-ACS, early coronary angiography within the first 12 hours was associated with lower risk of ischemic events at 6 months compared to delayed invasive strategy, where intervention was performed greater than 12 hours post hospital admission (11). In a more recent VERDICT
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trial, authors have concluded that early invasive strategy is not superior to delayed invasive strategy (12). With the availability of new
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data and the lack of consensus regarding the timing of intervention in these patients, we sought to examine the effect of early versus delayed invasive strategy in patients with NSTE-ACS.
METHODS
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Study Inclusion and Exclusion Criteria:
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Randomized controlled trials (RCTs) that compared early invasive vs late invasive strategy in patients with NSTE-ACS were included. Trials that compared early invasive therapy with conservative strategy or selective invasive strategies were excluded.
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Definition of “early invasive strategy” and “late invasive strategy” was adopted as enlisted in individual trials. For LIPSIA-NSTEMI trial, the very early group was included in the early invasive arm, early invasive group was included in late arm and selective invasive arm was excluded from the meta-analysis (!3). Similarly, in TAO trial, the very early and early arms were included in early invasive arm and delayed invasive was included in late invasive arm, to maintain the consistency across the comparison groups in our study (11). The rationale for above is that in very early (<12 hours) and early (12-24 hours) groups, invasive strategy was performed within 24
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hours in these 2 trials. The primary endpoint was all- cause mortality and myocardial infarction at longest follow up duration and secondary outcomes measured were non-fatal myocardial infarction at 30 days, revascularization and major bleeding as defined by the individual trials. Furthermore, major adverse cardiovascular event (MACE) as defined by the individual trials was measured in 3 pre-
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specified sub-groups: Patients with elevated troponin, high risk patients defined as elevated GRACE score more than 140 and low
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risk patient defined as GRACE score less than 140. The reason for switch to MACE as a measure of outcomes for subgroup analysis is that most of the included trials had reported composite events and not individual outcome for GRACE score and troponin elevation. Literature Search
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The current meta-analysis was designed according to the preferred Reporting Items for Systematic Reviews and Meta-analysis
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protocol and Cochrane Collaboration Recommendations (14). We searched PubMed/MEDLINE via OVID (1946 to October 2018),
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EMBASE via OVID (1980 to October 2018), and the Cochrane Central Register of Controlled Trials (inception to October 2018). We restricted our search to prior randomized controlled trials (RCTs) involving human participants and published in English language
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comparing early intervention strategy with late intervention strategy in patients with NSTE-ACS. Trials comparing early strategy with conservative strategy were excluded. The search was performed using a combination of the following words and medical subject heading (MeSH): “early or late intervention”, “non-ST acute coronary syndrome”, randomized controlled trials”. The trials were downloaded in Zotero (Roy Rosen Zweig, Center for History and New Media, Research Software), and duplicates were manually
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identified and eliminated by the software. Two authors (AA and NG) screened the search results based on previously stated criteria and extracted the data. Whenever there was a disagreement between authors, a third author (UF) was consulted for adjudication.
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Statistical Analysis
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Data analysis was performed according to the intention-to-treat principle with early invasive intervention compared to delayed intervention for each endpoint listed. All-cause mortality and incidence of myocardial infarction (MI) at longest duration of follow-up
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constituted the primary endpoints, while secondary outcomes were MI at 30 days, major bleeding and revascularization. Subgroup
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analyses based on major adverse cardiovascular events stratified by GRACE score and troponin elevation was
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also performed. Outcomes were analyzed using the relative risk (RR) and 95% CI as summary statistics. Pooled RRs were determined
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using Mantel-Haenszel (M-H) random-effects model, which can account for between study heterogeneity (18). The risk difference between the two groups for each outcome was calculated and the number needed to treat to benefit (NNT) was determined where
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appropriate. Between-study heterogeneity was assessed using Q statistics with the proportion of the total variability in the effect size estimates evaluated with the I2 index. I2 index value > 75% was considered as substantial heterogeneity (19). Funnel plots and Egger test was used to estimate the risk of publication bias. Sensitivity analyses were performed by removing one study at a time to determine the influence of each study on the overall effect estimate. A study is noted to be influential if the pooled effect estimate without it is not within the 95% CIs of the overall effect size. Statistical analysis was performed with Stata software version 13.1 for
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windows (Stata Corp LP, College Station, Texas, USA). Risk ratios were reported with 95% CI and two-tailed p-value < 0.05 was considered significant.
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Result
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After exclusion of studies based on criteria mentioned above, a total of 13 RCTs were included. There were a total of 11972 patients, with 7101 patients randomized into early invasive group and 4871 in late invasive group. Timing for early invasive strategy was
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between 2 to 24 hours and timings for late invasive group was between 8 hours to 120 hours. In all included trials, both groups were
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treated with at least aspirin, clopidogrel or Ticagrelor and an anticoagulant, Trial characteristics with primary and secondary outcomes
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along with duration of follow up is summarized in Table 1. Patient characteristics are summarized in Table 2.
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The demographics and baseline characteristics were well balanced between the two treatment groups with a mean age of 66.2 years in the early group vs. 66.8 years in the delayed group. There were 65.1% men in early group compared to 66.0% in the delayed group.
Primary Outcomes
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The primary endpoint was all-cause mortality and MI incidence at longest follow up duration.
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All-cause mortality All-cause mortality was reported by all the included trials. Individual and pooled RRs for all-cause mortality showed no statistically significant difference in effect size and heterogeneity between the two groups (Figure 1). Overall, there were 384 deaths (5.41%) in
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the early invasive group and 316 deaths (6.49%) in the delayed group (RR 0.882, [95% CI, 0.76-1.02], p=0.094; I2 = 0.0). Result was
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primarily driven by VERDICT (43.19%), TIMACS (24.29%) and TAO (22.64%) trials. There was no significant publication bias detected based on the Egger regression (Egger test for small study bias P=0.904) and visual inspection of the funnel plots that showed
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no asymmetry (Figure A1, Appendix Material). Sensitivity analyses showed that no single study significantly changed the current
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overall results for this mortality endpoint (Figure A2, Appendix Material).
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MI (longest duration of follow-up)
Data from the RCTs included in the analysis showed that MI incidence at the longest duration of follow-up (as pre-specified by each
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individual trial) was significantly reduced in the early invasive group compared with the delayed group (RR 0.847, [95% CI 0.740.95], p 0.009, I2 = 75.2) (figure 2). These results should be interpreted with caution because of high heterogeneity. The duration of follow-up was variable across the included trials with the maximum duration of follow-up of 5 years seen in 2 out of the 13 included trials (VERDICT and SISCA). The duration of follow up has been listed in table 1. These results should be interpreted with caution
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because of considerable heterogeneity. No significant publication bias estimate was detected (Egger test for small study bias p = 0.697) and visual inspection of the funnel plots showed no significant asymmetry (Figure A3, Appendix Material).
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Secondary outcomes
The secondary outcomes were MI within 30 days, revascularization rates, and major bleeding following coronary intervention.
MI Incidence at 30-day Follow-up
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At 30-day follow up, there was no significant difference in incidence of myocardial infarction in the two groups (M-H pooled RR
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0.85, [95% CI, 0.73-1.01], p=0.06; I = 71.3) (Figure A4, Appendix Material). Only 10 of the 13 RCTs reported data outcomes for this endpoint. Sensitivity analysis demonstrated that OPTIMA trial significantly affected the overall effect estimate of this outcome
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(Figure A5, Appendix Material). Exclusion of OPTIMA trial lead to a beneficial effect of early intervention in reducing recurrent MI at 30 days (M-H pooled RR 0.77 [95% 0.64-0.93], p= 0.007)
Repeat Revascularization or Re-intervention
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The impact of an early compared to a delayed invasive intervention on repeated revascularization was reported by 7 RCTs. The effect size on revascularization was not significantly different between the two groups (RR 0.916, [95% CI 0.78-1.08], p-value 0.292; I2=79.3 (Figure A6, Appendix Material).
