- Email: [email protected]
Complete versus culprit-only revascularization in patients with multi-vessel disease undergoing primary percutaneous coronary intervention: A meta-analysis of randomized trials
International Journal of Cardiology 186 (2015) 98–103
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Complete versus culprit-only revascularization in patients with multi-vessel disease undergoing primary percutaneous coronary intervention: A meta-analysis of randomized trials☆ Islam Y. Elgendy a, Tianyao Huo a, Ahmed Mahmoud a, Anthony A. Bavry a,b,⁎ a b
Department of Medicine, University of Florida, 1600 SW Archer Road, P.O. Box 100277, Gainesville, FL, 32610, USA North Florida/South Georgia Veterans Health Systems, 1601 SW Archer Road, Gainesville, FL 32608, USA
a r t i c l e
i n f o
Article history: Received 2 November 2014 Received in revised form 12 February 2015 Accepted 15 March 2015 Available online 17 March 2015 Keywords: Multivessel coronary artery disease Myocardial infarction Primary percutaneous coronary intervention Revascularization
a b s t r a c t Background: The best approach for revascularization of multi-vessel coronary disease in patients with STelevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) is controversial. Methods: We searched the Medline and Web of Science databases, the Cochrane Register of Controlled Trials, and major conference proceedings for clinical trials that randomized STEMI patients with multi-vessel disease to a complete versus culprit-only revascularization strategy. Random effects summary risk ratios (RR) were constructed using a DerSimonian–Laird model. Results: A total of 6 trials met our selection criteria, which yielded 1,190 patients. The mean follow-up duration was 20.5 months. The incidence of major adverse cardiac events was significantly reduced in the complete revascularization group versus the culprit-only revascularization group (RR 0.57, 95% confidence interval (CI) 0.41– 0.78, p b 0.001). This was due to a lower risk of urgent revascularization with complete revascularization (RR 0.55, 95% CI 0.35–0.86, p = 0.01). A non-significant reduction was observed with complete versus culprit-only revascularization for the combined outcome of mortality or myocardial infarction (RR 0.56, 95% CI 0.30–1.04, p = 0.06). Conclusion: Complete revascularization of significant coronary lesions at the time of primary PCI in patients with STEMI and multi-vessel disease was associated with better outcomes. This was primarily due to a reduction in the need for urgent revascularization. Larger trials are needed to determine if complete revascularization reduces death or myocardial infarction. Published by Elsevier Ireland Ltd.
1. Introduction Primary percutaneous coronary intervention (PCI) is considered the management of choice for patients with ST-elevation myocardial infarction (STEMI) [1,2]. At the time of primary PCI, 40–65% of the patients exhibit one or more concomitant coronary lesions (i.e., multi-vessel disease). Patients with multi-vessel disease at the time of primary PCI tend to have worse long-term outcomes compared to those with less extensive coronary disease [3,4]. The American College of Cardiology and European Society of Cardiology guidelines endorse revascularization of the culprit or infarct-related ☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Medical Service, Cardiology Section (111D), North Florida/ South Georgia Veterans Health System (Malcom Randall Veterans Administration Medical Center), 1601 SW Archer Road, Gainesville, FL 32608, USA. E-mail addresses: [email protected]fl.edu (I.Y. Elgendy), thuo@ufl.edu (T. Huo), [email protected]fl.edu (A. Mahmoud), [email protected] (A.A. Bavry).
http://dx.doi.org/10.1016/j.ijcard.2015.03.163 0167-5273/Published by Elsevier Ireland Ltd.
artery in the setting of primary PCI unless complicated by cardiogenic shock [5,6]. These recommendations were based on observational and non-randomized studies [7–10]. Several recent randomized trials demonstrated that complete revascularization for hemodynamically significant lesions at the time of primary PCI was associated with better long-term outcomes [11,12]. Given that the best approach for management of these patients remains controversial, we sought to perform a comprehensive metaanalysis to evaluate outcomes for patients with multi-vessel disease who underwent complete versus culprit-only revascularization at the time of primary PCI. 2. Materials and methods 2.1. Data sources We performed a computerized literature search of the Medline database without language restriction from inception until September 2014 using the search strategy shown in Fig. 1. We also searched both the
I.Y. Elgendy et al. / International Journal of Cardiology 186 (2015) 98–103
99
Fig. 1. Study selection flow diagram. Summary of how the systematic search was conducted and eligible studies were identified.
Web of Science database and the Cochrane Register of Controlled Trials using the keywords “percutaneous coronary intervention”, “myocardial infarction”, and “multi-vessel” which did not identify any additional studies beyond Medline. Additionally, we searched for abstracts of the major scientific sessions until September 2014 using the same keywords. To ensure that no potentially important studies were missed, the reference lists from the retrieved articles and prior meta-analyses were also checked. 2.2. Selection criteria We selected studies that reported clinical outcomes for patients with STEMI who were found to have multi-vessel disease at the time of primary PCI. We included studies which randomized patients to either a complete revascularization versus a culprit-only revascularization strategy. 2.3. Data extraction Two authors (IYE and AM) independently extracted data on study design, sample characteristics, sample size, intervention strategies, outcome measures, and other study characteristics from the included randomized trials. Any discrepancies were resolved by consensus of the authors. For all clinical outcomes, we tabulated the number of events that occurred in each arm of each trial.
2.5. Statistical analysis We analyzed outcomes by the intention-to-treat analysis. We constructed random effects summary risk ratios (RRs) using a DerSimonian–Laird model, as well as fixed effects summary RRs using a Mantel–Haenszel model [13,14]. Statistical heterogeneity for each outcome of interest was assessed using the I2 statistic. I2 statistic values b25%, 25% to 50%, N 50% were considered as low, moderate, and high degrees of heterogeneity, respectively [15]. We assessed the risk for publication bias using Egger's method [16]. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for conducting this meta-analysis [17]. Furthermore, we assessed the quality of the trials based on the adequate description of treatment allocation, blinded outcome assessment, and description of losses to follow-up [18]. All p-values were 2-tailed, with statistical significance set at 0.05, and confidence intervals (CIs) were calculated at the 95% level for the overall estimates effect. All analyses were performed using STATA software version 11 (STATA Corporation; College Station, Texas). For continuous variables, we calculated the mean and standard deviation using two-sided two sample t-test; if the study provided median and interquartile range we estimated the mean and standard deviation assuming that the data were normally distributed.
