Complete vs Culprit-Lesion-Only Revascularization for ST-Segment Elevation Myocardial Infarction: A Systematic Review and Meta-analysis | Acute Coronary Syndromes | JAMA Cardiology | JAMA Network
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Figure 1.  Forest Plot of Long-term Cardiovascular Death in Patients With Complete Revascularization or Culprit-Lesion-Only Percutaneous Coronary Intervention (PCI)
Forest Plot of Long-term Cardiovascular Death in Patients With Complete Revascularization or Culprit-Lesion-Only Percutaneous Coronary Intervention (PCI)

Size of markers represents weight. Squares and diamonds indicate odds ratios (ORs); error bars, 95% CIs. COMPARE-ACUTE indicates Fractional Flow Reserve Guided Primary Multivessel Percutaneous Coronary Intervention to Improve Guideline Indexed Actual Standard of Care for Treatment of ST-Elevation Myocardial Infarction in Patients With Multivessel Coronary Disease; COMPLETE, Complete vs Culprit-Only Revascularization to Treat Multivessel Disease After Early PCI for STEMI; CvLPRIT, Complete vs Lesion-Only Primary PCI Trial; DANAMI-3–PRIMULTI, Primary PCI in Patients With ST-Elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization; HELP AMI, Hepacoat for Culprit or Multivessel Stenting for Acute Myocardial Infarction; MH random, random-effects model using the Mantel-Haenszel method; and PRAMI, Preventive Angioplasty in Myocardial Infarction.

Figure 2.  Forest Plot of Long-term Cardiovascular Death or New Myocardial Infarction in Patients With Complete Revascularization or Culprit-Lesion-Only Percutaneous Coronary Intervention (PCI)
Forest Plot of Long-term Cardiovascular Death or New Myocardial Infarction in Patients With Complete Revascularization or Culprit-Lesion-Only Percutaneous Coronary Intervention (PCI)

Size of markers represents weight. Squares and diamonds indicate odds ratios (ORs); error bars, 95% CIs. COMPLETE indicates Complete vs Culprit-Only Revascularization to Treat Multivessel Disease After Early PCI for STEMI; DANAMI-3–PRIMULTI, Primary PCI in Patients With ST-Elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization; HELP AMI, Hepacoat for Culprit or Multivessel Stenting for Acute Myocardial Infarction; MH random, random-effects model using the Mantel-Haenszel method; and PRAMI, Preventive Angioplasty in Myocardial Infarction.

Figure 3.  Forest Plot of Long-term Cardiovascular Death or New Myocardial Infarction Stratified by Approach in Patients With Complete Revascularization or Culprit-Lesion-Only Percutaneous Coronary Intervention (PCI)
Forest Plot of Long-term Cardiovascular Death or New Myocardial Infarction Stratified by Approach in Patients With Complete Revascularization or Culprit-Lesion-Only Percutaneous Coronary Intervention (PCI)

Patients were stratified by a fractional flow reserve (FRR)– vs angiography-guided nonculprit-lesion approach. Size of markers represents weight. Squares and diamonds indicate odds ratios (ORs); error bars, 95% CIs. COMPLETE, Complete vs Culprit-Only Revascularization to Treat Multivessel Disease After Early PCI for STEMI; DANAMI-3–PRIMULTI, Primary PCI in Patients With ST-Elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization; HELP AMI, Hepacoat for Culprit or Multivessel Stenting for Acute Myocardial Infarction; MH random, random-effects model using the Mantel-Haenszel method; and PRAMI, Preventive Angioplasty in Myocardial Infarction.

Figure 4.  Forest Plot of Long-term Cardiovascular Death Stratified by Approach in Patients With Complete Revascularization or Culprit-Lesion-Only Percutaneous Coronary Intervention (PCI)
Forest Plot of Long-term Cardiovascular Death Stratified by Approach in Patients With Complete Revascularization or Culprit-Lesion-Only Percutaneous Coronary Intervention (PCI)

Patients were stratified by a fractional flow reserve (FRR)– vs angiography-guided nonculprit-lesion approach. Size of markers represents weight. Squares and diamonds indicate odds ratios (ORs); error bars, 95% CIs. COMPLETE indicates Complete vs Culprit-Only Revascularization to Treat Multivessel Disease After Early PCI for STEMI; CvLPRIT, Complete vs Lesion-Only Primary PCI Trial; DANAMI-3–PRIMULTI, Primary PCI in Patients With ST-Elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization; HELP AMI, Hepacoat for Culprit or Multivessel Stenting for Acute Myocardial Infarction; MH random, random-effects model using the Mantel-Haenszel method; and PRAMI, Preventive Angioplasty in Myocardial Infarction.

