- Research article
- Open Access
Fractional flow reserve-guided complete revascularization versus culprit-only revascularization in acute ST-segment elevation myocardial infarction and multi-vessel disease patients: a meta-analysis and systematic review
BMC Cardiovascular Disorders volume 19, Article number: 49 (2019)
Approximately 30–50% patients with acute ST-segment elevation myocardial infarction (STMEI) were found to have non-infarct-related coronary artery (IRA) disease, which was significantly associated with worse prognosis. However, challenges still remain for these patients: which non-infarct-related lesion should be treated and when should the procedure be performed? The present study aims to investigate Fractional flow reserve (FFR)-guided complete revascularization (CR) in comparison to culprit-only revascularization (COR) in patients with ST-segment elevation myocardial infarction (STEMI) and multi-vessel disease (MVD).
Three appropriate randomized controlled trials (RCTs) were selected from the PubMed/Medline, EMBASE, and the Cochrane library /CENTRAL databases. 1631 patients (688 patients underwent FFR-guided CR and 943 patients underwent COR) following-up 12–44 months was evaluated.
FFR-guided CR significantly reduced major adverse cardiac event (MACE) (OR 0.47, 95% CI: 0.35–0.62, P < 0.00001) and ischemia-driven repeat revascularization (OR 0.36, 0.26–0.51, P < 0.00001), as compared to COR. However, there is no difference in all-cause mortality (OR 1.24, 0.65–2.35, P = 0.51).
In patients with STEMI and MVD, FFR-guided CR is better than COR in terms of MACE and ischemia-driven repeat revascularization, while there are almost similar in all-cause mortality.
Approximately 30–50% patients with acute ST-segment elevation myocardial infarction (STMEI) were found to have non-infarct-related coronary artery (IRA) disease, which was significantly associated with worse prognosis [1, 2]. However, challenges still remain for these patients: which non-infarct-related lesion should be treated and when should the procedure be performed? Previously, many STEMI guidelines from AHA/ACC/ESC didn’t recommend to offer complete revascularization for STEMI patients with multi-vessel disease during primary percutaneous coronary intervention (PCI) without hemodynamic instability, which could increase the rate of mortality [3,4,5]. 2015 ACC/AHA guideline declared IIb recommendation for complete revascularization in selected STEMI patients with multi-vessel disease. Recently, for these patients, the updated 2017 ESC STEMI management guideline recommended complete revascularization that non-infarcted related artery lesion should be treated during either index procedure or index admission, following culprit lesion revascularization. This recommendation was based on the data from PRAMI, DANAMI-3-PRIMULTI, CVLPRIT and COMPARE-ACUTE trials, which favored the reductions in the risk of major adverse cardiovascular event (MACE) and repeat revascularization, not in all-cause or cardiovascular mortality rate. It is important to note that most of the time the evaluation of non-culprit lesion by angiography may not be accurate, because of underestimating or overestimating the lesion. Fractional flow reserve (FFR) can functionally evaluate the pathophysiological significance of the non-culprit lesion by using pressure wire in favor of functional angioplasty . Moreover, the data from Fraction Flow Reserve Versus Angiography for Multi-vessel Evaluation (FAME) study at two years, showed FFR-guided PCI in patients with stable coronary artery disease lowered mortality rate and the rate of re-infarction, compared to angiography-guided PCI . Therefore, we aimed to investigate whether FFR-guided functionally complete revascularization with PCI in patients with STEMI and multi-vessel disease could further improve the prognosis, especially the hard end point.
For this meta-analysis, we searched the PubMed/Medline, EMBASE, and the Cochrane library /CENTRAL databases and selected published RCTs which compared FFR-guided CR and COR in STEMI patients with multi-vessel disease up to May 12, 2018. The search terms included “Acute ST-segment elevation Myocardial Infarction”, “STEMI”, “Fractional flow reserve”, “FFR”, “Percutaneous Coronary Intervention”, “PCI”, “complete revascularization”, “culprit-only revascularization”, “Multi-vessel disease”, “culprit lesion” and “non-culprit lesion”. Additionally, presentations and abstracts were also searched from major cardiovascular conferences.
The inclusion criteria were: (1) published Randomized Controlled Trials (RCTs); (2) comparing FFR-guided complete revascularization PCI with culprit only revascularization PCI; (3) a study population of STEMI patients with multi-vessel disease.
The exclusion criteria were: (1) hemodynamic instability, such as cardiogenic shock; (2) previous meta-analysis or overlapping data.
