Meta-Analysis of Multivessel Versus Culprit-Only Percutaneous Coronary Intervention in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome and Multivessel Coronary Disease

Accepted Manuscript Meta-Analysis of Multivessel Versus Culprit-Only Percutaneous Coronary Intervention in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome and Multivessel Coronary Disease Jae-Sik Jang, MD, PhD, Han-Young Jin, MD, Jeong-Sook Seo, MD, PhD, Tae-Hyun Yang, MD, PhD, Dae-Kyeong Kim, MD, PhD, Dong-Soo Kim, MD, PhD, Kyoung-Im Cho, MD, PhD, Bo-Hyun Kim, MD, PhD, Yong Hyun Park, MD, PhD, Hyung-Gon Je, MD, PhD PII:

S0002-9149(15)00625-6

DOI:

10.1016/j.amjcard.2015.01.530

Reference:

AJC 20936

To appear in:

The American Journal of Cardiology

Received Date: 1 November 2014 Revised Date:

22 January 2015

Accepted Date: 27 January 2015

Please cite this article as: Jang J-S, Jin H-Y, Seo J-S, Yang T-H, Kim D-K, Kim D-S, Cho K-I, Kim B-H, Park YH, Je H-G, Meta-Analysis of Multivessel Versus Culprit-Only Percutaneous Coronary Intervention in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome and Multivessel Coronary Disease, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.01.530. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.

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Meta-Analysis of Multivessel Versus Culprit-Only Percutaneous Coronary Intervention in Patients With Non-ST-Segment Elevation

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Acute Coronary Syndrome and Multivessel Coronary Disease

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Running head: Multivessel revascularization in NSTE-ACS patients

Jae-Sik Jang, MD, PhDa, Han-Young Jin, MDa, Jeong-Sook Seo, MD, PhDa, Tae-Hyun Yang, MD, PhDa, Dae-Kyeong Kim, MD, PhDa, Dong-Soo Kim, MD, PhDa, Kyoung-

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Im Cho, MD, PhDb, Bo-Hyun Kim, MD, PhDc, Yong Hyun Park, MD, PhDd, HyungGon Je, MD, PhDd a

Busan Paik Hospital, University of Inje College of Medicine, Busan, Korea, bKosin

University Medical Center, Busan, Korea, cPusan National University Hospital, Busan,

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Korea, dPusan National University Yangsan Hospital, Yangsan, Korea.

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None of the authors have a conflict of interest

Corresponding Author: Jae-Sik Jang, MD, PhD

Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, 633-165 Gaegum-dong, Jin-gu, Busan, 614-735, KOREA Phone: +82-51-890-6418, Fax: +82-51-892-0273, E-mail: [email protected]

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ABSTRACT Even in the era of contemporary drug-eluting stents, it is not clear whether percutaneous coronary intervention (PCI) for non-culprit lesions can improve long-term outcomes in

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non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients with

multivessel coronary disease. Relevant studies published through August 2014 were

searched and identified in the electronic databases. Summary estimates were obtained

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using a random-effects model. From 368 initial citations, 8 observational studies with 8,425 patients (3,227 multivessel and 5,198 culprit-only PCI) were included. Mean

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follow-up duration was 18 months. There were no significant differences in all-cause mortality (odds ratios [OR] 0.85, 95% CI 0.70 to 1.04), myocardial infarction (OR 0.86, 95% CI 0.55 to 1.35). However, multivessel PCI was associated with a significantly lower rate of repeat revascularization (OR 0.75, 95% CI 0.56 to 1.00). Comparison of

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multivessel versus culprit-only PCI disclosed OR for major adverse cardiac events (MACE) of 0.74 (95% CI 0.57 to 0.97). In conclusion, multivessel PCI reduced repeat revascularization without significant benefits in terms of mortality or MI at the long-

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term follow-up in NSTE-ACS patients with multivessel coronary disease. Future randomized studies that examine the safety and efficacy of multivessel PCI in NSTE-

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ACS are warranted.