Table.  Summary of 10 RCTs Comparing Complete Revascularization With Culprit-Lesion-Only PCI
Summary of 10 RCTs Comparing Complete Revascularization With Culprit-Lesion-Only PCI
1.
Ibanez  B, James  S, Agewall  S,  et al; ESC Scientific Document Group.  2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).   Eur Heart J. 2018;39(2):119-177. doi:10.1093/eurheartj/ehx393 PubMedGoogle ScholarCrossref
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Levine  GN, Bates  ER, Blankenship  JC,  et al.  2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.   Circulation. 2016;133(11):1135-1147. doi:10.1161/CIR.0000000000000336 PubMedGoogle ScholarCrossref
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Bainey  KR, Welsh  RC, Toklu  B, Bangalore  S.  Complete vs culprit-only percutaneous coronary intervention in STEMI with multivessel disease: a meta-analysis and trial sequential analysis of randomized trials.   Can J Cardiol. 2016;32(12):1542-1551. doi:10.1016/j.cjca.2016.02.077 PubMedGoogle ScholarCrossref
4.
Mehta  SR, Wood  DA, Storey  RF,  et al; COMPLETE Trial Steering Committee and Investigators.  Complete revascularization with multivessel PCI for myocardial infarction.   N Engl J Med. 2019;381(15):1411-1421. doi:10.1056/NEJMoa1907775 PubMedGoogle ScholarCrossref
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Higgins  JPT, Green  S, eds. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011. https://training.cochrane.org/handbook
6.
Thiele  H, Akin  I, Sandri  M,  et al; CULPRIT-SHOCK Investigators.  PCI strategies in patients with acute myocardial infarction and cardiogenic shock.   N Engl J Med. 2017;377(25):2419-2432. doi:10.1056/NEJMoa1710261 PubMedGoogle ScholarCrossref
7.
Di Mario  C, Mara  S, Flavio  A,  et al.  Single vs multivessel treatment during primary angioplasty: results of the multicentre randomised Hepacoat for Culprit or Multivessel Stenting for Acute Myocardial Infarction (HELP AMI) study.   Int J Cardiovasc Intervent. 2004;6(3-4):128-133. doi:10.1080/14628840310030441 PubMedGoogle ScholarCrossref
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Politi  L, Sgura  F, Rossi  R,  et al.  A randomised trial of target-vessel versus multi-vessel revascularisation in ST-elevation myocardial infarction: major adverse cardiac events during long-term follow-up.   Heart. 2010;96(9):662-667. doi:10.1136/hrt.2009.177162 PubMedGoogle ScholarCrossref
9.
Ghani  A, Dambrink  JHE, van ’t Hof  AWJ, Ottervanger  JP, Gosselink  ATM, Hoorntje  JCA.  Treatment of non-culprit lesions detected during primary PCI: long-term follow-up of a randomised clinical trial.   Neth Heart J. 2012;20(9):347-353. doi:10.1007/s12471-012-0281-y PubMedGoogle ScholarCrossref
10.
Wald  DS, Morris  JK, Wald  NJ,  et al; PRAMI Investigators.  Randomized trial of Preventive Angioplasty in Myocardial Infarction.   N Engl J Med. 2013;369(12):1115-1123. doi:10.1056/NEJMoa1305520 PubMedGoogle ScholarCrossref
11.
Hlinomaz  O, Groch  L, Polokova  K,  et al; PRAGUE 13 Investigators. Multivessel coronary disease diagnosed at the time of primary PCI for STEMI: complete revascularization versus conservative strategy. PRAGUE 13 trial. In: EuroPCR 2015. Accessed April 17, 2020. https://media.pcronline.com/diapos/EuroPCR2015/2173-20150519_1445_Main_Arena_Hlinomaz_Ota_1111_(6859)/Hlinomaz_Ota_20150519_1445_Main_Arena.pdf
12.
Engstrøm  T, Kelbæk  H, Helqvist  S,  et al; DANAMI-3—PRIMULTI Investigators.  Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3—PRIMULTI): an open-label, randomised controlled trial.   Lancet. 2015;386(9994):665-671. doi:10.1016/S0140-6736(15)60648-1 PubMedGoogle ScholarCrossref
13.
Gershlick  AH, Khan  JN, Kelly  DJ,  et al.  Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial.   J Am Coll Cardiol. 2015;65(10):963-972. doi:10.1016/j.jacc.2014.12.038 PubMedGoogle ScholarCrossref
14.
Hamza  M, Mahmoud  N, Elgendy  IY.  A randomized trial of complete versus culprit-only revascularization during primary percutaneous coronary intervention in diabetic patients with acute ST elevation myocardial infarction and multi vessel disease.   J Interv Cardiol. 2016;29(3):241-247. doi:10.1111/joic.12293 PubMedGoogle ScholarCrossref
15.
Smits  PC, Abdel-Wahab  M, Neumann  F-J,  et al; COMPARE-ACUTE Investigators.  Fractional flow reserve–guided multivessel angioplasty in myocardial infarction.   N Engl J Med. 2017;376(13):1234-1244. doi:10.1056/NEJMoa1701067 PubMedGoogle ScholarCrossref
16.
Pavasini  R, Biscaglia  S, Barbato  E,  et al.  Complete revascularization reduces cardiovascular death in patients with ST-segment elevation myocardial infarction and multivessel disease: systematic review and meta-analysis of randomized clinical trials.   Eur Heart J. 2019;(December):ehz896. doi:10.1093/eurheartj/ehz896 PubMedGoogle Scholar
17.
Pinilla-Echeverri  N, Mehta  SR, Wang  J,  et al. Non-culprit lesion plaque morphology in patients with ST-segment elevation myocardial infarction: results from the COMPLETE Trial Optical Coherence Tomography (OCT) Substudy. Scientific Sessions. Posted November 19, 2019. Accessed April 17, 2020. https://www.crtonline.org/presentation-detail/non-culprit-lesion-plaque-morphology-in-patients-w
18.
De Bruyne  B, Pijls  NH, Bartunek  J,  et al.  Fractional flow reserve in patients with prior myocardial infarction.   Circulation. 2001;104(2):157-162. doi:10.1161/01.CIR.104.2.157 PubMedGoogle ScholarCrossref
19.
Samady  H, Lepper  W, Powers  ER,  et al.  Fractional flow reserve of infarct-related arteries identifies reversible defects on noninvasive myocardial perfusion imaging early after myocardial infarction.   J Am Coll Cardiol. 2006;47(11):2187-2193. doi:10.1016/j.jacc.2006.01.065 PubMedGoogle ScholarCrossref
20.
van der Hoeven  NW, Janssens  GN, de Waard  GA,  et al.  Temporal changes in coronary hyperemic and resting hemodynamic indices in nonculprit vessels of patients with ST-segment elevation myocardial infarction.   JAMA Cardiol. 2019;4(8):736-744. doi:10.1001/jamacardio.2019.2138 PubMedGoogle ScholarCrossref
21.
Thim  T, Götberg  M, Fröbert  O,  et al.  Nonculprit stenosis evaluation using instantaneous wave-free ratio in patients with ST-segment elevation myocardial infarction.   JACC Cardiovasc Interv. 2017;10(24):2528-2535. doi:10.1016/j.jcin.2017.07.021 PubMedGoogle ScholarCrossref
22.
Zimmermann  FM, Omerovic  E, Fournier  S,  et al.  Fractional flow reserve-guided percutaneous coronary intervention vs medical therapy for patients with stable coronary lesions: meta-analysis of individual patient data.   Eur Heart J. 2019;40(2):180-186. doi:10.1093/eurheartj/ehy812 PubMedGoogle ScholarCrossref
23.
Wood  DA, Cairns JA, Wang J,  et al.  Timing of staged non-culprit revascularization in ST-segment elevation myocardial infarction: insights from the COMPLETE trial.   J Am Coll Cardiol. 2019;74(22):2713-2723.Google Scholar
24.
Thiele  H, Akin  I, Sandri  M,  et al; CULPRIT-SHOCK Investigators.  One-year outcomes after PCI strategies in cardiogenic shock.   N Engl J Med. 2018;379(18):1699-1710. doi:10.1056/NEJMoa1808788 PubMedGoogle ScholarCrossref
Original Investigation
May 20, 2020