Independently, according to the inclusion and exclusion criteria, three authors (L.J.W, S.H and X.H.Z) assessed RCTs eligibility and bias risk (Additional file 1: Figure S1 and Additional file 2: Figure S2), and extracted data. Their disagreements would be resolved by consensus.
The outcomes involved in the current study were major adverse cardiovascular events (MACE), all-cause mortality, myocardial infarction (MI) and repeated revascularization.
The current meta-analysis followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) study guideline . Heterogeneity among the subgroups was estimated by the Cochrane Q-statistic test and I2-statistic test , whereby a P-value > 0.05 implied no statistically different result and a I2 value <50% suggested a fixed effect model by using funnel plots assessed publication bias. Meta-analysis were carried out with Review Manager (RevMan) version 5.3(Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) software, obtaining Odds Ratios (OR) and 95% Confidence Intervals (CIs). a P value <0.05 indicated a statistically significant result.
Initially, our search retrieved 608 records and 11 records were found. After reviewing, four records without using FFR [10,11,12,13] and three records related to ACS [14,15,16] were eliminated. According to the primary selection criteria, four records were obtained. Due to two of them were from the same study [17, 18], we excluded 1 trial and obtained three RCTs totally [17, 19, 20]. The study selection flow diagram was shown in Fig. 1.
Study characteristics and patient features
The current meta-analysis totally included 1631 patients (688 patients underwent FFR-guided CR and 943 patients underwent COR), with 12–44 months follow-up. General features of each study were represented in Table 1, including the number of patients, the cut-off value of FFR, the intervention time of non-culprit lesion, stent type, study time, follow-up term and medical treatment.
The baseline features of the patients involved in the current meta-analysis were showed in Table 2. The mean age (from 61 to 64 years) of the patients in each study was almost the same. The percentage of male patients in each study was similar, approximately 80%. DANAMI-3- PRIMULTI  and COMPARE-ACUTE  trial had a slightly higher rate of hypertension, Diabetes mellitus, dyslipidemia and Three-vessel disease than Ghani trial . The rate of smoking and Killip class II–IV in each study was nearly the same.
The incidence of all-cause mortality did not reveal statistically significant difference between FFR-guided CR group and COR group (3.3% vs. 2.2%; OR: 1.24, 95% CI: 0.65–2.35; P = 0.51) (Fig. 2). Furthermore, no significant heterogeneity was showed (I2 = 0%) among these trials (Fig. 2).
The incidence of all-cause mortality and MI was 8.5% in FFR-guided CR group versus 6.9% in COR group, which did not show any statistically significant difference between the two groups (OR: 1.06, 95% CI: 0.72–1.56; P = 0.78) (Fig. 3). Among trials moderate significant heterogeneity (I2 = 73%) was found (Fig. 3).
The incidence of non-fatal MI was also not significantly different between FFR-guided CR group and COR group (5.2% vs. 4.6%; OR: 0.96, 95% CI: 0.60–1.56; P = 0.88) (Fig. 4). The heterogeneity (I2 = 70%) among trials was also moderate significant (Fig. 4).
It is a remarkable fact that the incidence of repeat revascularization or major adverse cardiovascular event (MACE, comprising all-cause mortality, myocardial infarction and repeated revascularization here) shows a statistically significant difference between FFR guided CR group and COR group, respectively (repeat revascularization: 9.0% vs. 17.9%; OR 0.36, 95% CI 0.26–0.51; P < 0.00001; I2 = 70%; MACE: 13.2% vs. 21.5%; OR 0.47, 95% CI 0.35–0.62; P < 0.00001; I2 = 68%)(Fig. 5 and 6).
No significant evidence of publication bias was found through the funnel plot.
In this meta-analysis from the comparison between FFR-guided CR and COR in patients with STEMI and multi-vessel disease, we found that FFR-guided CR resulted in low rate of MACE, including all-cause mortality, non-fatal myocardial infarction and repeat revascularization. The reduction of repeat revascularization was similar to that of MACE, which suggested the decreased need for revascularization favored the low incidence of MACE during the follow up period. Moreover, additional FFR-guidance did not significantly increase the rate of all-cause mortality and non-fatal myocardial infarction.