Key Words: Acute coronary syndrome, Coronary artery disease, Percutaneous coronary intervention

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Approximately half of patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) presents with multiple coronary lesions that may be suitable for interventional treatment.1,2 Although early invasive strategy has been shown to improve

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clinical outcomes as compared with conservative strategy3-5 and is currently

recommended,6 there is still no formal guidelines of the extent of revascularization for those with multivessel coronary disease. Recently, there has been report of several

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randomized trials showing better outcomes in the ST-segment elevation myocardial infarction (STEMI) patients treated with preventive strategy.7,8 However, not a few

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presumed culprit lesions of NSTE-ACS patients might not have caused the index event and the interventional cardiologist facing those patients without obvious changes in electrocardiography (ECG) frequently encounters difficulties in determination of the culprit vessel and decision how to proceed with interventional treatment, as opposed to

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primary PCI cases in patients with STEMI. Therefore, we performed a systematic review of literature and meta-analyses to compare multivessel complete PCI to culprit-

METHODS

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only PCI in patients with NSTE-ACS and multivessel coronary disease.

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We identified relevant studies through electronic searches of MEDLINE,

EMBASE, and the Cochrane Central Register of Controlled Trials, ISI Web of Science, Scopus and Google Scholar databases from January 2001 through August 2014. We have also manually searched the contents pages of issues from recent major scientific meetings and performed cross-referencing of review articles to find out further potential publications. Medical subject headings and keyword searches included “multivessel”, “complete”, “staged”, “culprit”, “revascularization”, “angioplasty”, “PCI”,

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“revascularization”, “unstable angina”, “acute coronary syndrome”, and “myocardial infarction.” Two investigators (J.-S.J. and B.-H.K.) independently conducted the literature

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search, data extraction, and quality assessment by using a standardized approach.

Selected publications were reviewed by the same investigators to assess whether or not studies met the inclusion criteria: (1) studies comparing clinical outcomes of multivessel,

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complete revascularization to those of culprit-only revascularization at the time of index procedure in patients with NSTE-ACS and multivessel coronary disease and (2) follow-

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up duration ≥ 6 months. Exclusion criteria were: (1) studies comparing PCI with surgical revascularization; (2) studies with lack of control group. The end points of this study were all-cause mortality, myocardial infarction (MI), repeat revascularization and major adverse cardiac events (MACE) at the longest follow-up.

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We calculated odds ratios (ORs) for each outcome using the DerSimonian and Laird random-effects model.9 Crude OR with 95% confidence interval (CI) was used to assess the efficacy of treatment strategy on adverse clinical events in study populations.

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All p values were 2-tailed, with statistical significance set at 0.05. We assessed

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statistical heterogeneity between trials with I2 statistic, which is derived from Cochran’s Q and the degree of freedom [100×(Q

df)/Q)].10 I2 values greater than 25%, 50%, and

75% were considered evidence of low, moderate, and severe statistical heterogeneity, respectively. In case of heterogeneity across the studies, we did an influence analysis, in which the pooled estimates were recalculated omitting one study at a time, to assess the effect of individual studies on the summary estimate of effect. Publication bias was examined by visual inspection of constructed funnel plot for the all-cause mortality and mathematically by means of Egger's test and trim-and-fill method.11,12 4

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All statistical analyses were performed using the Review Manager Version 5.1 (The Nordic Cochrane Center, Copenhagen, Denmark) and MIX version 2.0 (BiostatXL,

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Sunnyvale, CA, USA).

RESULTS

A total of 427 publications were reviewed and 8 observational studies were

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selected for inclusion and evaluated (Figure 1).13-20 Two large registry studies were

excluded because they did not report clinical outcomes after hospital discharge.21,22

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Characteristics of the included studies are summarized in Table 1. Of the 8,425 patients, 3,227 patients underwent multivessel PCI and 5,198 underwent culprit-only revascularization at the time of index procedure. Two studies were prospective studies including 3,159 patients15,17 and the other 6 studies were retrospective observational

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studies including 5,266 patients with matched cohorts or consecutive patients comparing multivessel vs. culprit-only PCI strategies.13,14,16,18-20 Most of the included studies defined MACE as composite of all-cause death, MI, and repeat revascularization

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except for 2 studies, which included repeat revascularization for ACS13 and MI requiring hospitalization (excluding periprocedural MI)15 in their primary end point.

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More patients of culprit-only PCI group were likely to have a previous history of PCI in 3 studies (Table 2).18-20

There was no significant difference in the incidence of all-cause death at

follow-up (OR 0.85, 95% CI 0.70 to 1.04) between multivessel PCI and culprit-only PCI group (Figure 2A). Statistical heterogeneity was not found among the included studies. Pooled effects showed no significant difference in the incidence of MI at follow-up (OR 0.86, 95% CI 0.55 to 1.35; Figure 2B). There was evidence of

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heterogeneity among the included studies. The risk of repeat revascularization was significantly lower in patients undergoing multivessel PCI compared to those undergoing culprit-only PCI (OR 0.75, 95% CI 0.56 to 1.00; Figure 2C). There was

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statistically significant heterogeneity among the included studies.