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Major bleeding
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There was no statistically significant difference between the two groups in terms of major bleeding which was reported by 8 RCTs
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(RR 0.819, CI 0.61-1.09, p value 0.175, I2=0.0). The associated funnel plots for all secondary endpoints showed no significant
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asymmetry. Likewise, there was no small study effects bias detected (Egger’s regression p-value> 0.05)
Sub-group analysis
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Subgroup analyses was performed to examine the efficacy of early vs delayed intervention in reducing major adverse cardiovascular events based on GRACE score and troponin elevation status.
MACE stratified by GRACE Score
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We extracted data on patients with Grace score greater than 140 (elevated Grace score) from 6 RCTs. A total of 9938 patients had elevated GRACE score, with 6085 in early invasive arm and 3853 in late invasive arm. In patients with elevated GRACE score, early intervention led to decreased adverse events (M-H pooled RR 0.88 [95% CI 0.82-0.95], p-value 0.002) although significant
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heterogeneity was identified (P = <0.001, I² = 79.5%). The number of avoided events per 1000 was estimated at 26 (95% CI, 10 – 41)
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and the number needed to treat to benefit was 39. This result should be interpreted with caution given the high heterogeneity. (Figure A7, Appendix Material)
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There was no significant difference in major adverse clinical events as described by individual trials in patients with low GRACE
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score defined as less than 140 (RR 0.99 [95% CI 0.93-1.05], p-value 0.804) based on data reported by 5 RCTs.
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MACE stratified by troponin elevation
Data on elevated troponin was reported by 8 RCTs. There were 6418 patients in early intervention group and 4186 patients in late
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intervention group. Overall, the effect size was not significantly different between early invasive and delayed invasive intervention among this group of patients (RR 1.01 [95% CI 0.99-1.03}, p-value 0.262; I2 = 0). (Figure A8, Appendix Material) The associated funnel plots for the subgroup analysis was somewhat symmetrical, although given the limited number of trials involved, publication bias cannot be totally excluded. The p value of the Egger’s regression intercept was not significant.
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DISCUSSION This meta-analysis is one of the largest based on the number of patients included from RCTs comparing early with the late intervention in patients with NSTE-ACS. The number of patients in our meta-analysis were 11,972 which is higher than Li et al, that
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included 6624 patients (!5), Bonello et al, 6397 patients (!6) and Jobs et al, 5324 patients (10). We selectively included RCTs that
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improved the quality of the extracted data and robustness of the results.
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This meta-analysis shows that early coronary intervention within first 24 hours following NSTE-ACS leads to significant decrease in
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recurrence of long-term MI. However, no difference in mortality, MI at 30 days, rate of revascularization and major bleeding between the two groups was demonstrated. The findings of GRACE score were reported in 6 RCTs and of elevated troponin were reported in 8
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RCTs. Our study also showed that GRACE score is a strong predictor of major adverse cardiac events whereas, elevated serum
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troponin alone without high GRACE score did not have direct correlation with MACE, which is an interesting finding.
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Previous studies including Bonello et al (16), Milasinovic et al(17), and Navaresse et al(19), showed that there was no significant difference in all-cause mortality and myocardial infarction between early and late invasive groups however unlike our meta-analysis, these studies did not assess the impact of early invasive therapy on occurrence of 30 day and one year MI. Job and colleagues in their meta-analysis found that early invasive strategy does not have mortality benefit as compared to late intervention in patients following NSTE-ACS (10). Early invasive strategy however leads to decrease in mortality in high-risk patients
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that were defined as age >75 years, GRACE score >140, elevated troponin and diabetes mellitus. We however did not find a beneficial effect of early invasive therapy on adverse cardiovascular events in patients with elevated troponin alone. This lack of association between elevated troponin and mortality has not been demonstrated in previous meta analysis and is a new finding. We believe that
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this difference in our results pertaining to the lack of benefit with respect to elevated troponin was driven by inclusion of data from
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recent randomized trial (TAO and VERDICT). In these studies, benefit of early invasive strategy was seen in patients with elevated GRACE score without this benefit being evident in patients with troponin elevation alone.
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Several reasons can be postulated for lack of correlation between troponin elevation alone and increase mortality in NSTE-ACS.
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Firstly, troponin assay has undergone several reiterations over the years, which may affect its sensitivity and specificity. Secondly, the
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studies have not taken into account the level of troponin elevation. Troponin level of 0.04 ng/ml, which is barely above the 99th
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percentile, affords a different prognosis than troponin of 4.0 ng/ml. However, in these studies no differentiation was made based on level of troponin elevation. Thirdly, pattern of troponin elevation is also important in diagnosis of acute myocardial infarction. Based
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on fourth universal definition of myocardial infarction, a rise and fall pattern of troponin elevation is needed with either symptom compatible with myocardial infarction or imaging/electrographic findings consistent with ischemia. Whereas chronic myocardial injury leads to persistent elevation in troponin without typical rise and fall pattern (18). The management and prognosis is different for these 2 different entities. The current guidelines recommend early invasive strategy in patients with elevated troponin levels,
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especially in female population and discourage early intervention in women without elevated biomarkers. This recommendation also needs to be further validated in light of our finding of lack of mortality benefit with early invasive approach.
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We were unable to further evaluate some of these finding because of inherent limitations of meta-analysis. Our results should be
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interpreted considering few limitations. Firstly, there is an overlap between timings of early and late invasive strategies trials, hence precise timing for optimal intervention cannot be elucidated. This overlap is not unique to our meta-analysis and previous meta-
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analysis also had similar limitations. In most trials early intervention was performed within 24 hours except in the study by Liu et al,
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in which both early and late group had intervention done within 24 hours (19). However, sensitivity analysis performed with exclusion
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of Liu et al. showed similar results. Secondly, in pre-specified subgroup analysis, we used composite of primary outcome as defined
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by individual trials instead of individual outcomes, which differed in-between trials. Thirdly, there is variability in duration of trials follow up. Only VERDICT and SISCA have 5 years follow. Because of these variations, there is considerable heterogeneity in the
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results. The duration of follow up of individual trials are summarized in table 1. Nevertheless, these are unique findings which needs to be taken into account in future randomized studies.
Conclusion:
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The results of our meta-analysis demonstrate a trend towards reduction in myocardial infarction on long term follow-up with early invasive strategy following NSTE-ACS. However, no difference in all-cause mortality was observed between the two groups. In our subgroup analysis, in patients with elevated GRACE risk score, early intervention following NSTE-ACS did show a statistically
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significant trend toward reduction in major adverse clinical events without any difference in outcomes in patients with elevated
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troponin alone. However, given the inherent limitations of the meta-analysis a well designed and adequately powered randomized controlled trials will be needed to validate these findings.
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Acknowledgement:
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Authors would like to acknowledge Kristin Chaplin and Ahmed Arslan Awan, MD for reviewing the manuscript.
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3. Pilgrim T, Vranckx P, Valgimigli M, et al. Risk and timing of recurrent ischemic events among patients with stable ischemic heart disease, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction. Am Heart J. 2016 May;175:56–65.
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4. McCullough PA, O’Neill WW, Graham M, et al. A prospective randomized trial of triage angiography in acute coronary syndromes ineligible for thrombolytic therapy. Results of the medicine versus angiography in thrombolytic exclusion (MATE) trial. J Am Coll Cardiol. 1998 Sep;32(3):596–605.
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5. O’Donoghue ML, Vaidya A, Afsal R, et al. An invasive or conservative strategy in patients with diabetes mellitus and non-STsegment elevation acute coronary syndromes: a collaborative meta-analysis of randomized trials. J Am Coll Cardiol. 2012 Jul 10;60(2):106–11.
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6. Fox KAA, Clayton TC, Damman P, et al. Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data. J Am Coll Cardiol. 2010 Jun 1;55(22):2435–45.