Complete vs Culprit-Lesion-Only Revascularization for ST-Segment Elevation Myocardial Infarction: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
  • 2The Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 3Department of Cardiology, Maasstad Ziekenhuis, Rotterdam, the Netherlands
  • 4Department of Cardiovascular Sciences, University of Leicester and NIHR (National Institute of Heath Research) Leicester Cardiovascular Biomedical Research Unit, University Hospitals of Leicester NHS (National Health Service) Trust, Glenfield Hospital, Leicester, United Kingdom
  • 5Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  • 6Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
  • 7Centre for Cardiovascular Innovation, University of British Columbia, Vancouver, British Columbia, Canada
  • 8Zena and Michael A. Weiner Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York
  • 9Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
  • 10Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
JAMA Cardiol. 2020;5(8):881-888. doi:10.1001/jamacardio.2020.1251
Key Points

Question  Compared with a culprit-lesion-only percutaneous coronary intervention strategy, is a strategy of complete revascularization with multivessel percutaneous coronary intervention associated with decreased cardiovascular mortality in ST-segment elevation myocardial infarction, and what is the association when fractional flow reserve– and angiography-guided complete revascularization approaches are used?

Findings  In this systematic review and meta-analysis of 10 randomized clinical trials of 7030 unique patients, a 31% relative risk reduction in cardiovascular death (no significant reduction in all-cause mortality) was associated with a complete revascularization strategy. Consistent associations were found when a fractional flow reserve– or angiography-guided complete revascularization approach was used.

Meaning  These results potentially extend the benefit of a complete revascularization strategy to include a reduction in cardiovascular mortality with a consistent benefit of a fractional flow reserve– or angiography-guided percutaneous coronary intervention approach on hard clinical events.