The results of our meta-analysis were in accordance with some previous studies. PRAMI trial  showed that angiography guided complete revascularization in patients with STEMI and multi-vessel disease during the primary PCI, using the criteria of percentage diameter stenosis>50% in one view for non-culprit lesion treatment, significantly decreased the rate of MACE and repeat revascularization without the reduction of the rate of all-cause mortality, as compared to COR. With the treatment criteria of non-culprit lesion changed into percentage diameter stenosis>70% in one view or>50% in two views, CVLPRIT trial  reported that angiography guided complete revascularization (during primary PCI: 73%; during staged PCI: 27%) was merely associated with low rate of MACE and repeat revascularization, compared with COR. Nevertheless, as the same as PRAMI trial, the risk of all-cause mortality was not changed.
In consideration of the Dissociation Between Angiographic results and Clinical outcomes in coronary artery Disease , FFR was gradually considered to be a good measurement for making decision on treating or not treating the coronary artery lesion, based on its high sensitivity and specificity in identification of ischemia . In stead of the FFR threshold value of 0.75 , a FFR value of >0.8 suggested a non-ischemic lesion and good clinical outcome . The results from FAME II trial at 3 years follow-up, demonstrated FFR-guided PCI in patients with stable coronary artery disease to lower mortality rate and the rate of re-infarction, compared to angiography-guided PCI . A meta-analysis showed that FFR-guided PCI in patients with stable coronary artery disease was associated with significantly lower rate of re-infarction when compared to angiography-guided PCI . Beside the patients with stable coronary artery disease, FFR measurement could be used effectively and safely in patients with acute myocardial infarction . The data from a meta-analysis further confirmed the effectiveness and safety of FFR measurement in patients with acute coronary syndrome .
Ghani trial was the first RCTs of FFR measurement in patients with STEMI and multi-vessel disease. However, the result of this trial did not support FFR-guided CR early after primary PCI (described in Table 1) because of the high rate of the mortality and re-infarction . Subsequently, as a relatively large trial, DANAMI-3-PRIMULTI  showed FFR-guided CR with staged PCI strategy (2 days after primary PCI and before discharge) might favor the reduction of MACE not the all-cause mortality. However, the latest large and multi-center trial, COMPARE ACUTE trial  revealed FFR-guided CR (during index PCI procedure: 83%; during index hospitalization: 17%) could not only reduce the rate of MACE, also numerically decrease the incidence of death from any cause without statistically difference.
Our meta-analysis was consistent to another two meta-analyses [28, 29], they confirmed that CR (including angiography-guided and FFR-guided) could merely decrease the incident of MACE and repeat revascularization, not the hard end point (all-cause mortality). Intriguingly, the percentage of all-cause mortality in FFR guided complete revascularization group was 1.3% in the Compare Acute trial and 4.7% in the DANAMI-3–PRIMULTI trial, with 50 and 31% of non–infarct-related lesions with a negative FFR value respectively. Probably, these good results could be derived from the accurate choose of revascularization. Additionally, our data also supported the reliability, feasibility and safety of FFR-guided complete revascularization (PCI) during acute phase of STEMI.
There were some limitations in this meta-analysis, including: Firstly, the study population was small, only three RCTs with 1631 patients; Secondly, the study year difference among trials was too much. One was from 2004 to 2007, and others were from 2011 to 2014/2015. Different era might have different technique, different device (like stent type), different concept and different drug, which could affect the result; Thirdly, The cut-off value of FFR was different. The former one study was 0.75 and the latter two studies were 0.80; Finally, all trials included in this meta-analysis were open-label design, which induced potential bias.
In comparison to COR, among patients with acute STEMI and MVD, FFR-guided functionally CR favored the reduction of the risk of MACE and ischemia-driven repeat revascularization, without a reduction in the rate of all-cause mortality. In the future, further large RCTs are required to investigate whether FFR guidance of complete revascularization significantly affects hard end point (all-cause mortality).
Fractional flow reserve
infarct-related coronary artery
major adverse cardiovascular event
percutaneous coronary intervention
ST-segment elevation myocardial infarction
Shah R, Clare RM, Chiswell K, Jones WS, Kumar AS, Thiele H, Smalling RW, Chandra P, Cohen M, Perera D, Chew DP, French JK, Blaxill J, Ohman EM, Patel MR. Impact of non-infarct-related artery disease on infarct size and outcomes (from the CRISP-AMI trial). Am J Med. 2016;129:1307–15.
Park DW, Clare RM, Schulte PJ, Pieper KS, Shaw LK, Califf RM, Ohman EM, Vande Werf F, Hirji S, Harrington RA, Armstrong PW, Granger CB, Jeong MH, Patel MR. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA. 2014;312(19):2019–27.