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7. Fox K a. A, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina. Lancet Lond Engl. 2002 Sep 7;360(9335):743–51. 8. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-STElevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Dec 23;64(24):e139–228.
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9. Navarese EP, De Servi S, Gibson CM, et al. Early vs. delayed invasive strategy in patients with acute coronary syndromes without ST-segment elevation: a meta-analysis of randomized studies. QJM Mon J Assoc Physicians. 2011 Mar;104(3):193– 200. 10. Jobs A, Mehta SR, Montalescot G, et al. Optimal timing of an invasive strategy in patients with non-ST-elevation acute coronary syndrome: a meta-analysis of randomised trials. Lancet Lond Engl. 2017 Aug 19;390(10096):737–46.
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11. Deharo P, Ducrocq G, Bode C, et al. Timing of Angiography and Outcomes in High-Risk Patients With Non-ST-SegmentElevation Myocardial Infarction Managed Invasively: Insights From the TAO Trial (Treatment of Acute Coronary Syndrome With Otamixaban). Circulation. 2017 Nov 14;136(20):1895–907.
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12. Kofoed KF, Kelbæk H, Hansen PR, et al. Early Versus Standard Care Invasive Examination and Treatment of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome. Circulation. 2018 Dec 11;138(24):2741–50.
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13. Thiele H, Rach J, Klein N, et al. Optimal timing of invasive angiography in stable non-ST-elevation myocardial infarction: the Leipzig Immediate versus early and late PercutaneouS coronary Intervention triAl in NSTEMI (LIPSIA-NSTEMI Trial). Eur Heart J. 2012 Aug;33(16):2035–43.
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14. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. Int J Surg Lond Engl. 2010;8(5):336–41.
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15. Liu Z, Zhao L, Li Y, Wang Z, Liu L, Zhang F. Evaluation of early interventional treatment opportunity of the elderly & highrisk patients with non-ST segment elevation acute myocardial infarction. Pak J Med Sci. 2015 Oct;31(5):1053–6. 16. Bonello L, Laine M, Puymirat E, et al. Timing of Coronary Invasive Strategy in Non-ST-Segment Elevation Acute Coronary Syndromes and Clinical Outcomes: An Updated Meta-Analysis. JACC Cardiovasc Interv. 2016 28;9(22):2267–76. 17. Milasinovic D, Milosevic A, Marinkovic J, et al. Timing of invasive strategy in NSTE-ACS patients and effect on clinical outcomes: A systematic review and meta-analysis of randomized controlled trials. Atherosclerosis. 2015 Jul;241(1):48–54. 18. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Eur Heart J. 2018 Aug 25;
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19. Liu Z, Zhao L, Li Y, Wang Z, Liu L, Zhang F. Evaluation of early interventional treatment opportunity of the elderly & highrisk patients with non-ST segment elevation acute myocardial infarction. Pak J Med Sci. 2015 Oct;31(5):1053–6. 20. Montalescot G, Cayla G, Collet J-P, et al. Immediate vs delayed intervention for acute coronary syndromes: a randomized clinical trial. JAMA. 2009 Sep 2;302(9):947–54.
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21. Badings EA, The SHK, Dambrink J-HE, van Wijngaarden J, et al. Early or late intervention in high-risk non-ST-elevation acute coronary syndromes: results of the ELISA-3 trial. EuroIntervention J Eur Collab Work Group Interv Cardiol Eur Soc Cardiol. 2013 May 20;9(1):54–61.
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22. van ’t Hof AWJ, de Vries ST, Dambrink J-HE, et al. A comparison of two invasive strategies in patients with non-ST elevation acute coronary syndromes: results of the Early or Late Intervention in unStable Angina (ELISA) pilot study. 2b/3a upstream therapy and acute coronary syndromes. Eur Heart J. 2003 Aug;24(15):1401–5.
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23. Riezebos RK, Ronner E, Ter Bals E, et al. Immediate versus deferred coronary angioplasty in non-ST-segment elevation acute coronary syndromes. Heart Br Card Soc. 2009 May;95(10):807–12.
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24. Mehta SR, Granger CB, Boden WE, et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009 May 21;360(21):2165–75.
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25. Neumann F-J, Kastrati A, Pogatsa-Murray G, et al. Evaluation of prolonged antithrombotic pretreatment (“cooling-off” strategy) before intervention in patients with unstable coronary syndromes: a randomized controlled trial. JAMA. 2003 Sep 24;290(12):1593–9.
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26. Reuter P-G, Rouchy C, Cattan S, et al. Early invasive strategy in high-risk acute coronary syndrome without ST-segment elevation. The Sisca randomized trial. Int J Cardiol. 2015 Mar 1;182:414–8. 27. Milosevic A, Vasiljevic-Pokrajcic Z, Milasinovic D, et al. Immediate Versus Delayed Invasive Intervention for Non-STEMI Patients: The RIDDLE-NSTEMI Study. JACC Cardiovasc Interv. 2016 Mar 28;9(6):541–9. 28. Tekin K, Cagliyan CE, Tanboga IH, et al. Influence of the Timing of Percutaneous Coronary Intervention on Clinical Outcomes in Non-ST-Elevation Myocardial Infarction. Korean Circ J. 2013 Nov;43(11):725–30.
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Main Figures:
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Figure 1. Meta-analysis forest plot showing the effect of early intervention on mortality
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Meta-analysis showing effect of early vs delayed intervention on risk ratio for all-cause mortality in 13 trials. Individual and pooled RRs for all-cause mortality showed no statistically significant difference in effect size and heterogeneity between the two groups.
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Figure 2. Meta-analysis forest plot showing the effect of early intervention on MI incidence at longest
followup
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Meta-analysis showing effect of early vs delayed intervention on MI incidence at longest duration of follow up in 13 trials. MI
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incidence at longest duration of follow-up was significantly reduced in the early invasive group compared with the delayed group
TABLES: Table 1: Summary of Randomized Control Trials included in meta-analysis.