The incidence of MACE was significantly lower in the multivessel PCI group as compared to culprit-only PCI group (OR 0.74, 95% CI 0.57 to 0.97; Figure 3).

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Statistically significant heterogeneity was noted among the included studies. The

sensitivity analysis of the risk of MACE with multivessel PCI by excluding studies and

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repeating meta-analysis shifted ORs to rightward offsetting the statistically significant benefit of multivessel PCI over culprit-only PCI (Supplementary Figure 1). The cumulative analysis of the included studies up to a time point in a chronological order depicts the summary ORs of recently published studies favoring multivesel PCI

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(Supplementary Figure 2).

Assessment of publication bias using OR of MACE of the included studies showed existence of publication bias, confirmed by means of a positive Egger’s

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regression-based test (p = 0.05). The trim-and-fill analysis demonstrated that 3 missing

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studies were needed to achieve a symmetrical funnel plot (Figure 4).

DISCUSSION

In the present meta-analysis of 8 observational studies consisting of 8,425

NSTE-ACS patients with multivessel coronary disease (3,227 multivessel and 5,198 culprit-only PCI), we found that multivessel PCI strategy does not reduces risks of allcause death and MI but associated with a significantly lower risk of repeat revascularization, which translated into a lower incidence of the MACE as compared

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with culprit-only PCI strategy. To our knowledge, this is the first meta-analysis comparing the outcomes of multivessel versus culprit-only PCI strategy in NSTE-ACS setting. Although we provided useful information to physicians by showing outcomes of

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both treatment groups, the results of our study does not offer any evidence of the significant benefit of one strategy over the other in this clinical setting.

Treatment of significantly stenosed vessel other than culprit vessel has been a

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long-term therapeutic dilemma for physicians. Recent guidelines do not recommend

non-culprit PCI in the setting of primary PCI for patients with STEMI unless they are

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hemodynamically unstable.23,24 Treating the non-infarcted artery in ACS setting may increase the risk of stent thrombosis in a thrombotic condition and jeopardize the remained viable myocardium.25,26 Moreover, increased procedural time with higher exposure of radiocontrast agent may increase risk of contrast-induced acute kidney

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injury and lead to unexpected exposure to radiation hazard.

On the other hand, eliminating the potential risk and additional cost of nonculprit lesion related procedures could be attractive for both physicians and patients.

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Our meta-analysis showed that 38% of NSTE-ACS patients with multivessel coronary disease undergo more than single vessel intervention, which is consistent with previous

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reports.15,21 The efficacy of multivessel PCI in NSTE-ACS patients was examined in a subpopulation of the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) trial.20 There were no clinical benefits of multivessel PCI over single vessel PCI at 1 year. Though the results of our study do not support multivessel PCI on significant non-culprit lesions to reduce long-term mortality in patients with NSTEACS, it significantly reduced future revascularization rate and this was extrapolated to significant reduction in the rate of MACE. However, the majority of multivessel PCI are

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largely driven by consideration of clinical factors such as worsening clinical status and anatomical factors at time of PCI. Moreover, differences in disease severity and baseline comorbidities of the included patients might have influenced the physician’s decision

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whether or not to proceed with additional PCI and have led them to less invasive

procedure (culprit-only PCI) in relatively sicker patients. Although differences in

baseline risks and comorbidities may confound different therapeutic strategy, these

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factors could not be adjusted across patients receiving different strategy. Several studies are underway to comply with similar problems in patients with STEMI undergoing

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primary PCI.27-29 Because this is clinically important in NSTE-ACS patients as well, adequately powered randomized trials are strongly needed in this clinical setting. There are several limitations to be addressed in our study. First, the included studies in our analysis were observational studies from different cohorts, which brought

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about an insufficient power to the results. Although we investigated whether multivessel PCI might improve clinical outcomes in NSTE-ACS patients with multivessel coronary disease, revascularization strategy can be made based on patient’s condition, urgency of

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PCI and readiness of surgical back up. However, carefully selected studies performed in NSTE-ACS patients in our study would represent a real-world application of

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contemporary PCI. Second, some results of our meta-analysis have significant heterogeneity and unadjusted risk estimates from observational studies are prone to selection and performance bias. However, we tried to overcome heterogeneity problems by using random-effects models rather than fixed effects model and performed exclusion sensitivity analysis and cumulative analysis. Third, despite exhaustive search with sensitive tools for the retrieval of eligible studies, there was evidence of publication bias. Finally, different procedural strategies and stents were used during the

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revascularization among the included studies, which were likely to be influenced by physician preference or patient characteristics.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant

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funded by the Korea government (MSIP) (No. R13-2007-023-00000-0).