Hannan EL, Samadashvili Z, Walford G, Holmes DR, Jacobs AK, Stamato NJ, Venditti FJ, Sharma S, King SB. Culprit vessel percutaneous coronary intervention versus multivessel and staged percutaneous coronary intervention for ST-segment elevation myocardial infarction patients with multivessel disease. J Am Coll Cardiol Intv. 2010;3:22–31.
Toma M, Buller CE, Westerhout CM, Fu Y, O’Neill WW, Holmes Jr DR, Hamm CW, Granger CB, Paul W, Armstrong, for the APEX-AMI Investigators. Non-culprit coronary artery percutaneous coronary intervention during acute ST-segment elevation myocardial infarction: insights from the APEX-AMI trial. Eur Heart J. 2010;31:1701–7.
Vlaar PJ, Mahmoud KD, Holmes DR Jr, van Valkenhoef G, Hillege HL, van der Horst IC, Zijlstra F, de Smet BJ. Culprit vessel only versus multivessel and staged percutaneous coronary intervention for multivessel disease in patients presenting with ST-segment elevation myocardial infarction: a pairwise and network meta-analysis. J Am Coll Cardiol. 2011;58:692–703.
Tebaldi M, Campo G, Biscaglia S. Fractional flow reserve: current applications and overview of the available data. World J Clin Cases. 2015;3:678–81.
Pijls NH, Fearon WF, Tonino PA, Siebert U, Ikeno F, Bornschein B, van‘t Veer M, Klauss V, Manoharan G, Engstrøm T, Oldroyd KG, Ver Lee PN, PA MC, De Bruyne B, FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (fractional flow reserve VersusAngiography for multivessel evaluation) study. J Am Coll Cardiol. 2010;56:177–84.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. BMJ. 2009;339:b2700.
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.
Wald DS, Morris JK, Wald NJ, Chase AJ, Edwards RJ, Hughes LO, Berry C, Oldroyd KG, PRAMI Investigators. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013;369:1115–23.
Gershlick AH, Khan JN, Kelly DJ, Greenwood JP, Sasikaran T, Curzen N, Blackman DJ, Dalby M, Fairbrother KL, Banya W, Wang D, Flather M, Hetherington SL, Kelion AD, Talwar S, Gunning M, Hall R, Swanton H, McCann GP. Randomized trial of complete versus lesion-only revascularization inpatients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol. 2015;65:963–72.
Politi L, Sgura F, Rossi R, Monopoli D, Guerri E, Leuzzi C, Bursi F, Sangiorgi GM, Modena MG. 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;96:662–7.
Di Mario C, Mara S, Flavio A, Imad S, Antonio M, Anna P, Emanuela P, Stefano DS, Angelo R, Stefania C, Anna F, Carmelo C, Antonio C, Monzini N, Bonardi MA. 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 Interv. 2004;6:128–33.
Ntalianis A, Sels JW, Davidavicius G, Tanaka N, Muller O, Trana C, Barbato E, Hamilos M, Mangiacapra F, Heyndrickx GR, Wijns W, Pijls NH, De Bruyne B. Fractional flow Reserve for the Assessment of nonculprit coronary artery Stenoses in patients with acute myocardial infarction. J Am Coll Cardiol Intv. 2010;3:1274–81.
Layland J, Oldroyd KG, Curzen N, Sood A, Balachandran K, Das R, Junejo S, Ahmed N, Lee MM, Shaukat A, O'Donnell A, Nam J, Briggs A, Henderson R, McConnachie A, Berry C, investigators FAMOUS–NSTEMI. Fractional flow reserve vs. angiography in guiding management to optimize outcomes in non-ST-segment elevation myocardial infarction: the British Heart Foundation FAMOUS-NSTEMI randomized trial. Eur Heart J. 2015;36(2):100–11.
Lee JM, Choi KH, Koo BK, Shin ES, Nam CW, Doh JH, Hwang D, Park J, Zhang J, Lim HS, Yoon MH, Tahk SJ. Prognosis of deferred non-culprit lesions according to fractional flow reserve in patients with acute coronary syndrome. EuroIntervention. 2017;13(9):e1112–9.
Ghani A, Dambrink J-HE, 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;20:347–53.
Dambrink JH, Debrauwere JP, van ‘t Hof AW, Ottervanger JP, Gosselink AT, Hoorntje JC, de Boer MJ, Suryapranata H. Non-culprit lesions detected during primary PCI: treat invasively or follow the guidelines? EuroIntervention. 2010;5:968–75.