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Trial Name
Year
Time Early
Time Late
Pts Pts Early Late
ABOARD(20)
2009
<2 hrs
8-60 hrs
175
177
ELISA 3 (21)
2013
<12 hrs
>48hrs
269
265
ELISA 1 (22)
2003
<12 hrs
>48hrs
109
111
OPTIMA (23)
2009
Immediate
24-48 hrs
73
69
LIPSIA-NSTEMI(13)
2012
<2hrs
10-48hrs
TIMACS (24)
2009
<24hrs
Liu et al (19)
2015
ISAR-COOL (25)
2003
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2008
>36hrs
1593
1438
<12hrs
12-24hrs
22
20
<6hrs
3-5 days
203
207
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Primary: Peak troponin elevation Secondary: Composite of death, MI or urgent revascularization at 1 month follow up Follow up: 1 month Primary: Combined incidence of death, reinfarction and/or recurrent ischemia at 30-day follow up Secondary: Enzymatic infarct size and bleeding complications Follow up: 1 month Total death and recurrent myocardial infarction at 30 days Follow up: 1 month Primary: Composite of death, non-fatal MI, unplanned revascularization at 30 days. Secondary: Individual component, size of MI, revascularization, major bleeding, readmission and length of in-hospital stay Follow up: 6 months Primary: Peak Creatinine Kinase myocardial band Secondary: Composite of death, MI, refractory ischemia and re-hospitalization Follow up: 6 months Primary: Composite of death, MI or stroke at 6 months Secondary: Above and repeat intervention and refractory ischemia Follow up: 6 months Success of PCI, ischemia re-hospitalization, heart failure, arrhythmias, heart failure, bleeding and death Follow up: 6 months Primary: Composite of MI and death during 30 days Secondary: Bleeding complications Follow up: 1 month
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200
Outcomes and follow up
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SISCA (26)
2014
<6hrs
>6hr as per physician discretion, or as per guidelines. Not within 6hrs
83
86
TAO Trial ((11)
2017
Very early<12hr s Early 1224hrs
Delayed>24hrs
3068
1003
RIDDLE-NSTEMI (27)
2015
<2hrs
2-72hr
162
Tekin et al (28)
2013
<24hrs
>24-72hrs
69
VERDICT (12)
2018
12 hrs
48-72 hr
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1075
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Table 2: Baseline demographics of patients in individual trials
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161
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Primary: Composite of deaths, MI and revascularization at 30 days follow up Secondary: Treatment failure, revascularization, peak troponin, left ventricular ejection fraction, length of hospital stay, major or minor bleeding, long term mortality Follow up: 5 years Primary: Composite of all cause mortality and new MI at 180 days follow up Secondary: Above outcome at 7 days and 30 days, re-hospitalization, prolongation of hospitalization and stent thrombosis Follow up: 6 months Primary: Composite of death and MI at 30 days Secondary: Composite of death, new MI, recurrent ischemia at 30 days and 1 year. Follow up: 1year Repititive MI, hospitalization due to cardiac reason, death due to any reason Follow up: 3 months Primary: Combination of all cause death, acute myocardial infarction, refractory ischemia and heart failure Secondary: Procedure complication Follow up 5 years
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Study
Stud y type
Age mea n SD
Sex M/F (n)
Diabete s (n)
Hypertensio n (n)
Smokin g (n)
Dyslipidemi a (n)
Previou s MI (n)
Previou s CABG (n)
Previou s PCI (n)
ABOAR D
Early
62
31/48
38
115
56
100
29
9
Late Early Late Early Late Early Late Early
65 72.1 71.8 63±11 65±11 63 62 68
125/52 187/82 174/91 79/30 76/35 51/22 69/7 132/68
57 64 54 16 16 14 14 76
108 146 154 49 43 39 23 161
60 57 70 40 36 28 27 57
102 NA NA NA NA 28 22 79
33 48 52 19 14 15 18 35
12 37 32 12 8 8 1 10
Late Early Late Early
70 65.0 65.7 80.4 1 80.3 0 70
139/61 1038/555 940/498 11/11
85 422 394 11
161 1084 996 16
49 441 394 12
82 NA NA NA
46 313 300 8
13/7
11
14
13
NA
140
65
180
38
134 58/25 63/23 1968/110 0 653/ 368 114/48
53 35 28 1003
174 50 51 2419
49 44 41 620
342
Early
70 63.9 66.5 70.7 1 70.3 6 60.5
Late Early
63.0 58.1
106/55 41/28
52 22
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Late Early
55.6 63.6
Late
63.6
44/20 716/ 359 696/ 376
ELISA 3 ELISA OPTIMA LIPSIANSTEMI TIMACS Liu et al
Late ISAR COOL SISCA TAO
Early Late Early Late Early Late
RiddleSTEMI Tekin et al VERDIC T
l a NA
NA 45 45 1640
Previou s TIA (n)
9
Previou s Cancer (n) 7
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25 NA NA NA NA 5 3 NA
8 9 12 NA NA NA NA 9
1 NA NA NA NA NA NA NA
13 NA NA NA NA NA NA NA
31 221 204 NA
NA NA NA 11
NA NA NA NA
11 114 108 NA
NA NA NA NA
NA NA NA NA
Previou s Stroke (n)
18
54 49 55 16 16 20 13 32
7 NA NA NA NA 1 1 NA
15 111 105 NA NA
NA
8
NA
NA
NA
NA
52
28
48
NA
NA
NA
NA
NA
44 19 20 650
20 8 4 300
42 20 18 3067
NA NA NA 283
NA NA NA 215
NA NA NA 221
NA NA NA NA
NA NA NA NA
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Previou s PAD (n)
43
Cardiac Insuficienc y (n) 7
15
106
n r u 84
84
31
8
17
NA
NA
9
NA
NA
116 38
62 42
62 43
34 NA
12 NA
15 NA
NA NA
NA NA
16 NA
NA NA
NA NA
28 158
31 543
30 342
31 NA
NA 186
NA 57
NA 151
NA 302
NA NA
NA 94
NA NA
NA NA
173
578
323
NA
186
57
163
305
NA
82
NA
NA
35
789
203
574
235
105
1003
103
61
81
NA
NA
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Highlights
We performed this meta-analysis with available Randomized Controlled Trials (RCTs) to compare early versus late coronary intervention in patients with NSTE-ACS.
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Our study showed that early intervention leads to decreased in long-term myocardial infarction with no difference in mortality as compared to delayed group.
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In sub-group analysis, early intervention led to decrease in adverse events in patients with elevated GRACE (Global Registry of Acute Coronary Events) score>140, (M-H pooled RR 0.88 [95% CI 0.82-0.95], p-value 0.002 but no difference was seen in
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patients with elevated troponin.
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This meta-analysis is one of the largest based on the number of patients included from RCTs comparing early with the late intervention in patients with NSTE-ACS.
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Figure 1
Figure 2
Ahmad Awan, Richard Ogunti, Urooj Fatima, Hilda Gonzalez, Niteesha Ganta, Muhammad Rizwan, Ankit Mahajan, Isaac Opoku-Asare PII:
S1553-8389(19)30653-0
DOI:
https://doi.org/10.1016/j.carrev.2019.10.004
Reference:
CARREV 1718
To appear in:
Cardiovascular Revascularization Medicine
Received date:
27 July 2019
Revised date:
18 September 2019
Accepted date:
2 October 2019
Please cite this article as: A. Awan, R. Ogunti, U. Fatima, et al., Timing of Percutaneous coronary intervention in non-ST elevation acute coronary syndrome- Meta-analysis and systematic review of literature, Cardiovascular Revascularization Medicine(2019), https://doi.org/10.1016/j.carrev.2019.10.004
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
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Timing of Percutaneous Coronary Intervention in Non-ST Elevation Acute Coronary Syndrome- Meta-Analysis and Systematic Review of literature Keywords:
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Authors
Ahmad Awan MD1, Richard Ogunti MD2, Urooj Fatima, MD1, Hilda Gonzalez MD1, Niteesha Ganta MD2, Muhammad Rizwan MD2, Ankit Mahajan MD1, Isaac Opoku-Asare MD1.
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1. Department of Cardiology, Howard University Hospital, Washington DC. 2. Department of Internal Medicine, Howard University Hospital, Washington, DC. Corresponding Author: Ahmad Awan, MD [email protected] Cardiology Fellow Howard University Hospital, 2041 Georgia Avenue, NW Washington, DC. 20060. Disclosures: None Word Count: 4292
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ABSTRACT Background: Percutaneous coronary intervention (PCI) is the standard procedure of care for most patients with Non-ST elevation acute coronary syndrome (NSTE-ACS). However, the timing of PCI remains unclear. We performed this meta-analysis with available
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Randomized Controlled Trials (RCTs) to compare early versus late coronary intervention in patients with NSTE-ACS.
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Method: A total of 13 RCTs were selected through PubMed/MEDLINE via OVID, EMBASE via OVID and Cochrane Central Register of Controlled Trials (inception to October 2018) search. Outcomes were analyzed using the relative risk (RR) and 95% CI.
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Pooled RRs were determined using M-H random-effects model, which can account for between study heterogeneity.
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Results: We included 13 RCTs with 11972 patients were included. There were 7101 patients were randomized into early invasive
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group and 4871 in late invasive group. There was a significant decrease in myocardial infarction with long-term follow up in early
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invasive group compared to the delayed invasive group (RR 0.847 [95% CI 0.74-0.95], p=0.009) with no difference in mortality between early and late invasive group (5.41% vs 6.49%, RR 0.882 [95% CI, 0.76-1.02]). On subgroup analysis, data was available
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from 6 RCTs for GRACE (Global Registry of Acute Coronary Events) score and 8 RCTs for elevated troponin. Early intervention led to decrease in adverse events in patients with elevated GRACE score>140, (Mantel-Haenszel pooled RR 0.88 [95% CI 0.82-0.95], pvalue 0.002 but no difference was seen in patients with elevated troponin.