3. Results 2.4. Outcomes and definitions 3.1. Included studies The efficacy outcomes that were tested were major adverse cardiac events (MACE), all-cause mortality, non-fatal myocardial infarction (MI), revascularization, along with the combined outcome of mortality or MI. If the individual studies did not report the combined outcome of mortality or MI, we tabulated it from the individual outcomes.
Overall, we identified 6 studies with 1,190 patients available for analysis; 628 in the complete revascularization group and 562 in the culpritonly revascularization group [11,12,19–22]. MACE was defined as the composite of all-cause mortality, non-fatal MI, and revascularization in
100
I.Y. Elgendy et al. / International Journal of Cardiology 186 (2015) 98–103
Table 1 Study and procedural characteristics. Characteristic
CvLPRIT [11]
PRAMI [12]
Ghani et al. [19]
Politi et al. [20]
HELP AMI [21]
PRIMA [22]
Year Patients, n Age, years Male, % Diabetes mellitus, % Follow-up duration, months
2014 150/146 NR/NR NR/NR NR/NR 12
2013 234/231 62/62 76/81 15/21 23
2012 79/40 62/61 80/81 6/5 36
2010 65/84 65/67 77/76 14/24 30
2004 52/17 64/65 88/85 12/41 12
2004 48/44 65/67 73/75 31/34 6
Symptom to procedure time, hours Drug-eluting stents, % Glycoprotein IIb/IIIa inhibitors, % Procedure time (mean), min Contrast volume (mean), ml Fluoroscopy dose (mean), gycm Contrast-induced nephropathy, % Bleeding requiring surgery or transfusion, %
b12 NR NR NR NR NR NR NR
NR 63/58 79/78 63/45a 300/200a 90/71a 0.4/1.3b 3.0/2.6
NR 23/17 45/46 NR NR NR NR 6.3/2.4
b12 8/12 NR NR NR NR 3.6/1.5 NR
b12 NR 75/82 69/53 341/242 NR NR NR
b12 NR NR 66/85 316/244 NR NR 0/0
Data are reported as complete revascularization group/culprit-only revascularization group. NR = not reported. a Median was reported. b Contrast induced nephropathy requiring dialysis.
95% CI 0.41–0.78, I2 = 45%, p b 0.001) with no evidence of publication bias with Egger's method (p = 0.56) (Fig. 2). The incidence of the mortality or MI was 7% in the complete revascularization group versus 11% in the culprit-only revascularization group (RR 0.56, 95% CI 0.30–1.04, I2 = 38%, p = 0.06) (Fig. 3). The incidence of all-cause mortality was 4.0% in the complete revascularization group versus 6.2% in the culprit-only revascularization group (RR 0.68, 95% CI 0.40–1.14, I2 = 0%, p = 0.14). The incidence of non-fatal MI was 4.6% in the complete revascularization group versus 6.4% in the culprit-only revascularization group (RR 0.56, 95% CI 0.24–1.27, I2 = 38%, p = 0.17). The incidence of revascularization was 12.1% in the complete revascularization group versus 20.8% in the culprit-only revascularization group (RR 0.55, 95% CI 0.35–0.86, I2 = 60%, p = 0.01) (Fig. 4). In Table 3, we summarize the random and fixed effects models for the outcomes. Only one study reported the incidence of heart failure [11]. The risk of bleeding requiring transfusion or surgery was non-significantly higher in the complete revascularization group 3.3% versus 2.2% in the culprit -only revascularization group (RR 1.36, 95% CI 0.52–3.54, I2 = 0%, p = 0.53).
3 studies [19,21,22]. One study added heart failure to this definition [11] while another study added re-hospitalization for acute coronary syndrome [20]. The remaining study defined MACE as the composite of cardiac mortality, non-fatal MI, and refractory angina [12]. Only 2 studies reported the composite of death and MI [12,19]. Revascularization was defined as urgent in one study [22] and as ischemia-driven in two studies [11,20], while the remainder of the studies did not specifically define it. Most of the studies defined multi-vessel disease as an infarct-related artery plus N 70% angiographic stenosis in one or more non-infarct related arteries, except for two studies which used a 50% stenosis cut-off [11, 19]. One study used fractional flow reserve (FFR) to guide revascularization of the non-infarct related arteries [19]. Patients with cardiogenic shock at the time of presentation were explicitly excluded, except for one study which did not specify [19]. Two studies reported the incidence of contrast induced nephropathy [12,20], while the remainder did not assess for renal injury [11,19,21,22]. The mean follow-up duration was 20.5 months. Complete revascularization occurred at the time of the index procedure, except for one study in which staged PCI was performed in 27% of subjects within 1.5 days [11]. Data about the procedure time and contrast volume was not provided in 3 studies [11,19,20]. The mean procedure time and contrast volume was higher in the complete revascularization group (64 +/− 26 versus 51 +/− 20 min, p b 0.0001 and 309 +/− 124 versus 209 +/− 77 ml, p b 0.0001, respectively). Table 1 presents the characteristics of the included studies along with the procedural characteristics. Measures of study quality are shown in Table 2.
4. Discussion In our meta-analysis of 6 randomized trials with 1,190 patients, complete revascularization of significant concomitant coronary lesions was associated with improved long-term outcomes versus culpritonly revascularization at the time of primary PCI. We documented that complete revascularization was associated with a 43% reduction in the risk of MACE at a mean follow-up of 20.5 months. This was driven primarily by a reduction in the risk of urgent or ischemia-driven revascularization. All-cause mortality and non-fatal MI were each numerically lower in the complete revascularization group, however; the combined outcome of mortality or non-fatal MI was non-significantly reduced with complete revascularization (p = 0.06).