Abstract

Importance  Recently, the Complete vs Culprit-Only Revascularization to Treat Multivessel Disease After Early PCI (percutaneous coronary intervention) for STEMI (ST-segment elevation myocardial infarction [MI]) (COMPLETE) trial showed that angiography-guided PCI of the nonculprit lesion with the goal of complete revascularization reduced cardiovascular (CV) death or new MI compared with PCI of the culprit lesion only in STEMI. Whether complete revascularization also reduces CV mortality is uncertain. Moreover, whether the association of complete revascularization with hard clinical outcomes is consistent when fractional flow reserve (FFR)– and angiography-guided strategies are used is unknown.

Objective  To determine through a systematic review and meta-analysis (1) whether complete revascularization is associated with decreased CV mortality and (2) whether heterogeneity in the association occurs when FFR- and angiography-guided PCI strategies for nonculprit lesions are performed.

Data Sources  A systematic search of MEDLINE, Embase, ISI Web of Science, and CENTRAL (Cochrane Central Register of Controlled Trials) from database inception to September 30, 2019, was performed. Conference proceedings were also reviewed from January 1, 2002, to September 30, 2019.

Study Selection  English-language randomized clinical trials comparing complete revascularization vs culprit-lesion-only PCI in patients with STEMI and multivessel disease were included.

Data Extraction and Synthesis  The combined odds ratio (OR) was calculated with the random-effects model using the Mantel-Haenszel method (sensitivity with fixed-effects model). Heterogeneity was measured using the I2 statistic. Publication bias was evaluated using the inverted funnel plot approach. Data were analyzed from October 2019 to January 2020.

Main Outcomes and Measures  Cardiovascular death and the composite of CV death or new MI.

Results  Ten randomized clinical trials involving 7030 unique patients were included. The weighted mean follow-up time was 29.5 months. Complete revascularization was associated with reduced CV death compared with culprit-lesion-only PCI (80 of 3191 [2.5%] vs 106 of 3406 [3.1%]; OR, 0.69 [95% CI, 0.48-0.99]; P = .05; fixed-effects model OR, 0.74 [95% CI, 0.55-0.99]; P = .04). All-cause mortality occurred in 153 of 3426 patients (4.5%) in the complete revascularization group vs 177 of 3604 (4.9%) in the culprit-lesion-only group (OR, 0.84 [95% CI, 0.67-1.05]; P = .13; I2 = 0%). Complete revascularization was associated with a reduced composite of CV death or new MI (192 of 2616 [7.3%] vs 266 of 2586 [10.3%]; OR, 0.69 [95% CI, 0.55-0.87]; P = .001; fixed-effects model OR, 0.69 [95% CI, 0.57-0.84]; P < .001), with no heterogeneity in this outcome when complete revascularization was performed using an FFR-guided strategy (OR, 0.78 [95% CI, 0.43-1.44]) or an angiography-guided strategy (OR, 0.61 [95% CI, 0.38-0.97]; P = .52 for interaction).

Conclusions and Relevance  In patients with STEMI and multivessel disease, complete revascularization was associated with a reduction in CV mortality compared with culprit-lesion-only PCI. There was no differential association with treatment between FFR- and angiography-guided strategies on major CV outcomes.

Introduction

The 2017 European Society of Cardiology guidelines for management of ST-segment elevation myocardial infarction (STEMI) state that routine revascularization of non–infarct-related artery lesions should be considered in patients with multivessel disease before hospital discharge with a class IIA (level of evidence A) recommendation.1 The 2015 American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions focused update on STEMI supports nonculprit-vessel intervention as a class IIB (level of evidence B) recommendation.2 These recommendations were based on the results of recent randomized clinical trials (RCTs) and meta-analyses documenting improved outcomes with complete revascularization with percutaneous coronary intervention (PCI) in STEMI. However, these results have been driven mainly by composite end points that include subsequent ischemia-driven revascularization.3 Recently, the Complete vs Culprit-Only Revascularization to Treat Multivessel Disease After Early PCI for STEMI (COMPLETE) study demonstrated that a strategy of complete revascularization with staged PCI of the nonculprit lesion reduced the composite of cardiovascular (CV) death and new myocardial infarction (MI).4 The COMPLETE trial was not powered to detect reductions in CV death alone, hence it remains uncertain whether complete revascularization reduces this outcome. In addition, it is unclear whether a difference in CV events occurs when a fractional flow reserve (FFR)– or an angiography-guided strategy is used for complete revascularization. Accordingly, we performed a collaborative meta-analysis of RCTs to determine (1) whether complete revascularization is associated with decreased CV mortality and (2) the consistency of the association when FFR- and angiography-guided nonculprit-lesion PCI strategies are performed.

Methods

The present systematic review and meta-analysis was performed in accordance with the Cochrane Handbook for Systematic Reviews and Interventions.5 Analysis is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement in health care interventions.