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Conclusion- It can be postulated from these results that early invasive strategy leads to decrease in myocardial infarction but without significant decrease in mortality. In patients with elevated GRACE score (>140), early intervention did show a trend towards decrease in major adverse cardiac events, whereas in patients with elevated troponin alone, similar association was not observed. However,
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adequately powered randomized controlled trial is necessary to validate these findings.
Keywords: PCI, Coronary intervention, time factors.
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Abbreviations
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NSTE-ACS: Non-ST elevated Acute Coronary Syndrome GRACE: Global Registry of Acute Coronary Events RCT: Randomized Controlled Trials RR: Relative Risk
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M-H: Mantel-Haenszel
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PCI: Percutaneous coronary intervention MACE: Major adverse cardiac events CI: Confidence Interval
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INTRODUCTION:
The incidence of hospitalization for Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS) has steadily increased in United
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States over the last several years (1,2). Prior studies have demonstrated decrease in 30-day mortality and recurrent ischemic events
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following STEMI, however similar reduction in mortality has not been demonstrated for patients with NSTE-ACS that collectively incorporates patients admitted with Non-ST elevation MI and unstable angina (2). While there is consensus on the immediate primary
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Percutaneous Coronary Intervention (PCI) in STEMI, ambiguity remains regarding the optimum timing of coronary intervention
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following NSTE-ACS. Multiple prior randomized controlled studies have shown that an invasive strategy following NSTE-ACS has
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superior outcomes when compared to non-invasive approach (4-7), however the optimal timing of PCI remains a conundrum.
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Current ACC/AHA guidelines recommend urgent coronary intervention for patients with hemodynamic instability or refractory chest pain, whereas early invasive strategy (within <24 hours) and delayed approach (within 25-72 hours) for clinically stable patients is
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considered optimal (8). In a previous meta-analysis by Navarese et al, no difference in early versus late intervention was observed in patients with NSTE-ACS (9). In another meta-analysis, Jobs et al, found that early invasive strategy was superior to late invasive approach in high risk patients with elevated troponin, GRACE (Global Registry of Acute Coronary Events) Score >140, diabetes mellitus and age >75 years (10). Since these meta-analyses, recently several randomized trials have also looked into the timing of PCI and its impact on outcomes in patients with NSTE-ACS.
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TAO (Treatment of Acute Coronary Syndrome with Otamixaban) trial demonstrated that in high risk patients with NSTE-ACS, early coronary angiography within the first 12 hours was associated with lower risk of ischemic events at 6 months compared to delayed invasive strategy, where intervention was performed greater than 12 hours post hospital admission (11). In a more recent VERDICT
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trial, authors have concluded that early invasive strategy is not superior to delayed invasive strategy (12). With the availability of new
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data and the lack of consensus regarding the timing of intervention in these patients, we sought to examine the effect of early versus delayed invasive strategy in patients with NSTE-ACS.
METHODS
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Study Inclusion and Exclusion Criteria:
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Randomized controlled trials (RCTs) that compared early invasive vs late invasive strategy in patients with NSTE-ACS were included. Trials that compared early invasive therapy with conservative strategy or selective invasive strategies were excluded.
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Definition of “early invasive strategy” and “late invasive strategy” was adopted as enlisted in individual trials. For LIPSIA-NSTEMI trial, the very early group was included in the early invasive arm, early invasive group was included in late arm and selective invasive arm was excluded from the meta-analysis (!3). Similarly, in TAO trial, the very early and early arms were included in early invasive arm and delayed invasive was included in late invasive arm, to maintain the consistency across the comparison groups in our study (11). The rationale for above is that in very early (<12 hours) and early (12-24 hours) groups, invasive strategy was performed within 24
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hours in these 2 trials. The primary endpoint was all- cause mortality and myocardial infarction at longest follow up duration and secondary outcomes measured were non-fatal myocardial infarction at 30 days, revascularization and major bleeding as defined by the individual trials. Furthermore, major adverse cardiovascular event (MACE) as defined by the individual trials was measured in 3 pre-
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specified sub-groups: Patients with elevated troponin, high risk patients defined as elevated GRACE score more than 140 and low
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risk patient defined as GRACE score less than 140. The reason for switch to MACE as a measure of outcomes for subgroup analysis is that most of the included trials had reported composite events and not individual outcome for GRACE score and troponin elevation. Literature Search
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The current meta-analysis was designed according to the preferred Reporting Items for Systematic Reviews and Meta-analysis
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protocol and Cochrane Collaboration Recommendations (14). We searched PubMed/MEDLINE via OVID (1946 to October 2018),
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EMBASE via OVID (1980 to October 2018), and the Cochrane Central Register of Controlled Trials (inception to October 2018). We restricted our search to prior randomized controlled trials (RCTs) involving human participants and published in English language
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comparing early intervention strategy with late intervention strategy in patients with NSTE-ACS. Trials comparing early strategy with conservative strategy were excluded. The search was performed using a combination of the following words and medical subject heading (MeSH): “early or late intervention”, “non-ST acute coronary syndrome”, randomized controlled trials”. The trials were downloaded in Zotero (Roy Rosen Zweig, Center for History and New Media, Research Software), and duplicates were manually
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identified and eliminated by the software. Two authors (AA and NG) screened the search results based on previously stated criteria and extracted the data. Whenever there was a disagreement between authors, a third author (UF) was consulted for adjudication.
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Statistical Analysis
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Data analysis was performed according to the intention-to-treat principle with early invasive intervention compared to delayed intervention for each endpoint listed. All-cause mortality and incidence of myocardial infarction (MI) at longest duration of follow-up
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constituted the primary endpoints, while secondary outcomes were MI at 30 days, major bleeding and revascularization. Subgroup
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analyses based on major adverse cardiovascular events stratified by GRACE score and troponin elevation was
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also performed. Outcomes were analyzed using the relative risk (RR) and 95% CI as summary statistics. Pooled RRs were determined
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using Mantel-Haenszel (M-H) random-effects model, which can account for between study heterogeneity (18). The risk difference between the two groups for each outcome was calculated and the number needed to treat to benefit (NNT) was determined where
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appropriate. Between-study heterogeneity was assessed using Q statistics with the proportion of the total variability in the effect size estimates evaluated with the I2 index. I2 index value > 75% was considered as substantial heterogeneity (19). Funnel plots and Egger test was used to estimate the risk of publication bias. Sensitivity analyses were performed by removing one study at a time to determine the influence of each study on the overall effect estimate. A study is noted to be influential if the pooled effect estimate without it is not within the 95% CIs of the overall effect size. Statistical analysis was performed with Stata software version 13.1 for
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windows (Stata Corp LP, College Station, Texas, USA). Risk ratios were reported with 95% CI and two-tailed p-value < 0.05 was considered significant.
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Result
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After exclusion of studies based on criteria mentioned above, a total of 13 RCTs were included. There were a total of 11972 patients, with 7101 patients randomized into early invasive group and 4871 in late invasive group. Timing for early invasive strategy was
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between 2 to 24 hours and timings for late invasive group was between 8 hours to 120 hours. In all included trials, both groups were
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treated with at least aspirin, clopidogrel or Ticagrelor and an anticoagulant, Trial characteristics with primary and secondary outcomes
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along with duration of follow up is summarized in Table 1. Patient characteristics are summarized in Table 2.
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The demographics and baseline characteristics were well balanced between the two treatment groups with a mean age of 66.2 years in the early group vs. 66.8 years in the delayed group. There were 65.1% men in early group compared to 66.0% in the delayed group.
Primary Outcomes
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The primary endpoint was all-cause mortality and MI incidence at longest follow up duration.