3.2. Outcomes The incidence of MACE was 15.9% in the complete revascularization group versus 28.1% in the culprit-only revascularization group (RR 0.57,
Table 2 Assessment of study components. Component
CvLPRIT [11]
PRAMI [12]
Ghani et al. [19]
Politi et al. [20]
HELP AMI [21]
PRIMA [22]
Single/multicenter Primary outcome Blinded outcome assessment Generation of treatment assignment Follow-up completion,%
Multicenter MACE Open label NR 100/100
Multicenter MACE Open labela Computer generated 95.7/96.5
Single center Ejection fraction Open label Computer generated 98.8/97.6
Single center MACE Open label Random number 100/100
Multicenter Revascularization Open label NR 100/100
Single center Ejection fraction Open label NR 100/100
Data are reported as complete revascularization group/culprit-only revascularization group. MACE = major adverse cardiac events. NR = not reported. a Clinical event committee blinded to treatment allocation.
I.Y. Elgendy et al. / International Journal of Cardiology 186 (2015) 98–103
101
Fig. 2. Summary plot for major adverse cardiac events. The relative size of the data markers indicates the weight of the sample size from each study. CI = confidence interval; MACE = major adverse cardiac events; RR = risk ratio.
Fig. 3. Summary plot for the combined outcome of mortality or myocardial infarction. The relative size of the data markers indicates the weight of the sample size from each study. CI = confidence interval; MI = myocardial infarction; RR = risk ratio.
102
I.Y. Elgendy et al. / International Journal of Cardiology 186 (2015) 98–103
Fig. 4. Summary plot for all-cause mortality, non-fatal myocardial infarction, and revascularization. The relative size of the data markers indicates the weight of the sample size from each study. CI = confidence interval; RR = risk ratio.
In all studies included in our analysis, there was a trend towards better outcomes with a complete revascularization approach except for one study in which future revascularization was similar between treatment arms [19]. In that study, patients were randomized in a 2:1 pattern to either a complete revascularization strategy guided by FFR versus a Table 3 Random and fixed effect models comparing outcomes for complete revascularization versus culprit-only revascularization. p-Value I2%
Outcome
Incidence: Model complete, %/culprit-only, %
RR
95% CI
MACE
15.9/28.1
0.57 0.54 0.56 0.64 0.68 0.70 0.56 0.67 0.55 0.51
0.41–0.78 b0.001 0.43–0.67 b0.001 0.30–1.04 0.06 0.43–0.94 0.03 0.40–1.14 0.14 0.42–1.16 0.17 0.24–1.27 0.14 0.40–1.11 0.12 0.35–0.86 0.01 0.39–0.68 b0.001
Combined mortality and MI Mortality
7.0/11.0
MI
4.9/6.9
Revascularization
4.0/6.2
12.1/20.8
CI = confidence interval. MACE = major adverse cardiac events. MI = myocardial infarction. RR = relative risk.
Random Fixed Random Fixed Random Fixed Random Fixed Random Fixed
45 45 38 38 0 0 38 38 60 60
culprit-only revascularization strategy. In the complete revascularization group, they performed revascularization for non-culprit lesions only if FFR was b0.75 [19]. It is possible that the performance of FFR during STEMI resulted in false negative findings which later resulted in need for urgent revascularization [23]. A complete revascularization approach appeared to be associated with longer procedure time, a larger amount of contrast dye, and higher radiation exposure. The risk of bleeding requiring transfusion or surgery was similar between treatment strategies. The ongoing Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Primary PCI for STEMI (COMPLETE) is designed to be adequately powered for death or MI in both groups. In addition, it will address the risk of major bleeding with both strategies and answer whether an FFRguided approach for complete revascularization should be performed [24]. Prior published meta-analyses showed uncertain results regarding which is the best approach for management for patients with STEMI and multi-vessel disease; however, these meta-analyses mainly analyzed observational studies (which can be prone to bias) and the number of randomized trials were limited [25–27]. In our analysis, we only included randomized trials. There are several limitations of the current analysis. The patient and provider's knowledge about unrevascularized coronary lesions could have driven some of the future revascularization procedures among patients randomized to a culprit-only strategy. This same phenomenon
I.Y. Elgendy et al. / International Journal of Cardiology 186 (2015) 98–103
has been speculated within the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) II trial [28]. However, the counter argument is that complete revascularization with implantation of additional stents could also result in an increased risk of restenosis and repeat revascularization procedures [29,30]. It is reassuring that death or myocardial infarction was non-significantly reduced with a complete revascularization strategy. Second, the duration of follow-up ranged from 6 to 36 months, there was variation in the design of the studies (e.g., some allowed staged PCI and FFR-guided revascularization), and there was variation in the definition of MACE and multivessel disease (i.e., the stenosis cut-off in the non-infarct artery was 70% in most of the studies and 50% in 2 studies). This could have contributed to the modest heterogeneity observed with most of the outcomes. Third, we had limited data on short-term outcomes, such as acute kidney injury. Fourth, 3 of the included studies did not describe generation of treatment assignment, which could have resulted in allocation bias. Fifth, 2 studies did not report the symptom to the procedure time. Finally, this meta-analysis was underpowered for hard outcomes such as mortality or non-fatal MI. 5. Conclusion Complete revascularization of significant coronary lesions at the time of primary PCI in patients with STEMI and multi-vessel disease was associated with better outcomes. This was driven primarily by a reduction in the need for urgent revascularization. Larger trials are needed to determine if complete revascularization reduces death or non-fatal myocardial infarction. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] E.C. Keeley, J.A. Boura, C.L. Grines, Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials, Lancet 361 (2003) 13–20. [2] T. Huynh, S. Perron, J. O'Loughlin, et al., Comparison of primary percutaneous coronary intervention and fibrinolytic therapy in ST-segment-elevation myocardial infarction: Bayesian hierarchical meta-analyses of randomized controlled trials and observational studies, Circulation 119 (2009) 3101–3109. [3] P. Sorajja, B.J. Gersh, D.A. Cox, et al., Impact of multivessel disease on reperfusion success and clinical outcomes in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction, Eur. Heart J. 28 (2007) 1709–1716. [4] M. Toma, C.E. Buller, C.M. Westerhout, et al., Non-culprit coronary artery percutaneous coronary intervention during acute ST-segment elevation myocardial infarction: insights from the APEX-AMI trial, Eur. Heart J. 31 (2010) 1701–1707. [5] P.T. O'Gara, F.G. Kushner, D.D. Ascheim, et al., 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, J. Am. Coll. Cardiol. 61 (4) (2013) e78–e140. [6] P.G. Steg, S.K. James, D. Atar, et al., ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation, Eur. Heart J. 33 (2012) 2569–2619. [7] E.L. Hannan, Z. Samadashvili, G. Walford, et al., 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. 3 (2010) 22–31.