Search Strategy

We searched PubMed/MEDLINE, Ovid/Embase, ISI Web of Science, and CENTRAL (Cochrane Central Register of Controlled Trials) from database inception through the final search date of September 30, 2019, for studies published in English. Conference presentations and abstracts from the American Heart Association, American College of Cardiology, Transcatheter Therapeutics, European Society of Cardiology, and EuroPCR were hand-searched from January 1, 2002, to September 30, 2019. Reference lists of included studies, relevant articles, and related systematic reviews were assessed. The search strategy used the following keywords: “ST elevation myocardial infarction,” “myocardial infarction,” “complete revascularization,” “multivessel revascularization,” and “nonculprit coronary artery” (eTable in the Supplement).

Study Selection

Two reviewers (K.R.B., S.R.M.) independently screened for RCTs comparing complete vs culprit-lesion-only PCI in patients with STEMI and multivessel disease. Only RCTs comparing multivessel vs culprit-lesion-only PCI in patients with STEMI and multivessel disease undergoing primary PCI were included. Studies enrolling patients with a diagnosis other than STEMI or comparing revascularization strategies other than PCI were excluded. Full-text citations and abstracts (ie, unpublished) were selected and independently screened for eligibility. Unpublished citations were intentionally included to mitigate publication bias. A PRISMA flow diagram can be found in eFigure 1 in the Supplement.

Data Abstraction

Information regarding the study design, intervention performed, number of patients enrolled, inclusion and exclusion criteria, clinical outcomes, and follow-up duration was obtained. The quality of abstracted studies was assessed using the Cochrane Collaboration’s tool for assessing risk of bias for randomized studies. Only results calculated using the intention-to-treat principle were included.

Outcomes

Information regarding CV death and a composite of CV death or new MI were collected. The composite outcome was stratified according to FFR- or angiography-guided PCI.

Statistical Analysis

Data were analyzed from October 2019 to January 2020. All statistical analysis was performed using Review Manager, version 5 (Cochrane Center). Odds ratios (ORs) with 95% CIs were used as summary estimates. The pooled OR was calculated with the random-effects model using the Mantel-Haenszel method. Heterogeneity was measured using the I2 statistic ([I2 − Q − df]/Q], where Q is the χ2 statistic and df is degrees of freedom). A value for I2 of 0 to 30% represents low heterogeneity; greater than 30% to 60%, moderate heterogeneity; and greater than 60% to 90%, severe heterogeneity (ie, should be explored). Values greater than 90% to 100% must be evaluated with extreme caution. The potential for publication bias was evaluated using the inverted funnel plot approach. Two-sided P < .05 indicated significance and was calculated using a z test of the null hypothesis that there is no average effect in the random-effects model of complete revascularization versus culprit-lesion-only PCI.

Sensitivity Analysis

A pooled OR with 95% CI was calculated for the outcomes using a fixed-effects model with the Mantel-Haenszel method. A pooled OR with 95% CI was calculated for CV mortality with the addition of the CULPRIT-SHOCK (Culprit Lesion Only PCI Vs Multivessel PCI in Cardiogenic Shock) trial.6

Results
Search and Selection of Studies

In total, 125 abstracts were identified, and 31 were selected for full-text or abstract (unpublished) review. Of these 31 eligible studies, 21 were excluded for the following reasons: therapies were not randomly allocated (n = 14), a control group was not identified (n = 3), patients without STEMI were included (n = 3), or coronary artery bypass grafting surgery was performed (n = 1). Ten RCTs fulfilled the eligibility criteria and were included in the present systematic review.4,7-15 The inverted funnel plots for the primary outcome of CV mortality alone and CV mortality or new MI did not suggest publication bias (eFigures 2 and 3 in the Supplement).

Included Studies

Ten RCTs of complete vs culprit-lesion-only PCI involving 7030 patients (3426 undergoing complete revascularization and 3604 undergoing culprit-lesion-only PCI) were included.4,7-15 The weighted mean follow-up time was 29.5 months. The Table presents the characteristics of the included studies. Three studies performed complete revascularization with FFR-guided nonculprit-lesion PCI,9,12,15 whereas the 7 remaining studies used an angiography-guided approach for nonculprit-lesion PCI.4,7,8,10,11,13,14 Complete revascularization with multivessel PCI was performed exclusively during the same sitting in 2 studies7,10 and largely during the same sitting in a further 2 studies.13,15 In 1 study,8 nonculprit-lesion PCI was performed during the same sitting or as a staged procedure. In the 4 remaining studies,4,9,11,12 complete revascularization was performed only as a staged procedure.

Clinical Outcomes
Cardiovascular Death

A total of 80 CV deaths (2.5%) occurred in 3191 patients undergoing complete revascularization compared with 106 (3.1%) in 3406 patients undergoing culprit-lesion-only PCI, a 31% relative risk reduction, among the 7 trials reporting this outcome4,7,8,10,12,13,15 (OR, 0.69 [95% CI, 0.48-0.99]; P = .05; I2 = 9%) (Figure 1). Similar results were observed using a fixed-effects model (OR, 0.74 [95% CI, 0.55-0.99]; P = .04; I2 = 9%).