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All-cause mortality All-cause mortality was reported by all the included trials. Individual and pooled RRs for all-cause mortality showed no statistically significant difference in effect size and heterogeneity between the two groups (Figure 1). Overall, there were 384 deaths (5.41%) in
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the early invasive group and 316 deaths (6.49%) in the delayed group (RR 0.882, [95% CI, 0.76-1.02], p=0.094; I2 = 0.0). Result was
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primarily driven by VERDICT (43.19%), TIMACS (24.29%) and TAO (22.64%) trials. There was no significant publication bias detected based on the Egger regression (Egger test for small study bias P=0.904) and visual inspection of the funnel plots that showed
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no asymmetry (Figure A1, Appendix Material). Sensitivity analyses showed that no single study significantly changed the current
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overall results for this mortality endpoint (Figure A2, Appendix Material).
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MI (longest duration of follow-up)
Data from the RCTs included in the analysis showed that MI incidence at the longest duration of follow-up (as pre-specified by each
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individual trial) was significantly reduced in the early invasive group compared with the delayed group (RR 0.847, [95% CI 0.740.95], p 0.009, I2 = 75.2) (figure 2). These results should be interpreted with caution because of high heterogeneity. The duration of follow-up was variable across the included trials with the maximum duration of follow-up of 5 years seen in 2 out of the 13 included trials (VERDICT and SISCA). The duration of follow up has been listed in table 1. These results should be interpreted with caution
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because of considerable heterogeneity. No significant publication bias estimate was detected (Egger test for small study bias p = 0.697) and visual inspection of the funnel plots showed no significant asymmetry (Figure A3, Appendix Material).
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Secondary outcomes
The secondary outcomes were MI within 30 days, revascularization rates, and major bleeding following coronary intervention.
MI Incidence at 30-day Follow-up
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At 30-day follow up, there was no significant difference in incidence of myocardial infarction in the two groups (M-H pooled RR
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0.85, [95% CI, 0.73-1.01], p=0.06; I = 71.3) (Figure A4, Appendix Material). Only 10 of the 13 RCTs reported data outcomes for this endpoint. Sensitivity analysis demonstrated that OPTIMA trial significantly affected the overall effect estimate of this outcome
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(Figure A5, Appendix Material). Exclusion of OPTIMA trial lead to a beneficial effect of early intervention in reducing recurrent MI at 30 days (M-H pooled RR 0.77 [95% 0.64-0.93], p= 0.007)
Repeat Revascularization or Re-intervention
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The impact of an early compared to a delayed invasive intervention on repeated revascularization was reported by 7 RCTs. The effect size on revascularization was not significantly different between the two groups (RR 0.916, [95% CI 0.78-1.08], p-value 0.292; I2=79.3 (Figure A6, Appendix Material).
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Major bleeding
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There was no statistically significant difference between the two groups in terms of major bleeding which was reported by 8 RCTs
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(RR 0.819, CI 0.61-1.09, p value 0.175, I2=0.0). The associated funnel plots for all secondary endpoints showed no significant
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asymmetry. Likewise, there was no small study effects bias detected (Egger’s regression p-value> 0.05)
Sub-group analysis
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Subgroup analyses was performed to examine the efficacy of early vs delayed intervention in reducing major adverse cardiovascular events based on GRACE score and troponin elevation status.
MACE stratified by GRACE Score
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We extracted data on patients with Grace score greater than 140 (elevated Grace score) from 6 RCTs. A total of 9938 patients had elevated GRACE score, with 6085 in early invasive arm and 3853 in late invasive arm. In patients with elevated GRACE score, early intervention led to decreased adverse events (M-H pooled RR 0.88 [95% CI 0.82-0.95], p-value 0.002) although significant
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heterogeneity was identified (P = <0.001, I² = 79.5%). The number of avoided events per 1000 was estimated at 26 (95% CI, 10 – 41)
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and the number needed to treat to benefit was 39. This result should be interpreted with caution given the high heterogeneity. (Figure A7, Appendix Material)
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There was no significant difference in major adverse clinical events as described by individual trials in patients with low GRACE
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score defined as less than 140 (RR 0.99 [95% CI 0.93-1.05], p-value 0.804) based on data reported by 5 RCTs.
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MACE stratified by troponin elevation
Data on elevated troponin was reported by 8 RCTs. There were 6418 patients in early intervention group and 4186 patients in late
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intervention group. Overall, the effect size was not significantly different between early invasive and delayed invasive intervention among this group of patients (RR 1.01 [95% CI 0.99-1.03}, p-value 0.262; I2 = 0). (Figure A8, Appendix Material) The associated funnel plots for the subgroup analysis was somewhat symmetrical, although given the limited number of trials involved, publication bias cannot be totally excluded. The p value of the Egger’s regression intercept was not significant.
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DISCUSSION This meta-analysis is one of the largest based on the number of patients included from RCTs comparing early with the late intervention in patients with NSTE-ACS. The number of patients in our meta-analysis were 11,972 which is higher than Li et al, that
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included 6624 patients (!5), Bonello et al, 6397 patients (!6) and Jobs et al, 5324 patients (10). We selectively included RCTs that
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improved the quality of the extracted data and robustness of the results.
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This meta-analysis shows that early coronary intervention within first 24 hours following NSTE-ACS leads to significant decrease in
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recurrence of long-term MI. However, no difference in mortality, MI at 30 days, rate of revascularization and major bleeding between the two groups was demonstrated. The findings of GRACE score were reported in 6 RCTs and of elevated troponin were reported in 8
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RCTs. Our study also showed that GRACE score is a strong predictor of major adverse cardiac events whereas, elevated serum
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troponin alone without high GRACE score did not have direct correlation with MACE, which is an interesting finding.
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Previous studies including Bonello et al (16), Milasinovic et al(17), and Navaresse et al(19), showed that there was no significant difference in all-cause mortality and myocardial infarction between early and late invasive groups however unlike our meta-analysis, these studies did not assess the impact of early invasive therapy on occurrence of 30 day and one year MI. Job and colleagues in their meta-analysis found that early invasive strategy does not have mortality benefit as compared to late intervention in patients following NSTE-ACS (10). Early invasive strategy however leads to decrease in mortality in high-risk patients
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that were defined as age >75 years, GRACE score >140, elevated troponin and diabetes mellitus. We however did not find a beneficial effect of early invasive therapy on adverse cardiovascular events in patients with elevated troponin alone. This lack of association between elevated troponin and mortality has not been demonstrated in previous meta analysis and is a new finding. We believe that
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this difference in our results pertaining to the lack of benefit with respect to elevated troponin was driven by inclusion of data from
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recent randomized trial (TAO and VERDICT). In these studies, benefit of early invasive strategy was seen in patients with elevated GRACE score without this benefit being evident in patients with troponin elevation alone.
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Several reasons can be postulated for lack of correlation between troponin elevation alone and increase mortality in NSTE-ACS.
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Firstly, troponin assay has undergone several reiterations over the years, which may affect its sensitivity and specificity. Secondly, the
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studies have not taken into account the level of troponin elevation. Troponin level of 0.04 ng/ml, which is barely above the 99th
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percentile, affords a different prognosis than troponin of 4.0 ng/ml. However, in these studies no differentiation was made based on level of troponin elevation. Thirdly, pattern of troponin elevation is also important in diagnosis of acute myocardial infarction. Based
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on fourth universal definition of myocardial infarction, a rise and fall pattern of troponin elevation is needed with either symptom compatible with myocardial infarction or imaging/electrographic findings consistent with ischemia. Whereas chronic myocardial injury leads to persistent elevation in troponin without typical rise and fall pattern (18). The management and prognosis is different for these 2 different entities. The current guidelines recommend early invasive strategy in patients with elevated troponin levels,
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especially in female population and discourage early intervention in women without elevated biomarkers. This recommendation also needs to be further validated in light of our finding of lack of mortality benefit with early invasive approach.