103
[8] D. Qarawani, M. Nahir, M. Abboud, Y. Hazanov, Y. Hasin, Culprit only versus complete coronary revascularization during primary PCI, Int. J. Cardiol. 123 (2008) 288–292. [9] R. Kornowski, R. Mehran, G. Dangas, et al., Prognostic impact of staged versus “onetime” multivessel percutaneous intervention in acute myocardial infarction: analysis from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial, J. Am. Coll. Cardiol. 58 (2011) 704–711. [10] A.A. Khattab, M. Abdel-Wahab, C. Röther, et al., Multi-vessel stenting during primary percutaneous coronary intervention for acute myocardial infarction: a single-center experience, Clin. Res. Cardiol. 97 (2008) 32–38. [11] A.H. Gershlick, Managing multi-vessel disease detected at P-PCI for STEMI: the Complete versus Lesion-only PRimary PCI Trial (CvLPRIT), Presented at the European Society of Cardiology Scientific Sessions, Barcelona, Spain, 2014 (September 1). [12] D.S. Wald, J.K. Morris, N.J. Wald, et al., Randomized trial of preventive angioplasty in myocardial infarction, N. Engl. J. Med. 369 (2013) 1115–1123. [13] R. DerSimonian, N. Laird, Meta-analysis in clinical trials, Control. Clin. Trials 7 (1986) 177–188. [14] N. Mantel, W. Haenszel, Statistical aspects of the analysis of data from retrospective studies of disease, J. Natl. Cancer Inst. 22 (1959) 719–748. [15] J.P. Higgins, S.G. Thompson, J.J. Deeks, D.G. Altman, Measuring inconsistency in meta-analyses, BMJ 327 (2003) 557–560. [16] M. Egger, G. Davey Smith, M. Schneider, C. Minder, Bias in meta-analysis detected by a simple, graphical test, BMJ 315 (1997) 629–634. [17] D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, PRISMA Group, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, BMJ 339 (2009) b2535. [18] P. Juni, D.G. Altman, M. Egger, Systematic reviews in health care: assessing the quality of controlled clinical trials, BMJ 323 (2001) 42–46. [19] A. Ghani, J.H. Dambrink, A.W. van 't Hof, J.P. Ottervanger, A.T. Gosselink, J.C. Hoorntje, Treatment of non-culprit lesions detected during primary PCI: longterm follow-up of a randomised clinical trial, Neth. Heart J. 20 (2012) 347–353. [20] L. Politi, F. Sgura, R. Rossi, et al., A randomised trial of target-vessel versus multivessel revascularisation in ST-elevation myocardial infarction: major adverse cardiac events during long-term follow-up, Heart 96 (2010) 662–667. [21] C. Di Mario, S. Mara, A. Flavio, 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. 6 (2004) 128–133. [22] A. Ochala, G.A. Smolka, W. Wojakowski, et al., The function of the left ventricle after complete multivessel one-stage percutaneous coronary intervention in patients with acute myocardial infarction, J. Invasive Cardiol. 16 (2004) 699–702. [23] F. Cuculi, G.L. De Maria, P. Meier, et al., Impact of microvascular obstruction on the assessment of coronary flow reserve, index of microcirculatory resistance, and fractional flow reserve after ST-segment elevation myocardial infarction, J. Am. Coll. Cardiol. 64 (2014) 1894–1904. [24] M. Shamir, Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Primary PCI for STEMI, clinicaltrials.gov [Internet], National Library of Medicine (US), Bethesda (MD), 2000 ([cited 2014 Oct 29]. Available from: http://clinicaltrials.gov/show/ NCT01740479 NLM Identifier: NCT01740479). [25] P.J. Vlaar, K.D. Mahmoud, D.R. Holmes Jr., et al., 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. 58 (2011) 692–703. [26] K.R. Bainey, S.R. Mehta, T. Lai, R.C. Welsh, Complete vs culprit-only revascularization for patients with multivessel disease undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: a systematic review and meta-analysis, Am. Heart J. 167 (2014) 1–14. [27] N. Sekercioglu, F.A. Spencer, L. Cruz Lopes, G.H. Guyatt, Culprit vessel only vs immediate complete revascularization in patients with acute ST-segment elevation myocardial infarction: systematic review and meta-analysis, Clin. Cardiol. (2014)http://dx.doi.org/10.1002/clc.22333 (Sep 18. [Epub ahead of print]). [28] J.J. Rade, FFR-guided PCI–FAME may not be so fleeting after all, N. Engl. J. Med. 371 (2014) 1251–1253. [29] M.S. Chen, J.M. John, D.P. Chew, D.S. Lee, S.G. Ellis, D.L. Bhatt, Bare metal stent restenosis is not a benign clinical entity, Am. Heart J. 151 (2006) 1260–1264. [30] A.A. Bavry, D.L. Bhatt, Appropriate use of drug-eluting stents: balancing the reduction in restenosis with the concern of late thrombosis, Lancet 371 (2008) 2134–2143 (Erratum, Lancet. 2008; 372:536.).