Engstrøm T, Kelbæk H, Helqvist S, Høfsten DE, Kløvgaard L, Holmvang L, Jørgensen E, Pedersen F, Saunamäki K, Clemmensen P, De Backer O, Ravkilde J, Tilsted HH, Villadsen AB, Aarøe J, Jensen SE, Raungaard B, Køber L, DANAMI-3—PRIMULTI Investigators. Complete revascularisation versus treatment of the culprit lesion only in pa- tients with ST-segment elevation myocar- dial infarction and multivessel disease (DANAMI-3–PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015;386:665–71.
Smits PC, Abdel-Wahab M, Neumann FJ, Boxma-de Klerk BM, Lunde K, Schotborgh CE, Piroth Z, Horak D, Wlodarczak A, Ong PJ, Hambrecht R, Angerås O, Richardt G, Omerovic E, Investigators C-A. Fractional flow reserve– guided multivessel angioplasty in myocardial infarction. N Engl J Med. 2017;376:1234–44.
Kelly DJ, McCann GP, Blackman D, Curzen NP, Dalby M, Greenwood JP, Fairbrother K, Shipley L, Kelion A, Heatherington S, Khan JN, Nazir S, Alahmar A, Flather M, Swanton H, Schofield P, Gunning M, Hall R, Gershlick AH. Complete versus culprit-lesion only PRimary PCI trial (CVLPRIT): a multicentre trial testing management strategies when multivessel disease is detected at the time of primary PCI: rationale and design. EuroIntervention. 2013;8:1190–8.
Topol EJ, Nissen SE. Our preoccupation with coronary Luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation. 1995;92:2333–42.
Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, Bartunek J, Koolen JJ, Koolen JJ. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med. 1996;334:1703–8.
Watkins S, McGeoch R, Lyne J, Steedman T, Good R, McLaughlin MJ, Cunningham T, Bezlyak V, Ford I, Dargie HJ, Oldroyd KG. Validation of magnetic resonance myocardial perfusion imaging with fractional flow reserve for the detection of significant coronary heart disease. Circulation. 2009;120:2207–13.
Fearon WF, Nishi T, De Bruyne B, Boothroyd DB, Barbato E, Tonino P, Jüni P, NHJ P, Hlatky MA, for the FAME 2 trial in-vestigators. Clinical outcomes and cost-effectiveness of fractional flow reserve–guided percutaneous coronary intervention in patients with stable coronary artery disease three-year follow-up of the FAME 2 trial (fractional flow reserve versus angiography for multivessel evaluation). Circulation. 2018;137:480–7.
Bundhun PK, Yanamala CM, Huang F. Comparing the adverse clinical outcomes associated with fraction flow reserve-guided versus angiography-guided percutaneous coronary intervention: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 2016;16:249.
Briasoulis A, Palla M, Mostafa A, Afonso L, Grines C. Fractional flow-guided management in patients with acute coronary syndromes: a systematic review and meta-analysis. Int J Cardiol. 2015;187:334–7.
Wang C-H, Zhang S-Y, Jin X-F. Complete revascularization versus culprit-only revascularization in ST-segment elevation myocardial infarction and multivessel disease patients undergoing primary percutaneous coronary intervention: a meta-analysis and trial sequential analysis. Int J Cardiol. 2017;228:844–52.
Nguyen AV, Le Van Thanh MGK, Abdelrahman SAM, EL-Mekawy M, Mokhtar MA, Ali AA, Hoang NNN, Vuong NL, Abd-Elhay FA-E, Omer OA, Mohamed AA, Hirayama K, Huy NT. Optimal percutaneous coronary intervention in patients with ST-elevation myocardial infarction and multivessel disease: an updated, large-scale systematic review and meta-analysis. Int J Cardiol. 2017;244:67–76.
We appreciate Dr. Ning Wei carefully reviewing this manuscript.
Availability of data and materials
Ethics approval and consent to participate
All analyses were based on previous published studies, thus no ethical approval and patient consent are required.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Wang, Lj., Han, S., Zhang, XH. et al. Fractional flow reserve-guided complete revascularization versus culprit-only revascularization in acute ST-segment elevation myocardial infarction and multi-vessel disease patients: a meta-analysis and systematic review. BMC Cardiovasc Disord 19, 49 (2019). https://doi.org/10.1186/s12872-019-1022-6
- Fractional flow reserve
- Complete revascularization
- Culprit-only revascularization
- ST-segment elevation myocardial infarction
- Multi-vessel disease