Among the 10 studies reporting all-cause death,4,7-15 153 deaths (4.5%) among 3426 patients occurred with complete revascularization vs 177 deaths (4.9%) among 3604 patients with culprit-lesion-only PCI (OR, 0.84 [95% CI, 0.67-1.05]; P = .13; I2 = 0%) (eFigure 4 in the Supplement). Similar results were observed using a fixed-effects model (OR, 0.84 [95% CI, 0.67-1.05]; P = .13; I2 = 0%).

CV Death or New MI

Four studies4,7,10,12 reported CV death or new MI (Figure 2). Among these studies, 192 events (7.3%) occurred in the 2616 patients undergoing complete revascularization compared with 266 events (10.3%) in 2586 patients undergoing the culprit-lesion-only strategy (OR, 0.69 [95% CI, 0.55-0.87]; P = .001; I2 = 6%). Similar results were noted using a fixed-effects model (OR, 0.69 [95% CI, 0.57-0.84]; P < .001; I2 = 6%).

New MI

Ten studies4,7-15 reported new MI (eFigure 5 in the Supplement). A total of 175 new MIs (5.1%) occurred in the 3426 patients undergoing complete revascularization compared with 247 (6.9%) in 3604 patients undergoing culprit-lesion-only PCI (OR, 0.68 [95% CI, 0.49-0.96]; P = .03; I2 = 26%). This result was consistent when a fixed-effects model was used (OR, 0.70 [95% CI, 0.57-0.85]; P < .001; I2 = 26%).

FFR- vs Angiography-Guided Nonculprit-Lesion PCI

For CV death or new MI, a consistent benefit with complete revascularization was found compared with culprit-lesion-only PCI when an FFR-guided nonculprit-lesion PCI strategy was used (OR, 0.78 [95% CI, 0.43-1.44]; P = .43) and when an angiography-guided nonculprit-lesion PCI strategy was used (OR, 0.61 [95% CI, 0.38-0.97]; P = .04; I2 = 34%), with no evidence of heterogeneity between these subgroups (P = .52 for interaction) (Figure 3). Similarly, no differential association of treatment was found between an FFR-guided (OR, 0.69 [95% CI, 0.29-1.64]; P = .40; I2 = 0%) or an angiography-guided (OR, 0.57 [95% CI, 0.32-1.03]; P = .06; I2 = 34%) complete revascularization strategy compared with a culprit-lesion-only strategy on CV death alone (P = .73 for interaction) (Figure 4). In addition, there was no differential association with treatment between FFR-guided multivessel PCI (OR, 1.03 [95% CI, 0.32-3.29]; P = .95; I2 = 70%) or angiography-guided multivessel PCI (OR, 0.65 [95% CI, 0.52-0.82]; P < .001; I2 = 0%) on MI alone (P = .44 for interaction) (eFigure 6 in the Supplement).

Single-Sitting vs Staged Approach to Complete Revascularization

In an analysis stratified by timing of nonculprit-lesion PCI, complete revascularization compared with culprit-lesion-only PCI was associated with reduced CV death or new MI in patients undergoing same-sitting multivessel PCI (OR, 0.41 [95% CI, 0.20-0.81]; P = .01; I2 = 0%) as well those treated with a staged approach (OR, 0.73 [95% CI, 0.60-0.89]; P = .002; I2 = 0%), with no difference in the association of treatment (P = .11 for interaction) (eFigure 7 in the Supplement). Similar findings were observed with the individual end points of CV death alone for same-sitting PCI (OR, 0.49 [95% CI, 0.26-0.94]; P = .03; I2 = 0%) and staged-approach PCI (OR, 0.88 [95% CI, 0.62-1.24]; P = .46; I2 = 0%; P = .12 for interaction) (eFigure 8 in the Supplement) and MI alone for same-sitting PCI (OR, 0.46 [95% CI, 0.27-0.77]; P = .003; I2 = 0%) and staged PCI (OR, 0.93 [95% CI, 0.55-1.58]; P = .80; I2 = 50%; P = .06 for interaction) (eFigure 9 in the Supplement).

As a sensitivity analysis, we added the results of CV mortality (sudden cardiac death, death due to cardiogenic shock, or death due to recurrent MI) from the CULPRIT-SHOCK trial.6 We found a directionally consistent result for CV mortality (OR, 0.80 [95% CI, 0.58-1.09]; P = .15; I2 = 25%) (eFigure 10 in the Supplement).

Discussion

In the largest meta-analysis performed to date, a strategy of complete revascularization with nonculprit-lesion PCI was associated with a reduction in CV mortality compared with a strategy of culprit-lesion-only PCI in patients with STEMI and multivessel disease without cardiogenic shock at presentation. Furthermore, we have shown a reduction in the composite outcome of CV death or new MI with complete revascularization irrespective of whether it is performed with an FFR- or an angiography-guided nonculprit-lesion PCI strategy.