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Complete versus culprit-only revascularization in patients with multi-vessel disease undergoing primary percutaneous coronary intervention: A meta-analysis of randomized trials☆ Islam Y. Elgendy a, Tianyao Huo a, Ahmed Mahmoud a, Anthony A. Bavry a,b,⁎ a b
Department of Medicine, University of Florida, 1600 SW Archer Road, P.O. Box 100277, Gainesville, FL, 32610, USA North Florida/South Georgia Veterans Health Systems, 1601 SW Archer Road, Gainesville, FL 32608, USA
a r t i c l e
i n f o
Article history: Received 2 November 2014 Received in revised form 12 February 2015 Accepted 15 March 2015 Available online 17 March 2015 Keywords: Multivessel coronary artery disease Myocardial infarction Primary percutaneous coronary intervention Revascularization
a b s t r a c t Background: The best approach for revascularization of multi-vessel coronary disease in patients with STelevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) is controversial. Methods: We searched the Medline and Web of Science databases, the Cochrane Register of Controlled Trials, and major conference proceedings for clinical trials that randomized STEMI patients with multi-vessel disease to a complete versus culprit-only revascularization strategy. Random effects summary risk ratios (RR) were constructed using a DerSimonian–Laird model. Results: A total of 6 trials met our selection criteria, which yielded 1,190 patients. The mean follow-up duration was 20.5 months. The incidence of major adverse cardiac events was significantly reduced in the complete revascularization group versus the culprit-only revascularization group (RR 0.57, 95% confidence interval (CI) 0.41– 0.78, p b 0.001). This was due to a lower risk of urgent revascularization with complete revascularization (RR 0.55, 95% CI 0.35–0.86, p = 0.01). A non-significant reduction was observed with complete versus culprit-only revascularization for the combined outcome of mortality or myocardial infarction (RR 0.56, 95% CI 0.30–1.04, p = 0.06). Conclusion: Complete revascularization of significant coronary lesions at the time of primary PCI in patients with STEMI and multi-vessel disease was associated with better outcomes. This was primarily due to a reduction in the need for urgent revascularization. Larger trials are needed to determine if complete revascularization reduces death or myocardial infarction. Published by Elsevier Ireland Ltd.
1. Introduction Primary percutaneous coronary intervention (PCI) is considered the management of choice for patients with ST-elevation myocardial infarction (STEMI) [1,2]. At the time of primary PCI, 40–65% of the patients exhibit one or more concomitant coronary lesions (i.e., multi-vessel disease). Patients with multi-vessel disease at the time of primary PCI tend to have worse long-term outcomes compared to those with less extensive coronary disease [3,4]. The American College of Cardiology and European Society of Cardiology guidelines endorse revascularization of the culprit or infarct-related ☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Medical Service, Cardiology Section (111D), North Florida/ South Georgia Veterans Health System (Malcom Randall Veterans Administration Medical Center), 1601 SW Archer Road, Gainesville, FL 32608, USA. E-mail addresses: [email protected]fl.edu (I.Y. Elgendy), thuo@ufl.edu (T. Huo), [email protected]fl.edu (A. Mahmoud), [email protected] (A.A. Bavry).
http://dx.doi.org/10.1016/j.ijcard.2015.03.163 0167-5273/Published by Elsevier Ireland Ltd.
artery in the setting of primary PCI unless complicated by cardiogenic shock [5,6]. These recommendations were based on observational and non-randomized studies [7–10]. Several recent randomized trials demonstrated that complete revascularization for hemodynamically significant lesions at the time of primary PCI was associated with better long-term outcomes [11,12]. Given that the best approach for management of these patients remains controversial, we sought to perform a comprehensive metaanalysis to evaluate outcomes for patients with multi-vessel disease who underwent complete versus culprit-only revascularization at the time of primary PCI. 2. Materials and methods 2.1. Data sources We performed a computerized literature search of the Medline database without language restriction from inception until September 2014 using the search strategy shown in Fig. 1. We also searched both the
I.Y. Elgendy et al. / International Journal of Cardiology 186 (2015) 98–103
99
Fig. 1. Study selection flow diagram. Summary of how the systematic search was conducted and eligible studies were identified.
Web of Science database and the Cochrane Register of Controlled Trials using the keywords “percutaneous coronary intervention”, “myocardial infarction”, and “multi-vessel” which did not identify any additional studies beyond Medline. Additionally, we searched for abstracts of the major scientific sessions until September 2014 using the same keywords. To ensure that no potentially important studies were missed, the reference lists from the retrieved articles and prior meta-analyses were also checked. 2.2. Selection criteria We selected studies that reported clinical outcomes for patients with STEMI who were found to have multi-vessel disease at the time of primary PCI. We included studies which randomized patients to either a complete revascularization versus a culprit-only revascularization strategy. 2.3. Data extraction Two authors (IYE and AM) independently extracted data on study design, sample characteristics, sample size, intervention strategies, outcome measures, and other study characteristics from the included randomized trials. Any discrepancies were resolved by consensus of the authors. For all clinical outcomes, we tabulated the number of events that occurred in each arm of each trial.
2.5. Statistical analysis We analyzed outcomes by the intention-to-treat analysis. We constructed random effects summary risk ratios (RRs) using a DerSimonian–Laird model, as well as fixed effects summary RRs using a Mantel–Haenszel model [13,14]. Statistical heterogeneity for each outcome of interest was assessed using the I2 statistic. I2 statistic values b25%, 25% to 50%, N 50% were considered as low, moderate, and high degrees of heterogeneity, respectively [15]. We assessed the risk for publication bias using Egger's method [16]. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for conducting this meta-analysis [17]. Furthermore, we assessed the quality of the trials based on the adequate description of treatment allocation, blinded outcome assessment, and description of losses to follow-up [18]. All p-values were 2-tailed, with statistical significance set at 0.05, and confidence intervals (CIs) were calculated at the 95% level for the overall estimates effect. All analyses were performed using STATA software version 11 (STATA Corporation; College Station, Texas). For continuous variables, we calculated the mean and standard deviation using two-sided two sample t-test; if the study provided median and interquartile range we estimated the mean and standard deviation assuming that the data were normally distributed.