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We were unable to further evaluate some of these finding because of inherent limitations of meta-analysis. Our results should be
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interpreted considering few limitations. Firstly, there is an overlap between timings of early and late invasive strategies trials, hence precise timing for optimal intervention cannot be elucidated. This overlap is not unique to our meta-analysis and previous meta-
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analysis also had similar limitations. In most trials early intervention was performed within 24 hours except in the study by Liu et al,
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in which both early and late group had intervention done within 24 hours (19). However, sensitivity analysis performed with exclusion
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of Liu et al. showed similar results. Secondly, in pre-specified subgroup analysis, we used composite of primary outcome as defined
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by individual trials instead of individual outcomes, which differed in-between trials. Thirdly, there is variability in duration of trials follow up. Only VERDICT and SISCA have 5 years follow. Because of these variations, there is considerable heterogeneity in the
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results. The duration of follow up of individual trials are summarized in table 1. Nevertheless, these are unique findings which needs to be taken into account in future randomized studies.
Conclusion:
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The results of our meta-analysis demonstrate a trend towards reduction in myocardial infarction on long term follow-up with early invasive strategy following NSTE-ACS. However, no difference in all-cause mortality was observed between the two groups. In our subgroup analysis, in patients with elevated GRACE risk score, early intervention following NSTE-ACS did show a statistically
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significant trend toward reduction in major adverse clinical events without any difference in outcomes in patients with elevated
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troponin alone. However, given the inherent limitations of the meta-analysis a well designed and adequately powered randomized controlled trials will be needed to validate these findings.
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Acknowledgement:
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Authors would like to acknowledge Kristin Chaplin and Ahmed Arslan Awan, MD for reviewing the manuscript.
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1. Rogers WJ, Frederick PD, Stoehr E, et al. Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J. 2008 Dec;156(6):1026–34. 2. Roger VL, Weston SA, Gerber Y, et al. Trends in incidence, severity, and outcome of hospitalized myocardial infarction. Circulation. 2010 Feb 23;121(7):863–9.
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3. Pilgrim T, Vranckx P, Valgimigli M, et al. Risk and timing of recurrent ischemic events among patients with stable ischemic heart disease, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction. Am Heart J. 2016 May;175:56–65.
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4. McCullough PA, O’Neill WW, Graham M, et al. A prospective randomized trial of triage angiography in acute coronary syndromes ineligible for thrombolytic therapy. Results of the medicine versus angiography in thrombolytic exclusion (MATE) trial. J Am Coll Cardiol. 1998 Sep;32(3):596–605.
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5. O’Donoghue ML, Vaidya A, Afsal R, et al. An invasive or conservative strategy in patients with diabetes mellitus and non-STsegment elevation acute coronary syndromes: a collaborative meta-analysis of randomized trials. J Am Coll Cardiol. 2012 Jul 10;60(2):106–11.
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6. Fox KAA, Clayton TC, Damman P, et al. Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data. J Am Coll Cardiol. 2010 Jun 1;55(22):2435–45.
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7. Fox K a. A, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina. Lancet Lond Engl. 2002 Sep 7;360(9335):743–51. 8. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-STElevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Dec 23;64(24):e139–228.
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9. Navarese EP, De Servi S, Gibson CM, et al. Early vs. delayed invasive strategy in patients with acute coronary syndromes without ST-segment elevation: a meta-analysis of randomized studies. QJM Mon J Assoc Physicians. 2011 Mar;104(3):193– 200. 10. Jobs A, Mehta SR, Montalescot G, et al. Optimal timing of an invasive strategy in patients with non-ST-elevation acute coronary syndrome: a meta-analysis of randomised trials. Lancet Lond Engl. 2017 Aug 19;390(10096):737–46.
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11. Deharo P, Ducrocq G, Bode C, et al. Timing of Angiography and Outcomes in High-Risk Patients With Non-ST-SegmentElevation Myocardial Infarction Managed Invasively: Insights From the TAO Trial (Treatment of Acute Coronary Syndrome With Otamixaban). Circulation. 2017 Nov 14;136(20):1895–907.
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12. Kofoed KF, Kelbæk H, Hansen PR, et al. Early Versus Standard Care Invasive Examination and Treatment of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome. Circulation. 2018 Dec 11;138(24):2741–50.
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13. Thiele H, Rach J, Klein N, et al. Optimal timing of invasive angiography in stable non-ST-elevation myocardial infarction: the Leipzig Immediate versus early and late PercutaneouS coronary Intervention triAl in NSTEMI (LIPSIA-NSTEMI Trial). Eur Heart J. 2012 Aug;33(16):2035–43.
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14. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. Int J Surg Lond Engl. 2010;8(5):336–41.
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15. Liu Z, Zhao L, Li Y, Wang Z, Liu L, Zhang F. Evaluation of early interventional treatment opportunity of the elderly & highrisk patients with non-ST segment elevation acute myocardial infarction. Pak J Med Sci. 2015 Oct;31(5):1053–6. 16. Bonello L, Laine M, Puymirat E, et al. Timing of Coronary Invasive Strategy in Non-ST-Segment Elevation Acute Coronary Syndromes and Clinical Outcomes: An Updated Meta-Analysis. JACC Cardiovasc Interv. 2016 28;9(22):2267–76. 17. Milasinovic D, Milosevic A, Marinkovic J, et al. Timing of invasive strategy in NSTE-ACS patients and effect on clinical outcomes: A systematic review and meta-analysis of randomized controlled trials. Atherosclerosis. 2015 Jul;241(1):48–54. 18. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Eur Heart J. 2018 Aug 25;
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19. Liu Z, Zhao L, Li Y, Wang Z, Liu L, Zhang F. Evaluation of early interventional treatment opportunity of the elderly & highrisk patients with non-ST segment elevation acute myocardial infarction. Pak J Med Sci. 2015 Oct;31(5):1053–6. 20. Montalescot G, Cayla G, Collet J-P, et al. Immediate vs delayed intervention for acute coronary syndromes: a randomized clinical trial. JAMA. 2009 Sep 2;302(9):947–54.
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21. Badings EA, The SHK, Dambrink J-HE, van Wijngaarden J, et al. Early or late intervention in high-risk non-ST-elevation acute coronary syndromes: results of the ELISA-3 trial. EuroIntervention J Eur Collab Work Group Interv Cardiol Eur Soc Cardiol. 2013 May 20;9(1):54–61.
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22. van ’t Hof AWJ, de Vries ST, Dambrink J-HE, et al. A comparison of two invasive strategies in patients with non-ST elevation acute coronary syndromes: results of the Early or Late Intervention in unStable Angina (ELISA) pilot study. 2b/3a upstream therapy and acute coronary syndromes. Eur Heart J. 2003 Aug;24(15):1401–5.
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23. Riezebos RK, Ronner E, Ter Bals E, et al. Immediate versus deferred coronary angioplasty in non-ST-segment elevation acute coronary syndromes. Heart Br Card Soc. 2009 May;95(10):807–12.
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24. Mehta SR, Granger CB, Boden WE, et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009 May 21;360(21):2165–75.
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25. Neumann F-J, Kastrati A, Pogatsa-Murray G, et al. Evaluation of prolonged antithrombotic pretreatment (“cooling-off” strategy) before intervention in patients with unstable coronary syndromes: a randomized controlled trial. JAMA. 2003 Sep 24;290(12):1593–9.
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26. Reuter P-G, Rouchy C, Cattan S, et al. Early invasive strategy in high-risk acute coronary syndrome without ST-segment elevation. The Sisca randomized trial. Int J Cardiol. 2015 Mar 1;182:414–8. 27. Milosevic A, Vasiljevic-Pokrajcic Z, Milasinovic D, et al. Immediate Versus Delayed Invasive Intervention for Non-STEMI Patients: The RIDDLE-NSTEMI Study. JACC Cardiovasc Interv. 2016 Mar 28;9(6):541–9. 28. Tekin K, Cagliyan CE, Tanboga IH, et al. Influence of the Timing of Percutaneous Coronary Intervention on Clinical Outcomes in Non-ST-Elevation Myocardial Infarction. Korean Circ J. 2013 Nov;43(11):725–30.