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1. Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 1995;92:2333-2342.

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2. Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ. Atherothrombosis and highrisk plaque: part I: evolving concepts. J Am Coll Cardiol 2005;46:937-954.

3. Fox KA, Poole-Wilson PA, Henderson RA, Clayton TC, Chamberlain DA, Shaw TR,

SC

Wheatley DJ, Pocock SJ. Randomized Intervention Trial of unstable Angina

Investigators. Interventional versus conservative treatment for patients with unstable

M AN U

angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina. Lancet 2002;360:743-751.

4. Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N,

TE D

Neumann FJ, Robertson DH, DeLucca PT, DiBattiste PM, Gibson CM, Braunwald E, TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy)--Thrombolysis in Myocardial Infarction 18

EP

Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N

AC C

Engl J Med 2001;344:1879-1887. 5. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet 1999;354:708-715. 6. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE,Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P,

10

ACCEPTED MANUSCRIPT

Wenger NK, Zidar JP. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the

on Practice Guidelines. J Am Coll Cardiol 2012;60:645-681.

RI PT

American College of Cardiology Foundation/American Heart Association Task Force

7. Wald DS, Morris JK, Wald NJ, Chase AJ, Edwards RJ, Hughes LO, Berry C,

SC

Oldroyd KG, PRAMI Investigators. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med 2013;369:1115-1123.

M AN U

8. Gershlick AH. Complete versus Lesion only PRimary-PCI Trial (CvLPRIT): treat the infarct-related artery only or all lesions? Presented at: European Society of Cardiology Congress; September 1, Barcelona, Spain 2014.

9. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials

TE D

1986;7:177-188.

10. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ 2003;327:557-560.

EP

11. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-634.

AC C

12. Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56:455-463. 13. Brener SJ, Murphy SA, Gibson CM, DiBattiste PM, Demopoulos LA, Cannon CP, TACTICS-TIMI 18 Investigators. Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombosis in Myocardial Infarction. Efficacy and safety of multivessel percutaneous revascularization and

11

ACCEPTED MANUSCRIPT

tirofiban therapy in patients with acute coronary syndromes. Am J Cardiol 2002;90:631633. 14. Palmer ND, Causer JP, Ramsdale DR, Perry RA. Effect of completeness of

RI PT

revascularization on clinical outcome in patients with multivessel disease presenting with unstable angina who undergo percutaneous coronary intervention. J Invasive Cardiol 2004;16:185-188.

SC

15. Shishehbor MH, Lauer MS, Singh IM, Chew DP, Karha J, Brener SJ, Moliterno DJ, Ellis SG, Topol EJ, Bhatt DL. In unstable angina or non-ST-segment acute coronary

M AN U

syndrome, should patients with multivessel coronary artery disease undergo multivessel or culprit-only stenting? J Am Coll Cardiol 2007;49:849-854.

16. Zapata GO, Lasave LI, Kozak F, Damonte A, Meirino A, Rossi M, Carbo S, Pollice A, Paolasso E, Picabea E. Culprit-only or multivessel percutaneous coronary stenting in

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patients with non-ST-segment elevation acute coronary syndromes: one-year follow-up. J Interv Cardiol 2009;22:329-335.

17. Kim MC, Jeong MH, Ahn Y, Kim JH, Chae SC, Kim YJ, Hur SH, Seong IW, Hong

EP

TJ, Choi DH, Cho MC, Kim CJ, Seung KB, Chung WS, Jang YS, Cho SY, Rha SW, Bae JH, Cho JG, Park SJ, Korea Acute Myocardial Infarction Registry Investigators.

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What is optimal revascularization strategy in patients with multivessel coronary artery disease in non-ST-elevation myocardial infarction? Multivessel or culprit-only revascularization. Int J Cardiol 2011;153:148-153. 18. Lee HJ, Song YB, Hahn JY, Kim SM, Yang JH, Choi JH, Choi SH, Choi JH, Lee SH, Gwon HC. Multivessel vs single-vessel revascularization in patients with non-STsegment elevation acute coronary syndrome and multivessel disease in the drug-eluting stent era. Clin Cardiol 2011;34:160-165.