3. Results 2.4. Outcomes and definitions 3.1. Included studies The efficacy outcomes that were tested were major adverse cardiac events (MACE), all-cause mortality, non-fatal myocardial infarction (MI), revascularization, along with the combined outcome of mortality or MI. If the individual studies did not report the combined outcome of mortality or MI, we tabulated it from the individual outcomes.
Overall, we identified 6 studies with 1,190 patients available for analysis; 628 in the complete revascularization group and 562 in the culpritonly revascularization group [11,12,19–22]. MACE was defined as the composite of all-cause mortality, non-fatal MI, and revascularization in
100
I.Y. Elgendy et al. / International Journal of Cardiology 186 (2015) 98–103
Table 1 Study and procedural characteristics. Characteristic
CvLPRIT [11]
PRAMI [12]
Ghani et al. [19]
Politi et al. [20]
HELP AMI [21]
PRIMA [22]
Year Patients, n Age, years Male, % Diabetes mellitus, % Follow-up duration, months
2014 150/146 NR/NR NR/NR NR/NR 12
2013 234/231 62/62 76/81 15/21 23
2012 79/40 62/61 80/81 6/5 36
2010 65/84 65/67 77/76 14/24 30
2004 52/17 64/65 88/85 12/41 12
2004 48/44 65/67 73/75 31/34 6
Symptom to procedure time, hours Drug-eluting stents, % Glycoprotein IIb/IIIa inhibitors, % Procedure time (mean), min Contrast volume (mean), ml Fluoroscopy dose (mean), gycm Contrast-induced nephropathy, % Bleeding requiring surgery or transfusion, %
b12 NR NR NR NR NR NR NR
NR 63/58 79/78 63/45a 300/200a 90/71a 0.4/1.3b 3.0/2.6
NR 23/17 45/46 NR NR NR NR 6.3/2.4
b12 8/12 NR NR NR NR 3.6/1.5 NR
b12 NR 75/82 69/53 341/242 NR NR NR
b12 NR NR 66/85 316/244 NR NR 0/0
Data are reported as complete revascularization group/culprit-only revascularization group. NR = not reported. a Median was reported. b Contrast induced nephropathy requiring dialysis.
95% CI 0.41–0.78, I2 = 45%, p b 0.001) with no evidence of publication bias with Egger's method (p = 0.56) (Fig. 2). The incidence of the mortality or MI was 7% in the complete revascularization group versus 11% in the culprit-only revascularization group (RR 0.56, 95% CI 0.30–1.04, I2 = 38%, p = 0.06) (Fig. 3). The incidence of all-cause mortality was 4.0% in the complete revascularization group versus 6.2% in the culprit-only revascularization group (RR 0.68, 95% CI 0.40–1.14, I2 = 0%, p = 0.14). The incidence of non-fatal MI was 4.6% in the complete revascularization group versus 6.4% in the culprit-only revascularization group (RR 0.56, 95% CI 0.24–1.27, I2 = 38%, p = 0.17). The incidence of revascularization was 12.1% in the complete revascularization group versus 20.8% in the culprit-only revascularization group (RR 0.55, 95% CI 0.35–0.86, I2 = 60%, p = 0.01) (Fig. 4). In Table 3, we summarize the random and fixed effects models for the outcomes. Only one study reported the incidence of heart failure [11]. The risk of bleeding requiring transfusion or surgery was non-significantly higher in the complete revascularization group 3.3% versus 2.2% in the culprit -only revascularization group (RR 1.36, 95% CI 0.52–3.54, I2 = 0%, p = 0.53).
3 studies [19,21,22]. One study added heart failure to this definition [11] while another study added re-hospitalization for acute coronary syndrome [20]. The remaining study defined MACE as the composite of cardiac mortality, non-fatal MI, and refractory angina [12]. Only 2 studies reported the composite of death and MI [12,19]. Revascularization was defined as urgent in one study [22] and as ischemia-driven in two studies [11,20], while the remainder of the studies did not specifically define it. Most of the studies defined multi-vessel disease as an infarct-related artery plus N 70% angiographic stenosis in one or more non-infarct related arteries, except for two studies which used a 50% stenosis cut-off [11, 19]. One study used fractional flow reserve (FFR) to guide revascularization of the non-infarct related arteries [19]. Patients with cardiogenic shock at the time of presentation were explicitly excluded, except for one study which did not specify [19]. Two studies reported the incidence of contrast induced nephropathy [12,20], while the remainder did not assess for renal injury [11,19,21,22]. The mean follow-up duration was 20.5 months. Complete revascularization occurred at the time of the index procedure, except for one study in which staged PCI was performed in 27% of subjects within 1.5 days [11]. Data about the procedure time and contrast volume was not provided in 3 studies [11,19,20]. The mean procedure time and contrast volume was higher in the complete revascularization group (64 +/− 26 versus 51 +/− 20 min, p b 0.0001 and 309 +/− 124 versus 209 +/− 77 ml, p b 0.0001, respectively). Table 1 presents the characteristics of the included studies along with the procedural characteristics. Measures of study quality are shown in Table 2.
4. Discussion In our meta-analysis of 6 randomized trials with 1,190 patients, complete revascularization of significant concomitant coronary lesions was associated with improved long-term outcomes versus culpritonly revascularization at the time of primary PCI. We documented that complete revascularization was associated with a 43% reduction in the risk of MACE at a mean follow-up of 20.5 months. This was driven primarily by a reduction in the risk of urgent or ischemia-driven revascularization. All-cause mortality and non-fatal MI were each numerically lower in the complete revascularization group, however; the combined outcome of mortality or non-fatal MI was non-significantly reduced with complete revascularization (p = 0.06).