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Main Figures:
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Figure 1. Meta-analysis forest plot showing the effect of early intervention on mortality
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Meta-analysis showing effect of early vs delayed intervention on risk ratio for all-cause mortality in 13 trials. Individual and pooled RRs for all-cause mortality showed no statistically significant difference in effect size and heterogeneity between the two groups.
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Figure 2. Meta-analysis forest plot showing the effect of early intervention on MI incidence at longest
followup
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Meta-analysis showing effect of early vs delayed intervention on MI incidence at longest duration of follow up in 13 trials. MI
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incidence at longest duration of follow-up was significantly reduced in the early invasive group compared with the delayed group
TABLES: Table 1: Summary of Randomized Control Trials included in meta-analysis.
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Trial Name
Year
Time Early
Time Late
Pts Pts Early Late
ABOARD(20)
2009
<2 hrs
8-60 hrs
175
177
ELISA 3 (21)
2013
<12 hrs
>48hrs
269
265
ELISA 1 (22)
2003
<12 hrs
>48hrs
109
111
OPTIMA (23)
2009
Immediate
24-48 hrs
73
69
LIPSIA-NSTEMI(13)
2012
<2hrs
10-48hrs
TIMACS (24)
2009
<24hrs
Liu et al (19)
2015
ISAR-COOL (25)
2003
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2008
>36hrs
1593
1438
<12hrs
12-24hrs
22
20
<6hrs
3-5 days
203
207
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Primary: Peak troponin elevation Secondary: Composite of death, MI or urgent revascularization at 1 month follow up Follow up: 1 month Primary: Combined incidence of death, reinfarction and/or recurrent ischemia at 30-day follow up Secondary: Enzymatic infarct size and bleeding complications Follow up: 1 month Total death and recurrent myocardial infarction at 30 days Follow up: 1 month Primary: Composite of death, non-fatal MI, unplanned revascularization at 30 days. Secondary: Individual component, size of MI, revascularization, major bleeding, readmission and length of in-hospital stay Follow up: 6 months Primary: Peak Creatinine Kinase myocardial band Secondary: Composite of death, MI, refractory ischemia and re-hospitalization Follow up: 6 months Primary: Composite of death, MI or stroke at 6 months Secondary: Above and repeat intervention and refractory ischemia Follow up: 6 months Success of PCI, ischemia re-hospitalization, heart failure, arrhythmias, heart failure, bleeding and death Follow up: 6 months Primary: Composite of MI and death during 30 days Secondary: Bleeding complications Follow up: 1 month
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200
Outcomes and follow up
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SISCA (26)
2014
<6hrs
>6hr as per physician discretion, or as per guidelines. Not within 6hrs
83
86
TAO Trial ((11)
2017
Very early<12hr s Early 1224hrs
Delayed>24hrs
3068
1003
RIDDLE-NSTEMI (27)
2015
<2hrs
2-72hr
162
Tekin et al (28)
2013
<24hrs
>24-72hrs
69
VERDICT (12)
2018
12 hrs
48-72 hr
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1075
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Table 2: Baseline demographics of patients in individual trials
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161
62
Primary: Composite of deaths, MI and revascularization at 30 days follow up Secondary: Treatment failure, revascularization, peak troponin, left ventricular ejection fraction, length of hospital stay, major or minor bleeding, long term mortality Follow up: 5 years Primary: Composite of all cause mortality and new MI at 180 days follow up Secondary: Above outcome at 7 days and 30 days, re-hospitalization, prolongation of hospitalization and stent thrombosis Follow up: 6 months Primary: Composite of death and MI at 30 days Secondary: Composite of death, new MI, recurrent ischemia at 30 days and 1 year. Follow up: 1year Repititive MI, hospitalization due to cardiac reason, death due to any reason Follow up: 3 months Primary: Combination of all cause death, acute myocardial infarction, refractory ischemia and heart failure Secondary: Procedure complication Follow up 5 years
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Study
Stud y type
Age mea n SD
Sex M/F (n)
Diabete s (n)
Hypertensio n (n)
Smokin g (n)
Dyslipidemi a (n)
Previou s MI (n)
Previou s CABG (n)
Previou s PCI (n)
ABOAR D
Early
62
31/48
38
115
56
100
29
9
Late Early Late Early Late Early Late Early
65 72.1 71.8 63±11 65±11 63 62 68
125/52 187/82 174/91 79/30 76/35 51/22 69/7 132/68
57 64 54 16 16 14 14 76
108 146 154 49 43 39 23 161
60 57 70 40 36 28 27 57
102 NA NA NA NA 28 22 79
33 48 52 19 14 15 18 35
12 37 32 12 8 8 1 10
Late Early Late Early
70 65.0 65.7 80.4 1 80.3 0 70
139/61 1038/555 940/498 11/11
85 422 394 11
161 1084 996 16
49 441 394 12
82 NA NA NA
46 313 300 8
13/7
11
14
13
NA
140
65
180
38
134 58/25 63/23 1968/110 0 653/ 368 114/48
53 35 28 1003
174 50 51 2419
49 44 41 620
342
Early
70 63.9 66.5 70.7 1 70.3 6 60.5
Late Early
63.0 58.1
106/55 41/28
52 22
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Late Early
55.6 63.6
Late
63.6
44/20 716/ 359 696/ 376
ELISA 3 ELISA OPTIMA LIPSIANSTEMI TIMACS Liu et al
Late ISAR COOL SISCA TAO
Early Late Early Late Early Late
RiddleSTEMI Tekin et al VERDIC T
l a NA
NA 45 45 1640
Previou s TIA (n)
9
Previou s Cancer (n) 7
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25 NA NA NA NA 5 3 NA
8 9 12 NA NA NA NA 9
1 NA NA NA NA NA NA NA
13 NA NA NA NA NA NA NA
31 221 204 NA
NA NA NA 11
NA NA NA NA
11 114 108 NA
NA NA NA NA
NA NA NA NA
Previou s Stroke (n)
18
54 49 55 16 16 20 13 32
7 NA NA NA NA 1 1 NA
15 111 105 NA NA
NA
8
NA
NA
NA
NA
52
28
48
NA
NA
NA
NA
NA
44 19 20 650
20 8 4 300
42 20 18 3067
NA NA NA 283
NA NA NA 215
NA NA NA 221
NA NA NA NA
NA NA NA NA
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Previou s PAD (n)
43
Cardiac Insuficienc y (n) 7
15
106
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84
31
8
17
NA
NA
9
NA
NA
116 38
62 42
62 43
34 NA
12 NA
15 NA
NA NA
NA NA
16 NA
NA NA
NA NA
28 158
31 543
30 342
31 NA
NA 186
NA 57
NA 151
NA 302
NA NA
NA 94
NA NA
NA NA
173
578
323
NA
186
57
163
305
NA
82
NA
NA
35
789
203
574
235
105
1003
103
61
81
NA
NA
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Highlights
We performed this meta-analysis with available Randomized Controlled Trials (RCTs) to compare early versus late coronary intervention in patients with NSTE-ACS.
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Our study showed that early intervention leads to decreased in long-term myocardial infarction with no difference in mortality as compared to delayed group.
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In sub-group analysis, early intervention led to decrease in adverse events in patients with elevated GRACE (Global Registry of Acute Coronary Events) score>140, (M-H pooled RR 0.88 [95% CI 0.82-0.95], p-value 0.002 but no difference was seen in
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patients with elevated troponin.
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This meta-analysis is one of the largest based on the number of patients included from RCTs comparing early with the late intervention in patients with NSTE-ACS.
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Figure 1
Figure 2