12

ACCEPTED MANUSCRIPT

19. Onuma Y, Muramatsu T, Girasis C, Kukreja N, Garcia-Garcia HM, Daemen J, Gonzalo N, Piazza N, Einthoven J, van Domburg R, Serruys PW, interventional cardiologists of the Thoraxcenter (2000-5). Single-vessel or multivessel PCI in patients

RI PT

with multivessel disease presenting with non-ST-elevation acute coronary syndromes. EuroIntervention 2013;9:916-922.

20. Hassanin A, Brener SJ, Lansky AJ, Xu K, Stone GW. Prognostic impact of

SC

multivessel versus culprit vessel only percutaneous intervention for patients with multivessel coronary artery disease presenting with acute coronary syndrome.

M AN U

EuroIntervention 2014. doi: 10.4244/EIJY14M08_05. [Epub ahead of print] 21. Brener SJ, Milford-Beland S, Roe MT, Bhatt DL, Weintraub WS, Brindis RG, American College of Cardiology National Cardiovascular Database Registry. Culpritonly or multivessel revascularization in patients with acute coronary syndromes: an

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American College of Cardiology National Cardiovascular Database Registry report. Am Heart J 2008;155:140-146.

22. Bauer T, Zeymer U, Hochadel M, Mollmann H, Weidinger F, Zahn R, Nef HM,

EP

Hamm CW, Marco J, Gitt AK. Prima-vista multi-vessel percutaneous coronary intervention in haemodynamically stable patients with acute coronary syndromes:

AC C

analysis of over 4.400 patients in the EHS-PCI registry. Int J Cardiol 2013;166:596-600. 23. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, Borger MA, Di Mario C, Dickstein K, Ducrocq G, FernandezAviles F, Gershlick AH, Giannuzzi P, Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW, Valgimigli M, van 't Hof A, Widimsky P, Zahger D. ESC

13

ACCEPTED MANUSCRIPT

Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569-2619. 24. O'Gara PT, Kushner FG, Ascheim DD, Casey DE,Jr, Chung MK, de Lemos JA,

RI PT

Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM,

Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-

Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK,

SC

Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW. American

M AN U

College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation

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2013;127:e362-425.

25. Moreno R, Fernandez C, Hernandez R, Alfonso F, Angiolillo DJ, Sabate M, Escaned J, Banuelos C, Fernandez-Ortiz A, Macaya C. Drug-eluting stent thrombosis:

EP

results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol 2005;45:954-959.

AC C

26. Chu WW, Kuchulakanti PK, Rha SW, GebreEyesus A, Aggrey G, Torguson R, Wang B, Xue Z, Clavijo LC, Suddath WO, Pichard AD, Satler LF, Kent KM, Waksman R. Impact of three or more versus a single sirolimus-eluting stent on outcomes in patients who undergo percutaneous coronary intervention. Am J Cardiol 2006;97:606610.

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27. Complete Lesion Versus Culprit Lesion Revascularization (COCUA). Clinicaltrials.Gov 2015. http://clinicaltrials.Gov/ct2/show/nct01180218. Accessed January 2015.

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28. Complete vs Culprit-Only Revascularization to Treat Multi-Vessel Disease After Primary PCI for STEMI (COMPLETE). Clinicaltrials.Gov 2015.

https://clinicaltrials.gov/ct2/show/NCT01740479. Accessed January 2015.

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29. Primary PCI in Patients With ST-elevation Myocardial Infarction and Multivessel

Disease: Treatment of Culprit Lesion Only or Complete Revascularization (DANAMI-

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3-PRIMULTI). Clinicaltrials.Gov 2015.

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https://clinicaltrials.gov/ct2/show/NCT01960933. Accessed January 2015.

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FIGURE LEGENDS Figure 1. Flow diagram demonstrating inclusion/exclusion process for studies

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incorporated into the final analyses.

Figure 2. Forest plots of odds ratios according to the revascularization strategy on all-

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cause mortality (A), myocardial infarction (B) and repeat revascularization (C).

groups.

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Figure 3. Forest plot of odds ratio for MACE in multivessel PCI vs. culprit-only PCI

Figure 4. Funnel plot of MACE indicates the existence of publication bias with an asymmetric funnel plot. Three open circles by trim-and-fill method represent the

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hypothetical missing studies.