3.2. Outcomes The incidence of MACE was 15.9% in the complete revascularization group versus 28.1% in the culprit-only revascularization group (RR 0.57,
Table 2 Assessment of study components. Component
CvLPRIT [11]
PRAMI [12]
Ghani et al. [19]
Politi et al. [20]
HELP AMI [21]
PRIMA [22]
Single/multicenter Primary outcome Blinded outcome assessment Generation of treatment assignment Follow-up completion,%
Multicenter MACE Open label NR 100/100
Multicenter MACE Open labela Computer generated 95.7/96.5
Single center Ejection fraction Open label Computer generated 98.8/97.6
Single center MACE Open label Random number 100/100
Multicenter Revascularization Open label NR 100/100
Single center Ejection fraction Open label NR 100/100
Data are reported as complete revascularization group/culprit-only revascularization group. MACE = major adverse cardiac events. NR = not reported. a Clinical event committee blinded to treatment allocation.
I.Y. Elgendy et al. / International Journal of Cardiology 186 (2015) 98–103
101
Fig. 2. Summary plot for major adverse cardiac events. The relative size of the data markers indicates the weight of the sample size from each study. CI = confidence interval; MACE = major adverse cardiac events; RR = risk ratio.
Fig. 3. Summary plot for the combined outcome of mortality or myocardial infarction. The relative size of the data markers indicates the weight of the sample size from each study. CI = confidence interval; MI = myocardial infarction; RR = risk ratio.
102
I.Y. Elgendy et al. / International Journal of Cardiology 186 (2015) 98–103
Fig. 4. Summary plot for all-cause mortality, non-fatal myocardial infarction, and revascularization. The relative size of the data markers indicates the weight of the sample size from each study. CI = confidence interval; RR = risk ratio.
In all studies included in our analysis, there was a trend towards better outcomes with a complete revascularization approach except for one study in which future revascularization was similar between treatment arms [19]. In that study, patients were randomized in a 2:1 pattern to either a complete revascularization strategy guided by FFR versus a Table 3 Random and fixed effect models comparing outcomes for complete revascularization versus culprit-only revascularization. p-Value I2%
Outcome
Incidence: Model complete, %/culprit-only, %
RR
95% CI
MACE
15.9/28.1
0.57 0.54 0.56 0.64 0.68 0.70 0.56 0.67 0.55 0.51
0.41–0.78 b0.001 0.43–0.67 b0.001 0.30–1.04 0.06 0.43–0.94 0.03 0.40–1.14 0.14 0.42–1.16 0.17 0.24–1.27 0.14 0.40–1.11 0.12 0.35–0.86 0.01 0.39–0.68 b0.001
Combined mortality and MI Mortality
7.0/11.0
MI
4.9/6.9
Revascularization
4.0/6.2
12.1/20.8
CI = confidence interval. MACE = major adverse cardiac events. MI = myocardial infarction. RR = relative risk.
Random Fixed Random Fixed Random Fixed Random Fixed Random Fixed
45 45 38 38 0 0 38 38 60 60
culprit-only revascularization strategy. In the complete revascularization group, they performed revascularization for non-culprit lesions only if FFR was b0.75 [19]. It is possible that the performance of FFR during STEMI resulted in false negative findings which later resulted in need for urgent revascularization [23]. A complete revascularization approach appeared to be associated with longer procedure time, a larger amount of contrast dye, and higher radiation exposure. The risk of bleeding requiring transfusion or surgery was similar between treatment strategies. The ongoing Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Primary PCI for STEMI (COMPLETE) is designed to be adequately powered for death or MI in both groups. In addition, it will address the risk of major bleeding with both strategies and answer whether an FFRguided approach for complete revascularization should be performed [24]. Prior published meta-analyses showed uncertain results regarding which is the best approach for management for patients with STEMI and multi-vessel disease; however, these meta-analyses mainly analyzed observational studies (which can be prone to bias) and the number of randomized trials were limited [25–27]. In our analysis, we only included randomized trials. There are several limitations of the current analysis. The patient and provider's knowledge about unrevascularized coronary lesions could have driven some of the future revascularization procedures among patients randomized to a culprit-only strategy. This same phenomenon
I.Y. Elgendy et al. / International Journal of Cardiology 186 (2015) 98–103
has been speculated within the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) II trial [28]. However, the counter argument is that complete revascularization with implantation of additional stents could also result in an increased risk of restenosis and repeat revascularization procedures [29,30]. It is reassuring that death or myocardial infarction was non-significantly reduced with a complete revascularization strategy. Second, the duration of follow-up ranged from 6 to 36 months, there was variation in the design of the studies (e.g., some allowed staged PCI and FFR-guided revascularization), and there was variation in the definition of MACE and multivessel disease (i.e., the stenosis cut-off in the non-infarct artery was 70% in most of the studies and 50% in 2 studies). This could have contributed to the modest heterogeneity observed with most of the outcomes. Third, we had limited data on short-term outcomes, such as acute kidney injury. Fourth, 3 of the included studies did not describe generation of treatment assignment, which could have resulted in allocation bias. Fifth, 2 studies did not report the symptom to the procedure time. Finally, this meta-analysis was underpowered for hard outcomes such as mortality or non-fatal MI. 5. Conclusion Complete revascularization of significant coronary lesions at the time of primary PCI in patients with STEMI and multi-vessel disease was associated with better outcomes. This was driven primarily by a reduction in the need for urgent revascularization. Larger trials are needed to determine if complete revascularization reduces death or non-fatal myocardial infarction. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] E.C. Keeley, J.A. Boura, C.L. Grines, Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials, Lancet 361 (2003) 13–20. [2] T. Huynh, S. Perron, J. O'Loughlin, et al., Comparison of primary percutaneous coronary intervention and fibrinolytic therapy in ST-segment-elevation myocardial infarction: Bayesian hierarchical meta-analyses of randomized controlled trials and observational studies, Circulation 119 (2009) 3101–3109. [3] P. Sorajja, B.J. Gersh, D.A. Cox, et al., Impact of multivessel disease on reperfusion success and clinical outcomes in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction, Eur. Heart J. 28 (2007) 1709–1716. [4] M. Toma, C.E. Buller, C.M. Westerhout, et al., Non-culprit coronary artery percutaneous coronary intervention during acute ST-segment elevation myocardial infarction: insights from the APEX-AMI trial, Eur. Heart J. 31 (2010) 1701–1707. [5] P.T. O'Gara, F.G. Kushner, D.D. Ascheim, et al., 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, J. Am. Coll. Cardiol. 61 (4) (2013) e78–e140. [6] P.G. Steg, S.K. James, D. Atar, et al., ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation, Eur. Heart J. 33 (2012) 2569–2619. [7] E.L. Hannan, Z. Samadashvili, G. Walford, et al., 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. 3 (2010) 22–31.