None of the individual RCTs comparing complete revascularization with a culprit-lesion-only strategy were adequately powered to detect reductions in CV mortality. In the largest meta-analysis, to our knowledge, involving more than 7000 patients from these trials, we observed a 31% relative risk reduction in CV mortality with complete revascularization. Although this outcome was nominally significant, a fixed-effects analysis demonstrated a similar outcome. Moreover, our findings have been confirmed in a recent meta-analysis of 6 randomized studies16 (6528 patients) showing a 38% reduction in CV death. This reduction in CV mortality is consistent with a robust reduction in new MI observed with complete revascularization. Results from the Optical Coherence Tomography (OCT) COMPLETE substudy have demonstrated that approximately one-half of obstructive nonculprit lesions contain unstable plaque morphology.17 Hence, routine nonculprit-lesion PCI as a preventive strategy could reduce subsequent MI and potentially improve CV long-term survival.

A novel finding of our meta-analysis is the consistent benefit of an FFR- and angiography-guided, nonculprit-lesion complete revascularization approach. Although FFR might underestimate in some cases the severity of nonculprit lesions in the acute and subacute phases,18,19 the outcomes of the FFR-guided trials were consistent with those of the angiography-guided studies, even after deferring PCI of nonculprit lesions in 31% to 44% of the patients.12,15 Still, a recent study has speculated regarding the accuracy of hyperemic and resting indices of nonculprit STEMI lesions,20 and the optimal timing of performing these measurements is unclear.21 Moreover, unlike an angiography-guided approach, the individual FFR-guided PCI trials have not shown a reduction in CV death or MI. However, a recent patient-level pooled analysis of FAME II (Fractional Flow Reserve-Guided Percutaneous Coronary Intervention Plus Optimal Medical Treatment Vs Optimal Medical Treatment Alone in Patients With Stable Coronary Artery Disease), DANAMI-PRIMULTI (Primary PCI in Patients With ST-Elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization), and COMPARE-ACUTE (Fractional Flow Reserve Guided Primary Multivessel Percutaneous Coronary Intervention to Improve Guideline Indexed Actual Standard of Care for Treatment of ST-Elevation Myocardial Infarction in Patients With Multivessel Coronary Disease) did show a reduction in CV death or MI (mainly driven by a decreased risk of MI) with FFR-guided PCI.22 Hence, we believe there is equipoise as to the optimal strategy for complete revascularization in STEMI with multivessel disease that needs to be addressed in a large RCT.

We demonstrated consistent benefits of complete revascularization regardless of whether the nonculprit-lesion PCI procedure was performed during the same sitting or as a staged procedure. In the COMPLETE trial, recurrent events were reduced mainly during the long term with complete revascularization, with little difference in the first 45 days after the index STEMI.4 No heterogeneity in the association with treatment was detected in those patients with staged complete revascularization early during the index hospitalization or electively as an outpatient (≤45 days).23 This finding suggests that early events after STEMI are mainly owing to the size and severity of the index STEMI itself rather than nonculprit lesions. Analogous to revascularization outcomes with coronary artery bypass grafting surgery, the benefits of complete revascularization with PCI appear to accrue long term. Hence, our data provide reassurance to clinicians who are contemplating the timing of complete revascularization with PCI.

In the context of our meta-analysis, the findings of the CULPRIT-SHOCK trial deserve attention. In patients with acute MI (STEMI or non-STEMI) and cardiogenic shock, a significant reduction in the primary composite of all-cause death or severe renal failure requiring renal replacement therapy was observed with a culprit-lesion-only strategy compared with compete revascularization during the index event, with an 8.2% absolute reduction in mortality at 30 days (recognizing staged revascularization was encouraged in the culprit-lesion-only strategy because 21.5% underwent staged or urgent repeated revascularization).6 At 1 year, no significant difference in all-cause mortality was observed.24 Although provocative, the issue with cardiogenic shock is that early mortality is high and the ability to perform complete revascularization is low (<50% in CULPRIT-SHOCK), which does not allow for proper evaluation of complete revascularization. As well, not all patients in the trial presented with STEMI (approximately 40% had non-STEMI). The studies included in our meta-analysis largely excluded cardiogenic shock.

Before the COMPLETE trial, guideline recommendations were limited to small-sample-size RCTs with lower power to detect differences in CV death or new MI. In addition, most trials included revascularization in the primary composite outcome, which is subject to criticism in an open-label trial. We now believe reasonable conclusions can be made with the results of our meta-analysis on hard clinical end points, including the potential for reduction in CV death alone. Moreover, these results appear consistent with FFR- and angiography-guided complete revascularization.