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SUPPLEMENTARY FIGURE LEGENDS Supplementary Figure 1. Exclusion sensitivity analysis of the risk of MACE with

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multivessel PCI representing the influence of each study on the overall results.

Supplementary Figure 2. Cumulative analysis of the risk of MACE with multivessel PCI versus culprit-only PCI. This figure depicts the summary ORs of all trials published up to a time point in a chronological order.

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Table 1. Characteristics of included studies

period 1997~ 1998 Palmer et al.14

2004

2000~ 2001

Shishehbor et al.15

2007

1995~ 2005

Zapata et al.16

2009

1996~ 2006

Kim et al.17

2011

2005~ 2008

Lee et al.18

2011

2003~ 2006

Retrospective,

66/224

Composite of death, MI, and repeat

71/80

Previous CABG, LM

10

Composite of death, MI requiring

CTOs, staged PCI, prior

28

hospitalization, or any revascularization

CABG

observational Prospective, observational Retrospective, observational

Recurrent angina, repeat PCI or elective CABG, non-fatal MI, death

479/761

observational Retrospective,

(in months)

revascularization for ACS

observational Prospective,

Follow-up

6

observational Retrospective,

Exclusion criteria

PCI at non-culprit only

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2002

Primary end point

strategy*

201/404

1,011/908

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Brener et al.13

PCI

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Design

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Study

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Year

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Study

179/187

MACE, defined as death, MI, or any repeat

Persistent ST-elevation,

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revascularization

CTO, or staged PCI

MACE, defined as all-cause deaths, MI,

ST elevation on ECG

12

MACE, defined as the composite of any

Prior CABG, LM, CTOs,

36

death, MI, or any revascularization

shock, staged PCI

any repeat revascularization

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2013

2000~ 2005

Hassanin et al.20

2014

2003~ 2005

Retrospective,

611/379

Composite of all-cause mortality or MI

609/2,255

MACE, defined as the composite of any

Prior CABG, staged PCI

36

Staged PCI

12

observational Retrospective, observational

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Onuma et al.19

cause death, MI, or ischemia-driven PCI

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*Data are presented as multivessel/culprit-only PCI. ACS = acute coronary syndrome; APEX-AMI = Assessment of Pexelizumab in Acute

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Myocardial Infarction; CABG = coronary artery bypass grafting; CTO = chronic total occlusion; ECG = electrocardiography; LM = left main;

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MACE = major adverse cardiac events; MI = myocardial infarction; PCI = percutaneous coronary intervention.

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Table 2. Baseline characteristics of patients Age

Male

Hypertens

Diabetes

Hyperlipi

Smokers

gender (%)

ion (%)

(%)

demia (%)

(%)

Renal

Previous

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Study

Previous

Previous

Cardiogenic

failure (%)

MI (%)

PCI (%)

CVA (%)

shock (%)

NA

44/43/43

NA

NA

NA

NA

42/37/39

17/20/19

NA

NA

62/62/62

71/67/68

64/70/69

30/27/28

68/67/67

32/26/27

Palmer et al.14

62/63/63

69/66/67

34/40/37

21/21/21

82/81/81

72/70/71

Shishehbor et al.15

66/65/65

64/65/65

NA

32/31/31

NA

19/26/23*

6/6/6

46/47/47

NA

NA

NA

Zapata et al.16

61/62/62

82/83/83

66/65/65

20/22/21

66/62/63

30/31/31

3/4/4

26/27/27

11/17/15

NA

NA

Kim et al.17

65/66/65

65/69/67

57/60/58

34/35/34

14/12/13

52/55/53

NA

NA

NA

NA

NA

Lee et al.18

65/65/65

72/63/67

58/63/61

34/41/38

32/28/30

25/19/22

6/6/6

9/8/8

8/16/12*

9/8/8

Excluded

Onuma et al.19

65/64/65

31/30/31

44/42/43

20/19/20

54/54/54

23/25/24

NA

45/52/48*

15/33/22*

NA

NA

Hassanin et al.20

62/62/62

71/72/72

69/72/71

35/32/33

61/64/63

31/31/31

16/18/18

35/38/37

46/52/51*

NA

NA

TE D

M AN U

SC

Brener et al.13

AC C

other abbreviations as in Table 1.

EP

Data are presented as multivessel/culprit-only PCI/weighted mean value. *p<0.05. CVA = cerebrovascular accident; NA = not applicable;

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

Figure 3

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C EP TE D

SC

M AN U

RI PT

AC C EP TE D

SC

M AN U

RI PT