103
[8] D. Qarawani, M. Nahir, M. Abboud, Y. Hazanov, Y. Hasin, Culprit only versus complete coronary revascularization during primary PCI, Int. J. Cardiol. 123 (2008) 288–292. [9] R. Kornowski, R. Mehran, G. Dangas, et al., Prognostic impact of staged versus “onetime” multivessel percutaneous intervention in acute myocardial infarction: analysis from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial, J. Am. Coll. Cardiol. 58 (2011) 704–711. [10] A.A. Khattab, M. Abdel-Wahab, C. Röther, et al., Multi-vessel stenting during primary percutaneous coronary intervention for acute myocardial infarction: a single-center experience, Clin. Res. Cardiol. 97 (2008) 32–38. [11] A.H. Gershlick, Managing multi-vessel disease detected at P-PCI for STEMI: the Complete versus Lesion-only PRimary PCI Trial (CvLPRIT), Presented at the European Society of Cardiology Scientific Sessions, Barcelona, Spain, 2014 (September 1). [12] D.S. Wald, J.K. Morris, N.J. Wald, et al., Randomized trial of preventive angioplasty in myocardial infarction, N. Engl. J. Med. 369 (2013) 1115–1123. [13] R. DerSimonian, N. Laird, Meta-analysis in clinical trials, Control. Clin. Trials 7 (1986) 177–188. [14] N. Mantel, W. Haenszel, Statistical aspects of the analysis of data from retrospective studies of disease, J. Natl. Cancer Inst. 22 (1959) 719–748. [15] J.P. Higgins, S.G. Thompson, J.J. Deeks, D.G. Altman, Measuring inconsistency in meta-analyses, BMJ 327 (2003) 557–560. [16] M. Egger, G. Davey Smith, M. Schneider, C. Minder, Bias in meta-analysis detected by a simple, graphical test, BMJ 315 (1997) 629–634. [17] D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, PRISMA Group, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, BMJ 339 (2009) b2535. [18] P. Juni, D.G. Altman, M. Egger, Systematic reviews in health care: assessing the quality of controlled clinical trials, BMJ 323 (2001) 42–46. [19] A. Ghani, J.H. Dambrink, A.W. van 't Hof, J.P. Ottervanger, A.T. Gosselink, J.C. Hoorntje, Treatment of non-culprit lesions detected during primary PCI: longterm follow-up of a randomised clinical trial, Neth. Heart J. 20 (2012) 347–353. [20] L. Politi, F. Sgura, R. Rossi, et al., A randomised trial of target-vessel versus multivessel revascularisation in ST-elevation myocardial infarction: major adverse cardiac events during long-term follow-up, Heart 96 (2010) 662–667. [21] C. Di Mario, S. Mara, A. Flavio, 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. 6 (2004) 128–133. [22] A. Ochala, G.A. Smolka, W. Wojakowski, et al., The function of the left ventricle after complete multivessel one-stage percutaneous coronary intervention in patients with acute myocardial infarction, J. Invasive Cardiol. 16 (2004) 699–702. [23] F. Cuculi, G.L. De Maria, P. Meier, et al., Impact of microvascular obstruction on the assessment of coronary flow reserve, index of microcirculatory resistance, and fractional flow reserve after ST-segment elevation myocardial infarction, J. Am. Coll. Cardiol. 64 (2014) 1894–1904. [24] M. Shamir, Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Primary PCI for STEMI, clinicaltrials.gov [Internet], National Library of Medicine (US), Bethesda (MD), 2000 ([cited 2014 Oct 29]. Available from: http://clinicaltrials.gov/show/ NCT01740479 NLM Identifier: NCT01740479). [25] P.J. Vlaar, K.D. Mahmoud, D.R. Holmes Jr., et al., 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. 58 (2011) 692–703. [26] K.R. Bainey, S.R. Mehta, T. Lai, R.C. Welsh, Complete vs culprit-only revascularization for patients with multivessel disease undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: a systematic review and meta-analysis, Am. Heart J. 167 (2014) 1–14. [27] N. Sekercioglu, F.A. Spencer, L. Cruz Lopes, G.H. Guyatt, Culprit vessel only vs immediate complete revascularization in patients with acute ST-segment elevation myocardial infarction: systematic review and meta-analysis, Clin. Cardiol. (2014)http://dx.doi.org/10.1002/clc.22333 (Sep 18. [Epub ahead of print]). [28] J.J. Rade, FFR-guided PCI–FAME may not be so fleeting after all, N. Engl. J. Med. 371 (2014) 1251–1253. [29] M.S. Chen, J.M. John, D.P. Chew, D.S. Lee, S.G. Ellis, D.L. Bhatt, Bare metal stent restenosis is not a benign clinical entity, Am. Heart J. 151 (2006) 1260–1264. [30] A.A. Bavry, D.L. Bhatt, Appropriate use of drug-eluting stents: balancing the reduction in restenosis with the concern of late thrombosis, Lancet 371 (2008) 2134–2143 (Erratum, Lancet. 2008; 372:536.).