Limitations

Publication bias supporting multivessel PCI in STEMI is a potential limitation, although we included unpublished abstracts to minimize such bias. Furthermore, we performed an inverted funnel plot for CV death alone and CV death or new MI and found no publication bias (eFigures 2 and 3 in the Supplement). Individual patient data were not available for all included studies, precluding subgroup and other exploratory analyses. Admission and follow-up medications were not summarized. Follow-up left ventricular systolic function was not captured. We were not able to evaluate chronic total occlusions because most of the selected studies did not report this finding in STEMI. Limited randomized studies were available for FFR-guided multivessel PCI compared with angiographic-guided multivessel PCI, making it difficult to draw any firm conclusions on which of these approaches to complete revascularization is optimal. Finally, although we did find a significant reduction in CV mortality, the largest trial, COMPLETE, did not show a significant reduction in CV mortality alone but was not powered for this outcome (hence the reason for performing this meta-analysis). Still, we acknowledge the contribution of smaller RCTs with large CV mortality differences, which could conceivably influence our results.

Conclusions

Among patients with STEMI and multivessel disease, our meta-analysis involving 7030 patients found complete revascularization was associated with reduction in CV death compared with a culprit-lesion-only PCI in patients without cardiogenic shock at presentation. Moreover, consistency in the results was found for hard clinical outcomes when an FFR- or angiography-guided nonculprit-lesion PCI approach was used.

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Article Information

Accepted for Publication: March 12, 2020.

Corresponding Author: Shamir R. Mehta, MD, MSc, Population Health Research Institute, Hamilton Health Sciences, McMaster University, 237 Barton St E, Hamilton, ON L8L 2X2, Canada (smehta@mcmaster.ca).

Published Online: May 20, 2020. doi:10.1001/jamacardio.2020.1251

Author Contributions: Dr Mehta was the senior author for the study. Drs Bainey and Mehta had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Bainey, Engstrøm, Gershlick, James, Storey, Wood, Mehran, Cairns, Mehta.

Acquisition, analysis, or interpretation of data: Bainey, Engstrøm, Smits, Gershlick, James, Storey, Wood, Mehran, Mehta.

Drafting of the manuscript: Bainey, Mehta.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Bainey.

Obtained funding: Engstrøm, Cairns, Mehta.

Administrative, technical, or material support: Cairns, Mehta.

Supervision: James, Storey, Wood, Mehran, Cairns, Mehta.

Conflict of Interest Disclosures: Dr Bainey reported receiving grants and personal fees from AstraZeneca, Bayer AS, Boehringer Ingelheim, and Bristol-Myers Squibb/Pfizer, Inc, during the conduct of the study. Dr Engstrøm reported receiving personal fees from Bayer AS, Novo Nordisk A/S, Bristol-Myers Squibb, and Abbott Laboratories. Dr Smits reported receiving speaker and consultancy fees from Terumo Corporation and Abbott Vascular. Dr Gershlick reported receiving lecture fees and travel support from Abbott Vascular and grants from St. Jude Medical during the conduct of the study and grants and personal fees from Terumo Corporation and personal fees from AstraZeneca outside the submitted work. Dr James reported receiving grants from AstraZeneca, Janssen Pharmaceutica, Bayer AS, PhaseBio Pharmaceuticals, Inc, The Medicines Company, Medtronic plc, Boston Scientific, and Abbott Laboratories outside the submitted work. Dr Storey reported receiving grants and personal fees from PlaqueTec, AstraZeneca, GlyCardial Diagnostics, and Thromboserin Ltd and personal fees from Amgen, Inc, Bayer AS, Novartis International AG, Idorsia Ltd, Thromboserin Ltd, Haemonetics Corporation, GlyCardial Diagnostics, Bristol-Myers Squibb/Pfizer, Inc, Portola Pharmaceuticals, and Medscape outside the submitted work. Dr Wood reported receiving grants from the Canadian Institute of Health Research during the conduct of the study and consulting for Edwards Lifesciences and Medtronic plc and receiving research funding from Edwards Lifesciences, Boston Scientific, and Abbott Vascular outside the submitted work. Dr Mehran reported receiving grants and personal fees from Abbott Laboratories; grants from AstraZeneca, Bayer AS, Beth Israel Deaconess, CSL Behring, DSI, Medtronic plc, Novartis Pharmaceuticals, and OrbusNeich; grants from Bristol-Myers Squibb; personal fees from Boston Scientific, Janssen Scientific Affairs, Medscape/WebMD, Medtelligence (Janssen Scientific Affairs), Roivant Services, Sanofi SA, Siemens Medical Solutions USA, Inc, ACC, and the American Medical Association; nonfinancial support from Idorsia Pharmaceuticals Ltd and Regeneron Pharmaceuticals, Inc; from Abiomed, The Medicines Company, Spectranetics Corporation/Philips Healthcare/Volcano Corporation, Watermark Research Partners, Claret Medical, and Elixir Medical Corporation outside the submitted work; and having a spouse consulting for The Medicines Company and Abiomed. Dr Cairns reported receiving grants from Boston Scientific, AstraZeneca, and the Canadian Institute of Health Research during the conduct of the study and personal fees from Abbott Laboratories, Bayer, and Bristol-Myers Squibb/Pfizer, Inc, outside the submitted work. Dr Mehta reported receiving grants from AstraZeneca and Boston Scientific during the conduct of the study and grants from Sanofi SA outside the submitted work. No other disclosures were reported.

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