Role of Second-Generation Drug-Eluting Stents and Bypass Grafting in Coronary Artery Disease: A Systematic Review and Meta-analysis

Abstract

Background: The safety and efficacy of coronary artery bypass grafting (CABG) and second-generation drug-eluting stents (DESs) in patients with coronary artery disease (CAD) remain controversial. Therefore we aimed to compare the outcomes of CAD patients treated with CABG and second-generation DESs.

Methods: We systematically searched the PubMed, Cochrane Library, Ovid, and Elsevier databases. Studies comparing second-generation DESs with CABG in CAD patients were included. RevMan 5.3 was used to extract and pool the data from the applicable studies.

Results: Six trials (N=6604 participants) were included in this meta-analysis. Among all of the CAD patients, second-generation DESs were associated with no differences in the risks of all-cause death [risk ratio (RR) 1.18, 95% confidence interval (CI) 0.98–1.43, P=0.09], cardiovascular death (RR 1.14, 95% CI 0.81–1.59, P=0.45), myocardial infarction (RR 1.22, 95% CI 0.98–1.54, P=0.08), and stroke (RR 0.83, 95% CI 0.59–1.17, P=0.29), but increased the risks of revascularization (RR 1.95, 95% CI 1.66–2.30, P<0.001) and major adverse cardiac and cerebrovascular events (RR 1.72, 95% CI:1.31–2.26, P<0.001) when compared with CABG.

Conclusions: In the treatment of CAD patients, second-generation DESs was not associated with increased risks of all-cause death, cardiovascular death, myocardial infarction, and stroke, but increased the risks of revascularization and major adverse cardiac and cerebrovascular events when compared with CABG.

Main article text

Introduction

Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are treatment options for patients with coronary artery disease (CAD) [1]. For the past 30 years, CABG was seen as a better choice compared with PCI therapy for CAD by improving the long-term prognosis [2]. PCI has gradually matured and developed to include drug-eluting stents (DESs), and newer PCI further fueled the lowering of restenosis rates [3]. Since 2002, two types of first-generation DESs – sirolimus-eluting stents and paclitaxel-eluting stents – have been used in the treatment of CAD [4]. Previous meta-analyses have compared CABG and first-generation DESs as treatments for CAD [5–9]. These studies have indicated that CABG might be more efficacious than first-generation DESs in reducing the risk of death, myocardial infarction (MI) and revascularization, although CABG is associated with an increased risk of stroke. With the introduction of second-generation DESs, which include zotarolimus-eluting stents (ZESs) and everolimus-eluting stents (EESs), researchers have started to compare the role of second-generation DESs with that of CABG. In 2012, Kim et al. [10] first showed that second-generation DESs are associated with a similar risk of major adverse cardiac and cerebrovascular events (MACCEs; mainly including death, MI, revascularization, and stroke) as for CABG for CAD patients after 2 years of follow-up [10]. Increasing numbers of studies have been designed to compare CABG with second-generation DESs [11–14]. Therefore we aimed to perform a systematic review and meta-analysis to compare the outcomes with regard to second-generation DESs and CABG for patients with CAD.

Methods

Study Selection

The inclusion criteria for eligible trials included the following:

1. Types of studies: randomized controlled trials (RCTs) and nonrandomized controlled trials (NRCTs) comparing the safety and efficacy of CABG and second-generation DESs. Studies with a follow-up time of less than 1 year were excluded.

2. Study participants: patients with CAD (diagnostic coronary angiography showing severe stenosis of 70% or more in major epicardium coronary arteries [11] and/or diagnostic coronary angiography showing unprotected stenosis of more than 50% of the diameter of the left main coronary artery [15]).

3. Outcomes: all-cause death, cardiovascular death, MI, revascularization, stroke and MACCEs.

The following exclusion criteria were applied:

1. Studies including participants who had undergone other cardiac surgery (valve surgery or CABG) because these patients are less likely to undergo repeated CABG than be treated with a second-generation DES.

2. Duplicate studies, basic research studies, and certain publication types (e.g., review, letter, case report, comment).

3. Studies with insufficient data and for which we were unable to obtain sufficient data because the author could not be contacted or did not reply.

Literature Search Strategy

We performed a systematic search using the PubMed, Cochrane Library, Ovid, and Elsevier databases for studies comparing the safety and efficacy of CABG and second-generation DESs in patients with CAD. There were no language restrictions. The search of the databases was done from their inception through December 2016 with the terms “coronary artery bypass graft,” “drug-eluting stents,” “everolimus-eluting stents,” “second-generation drug-eluting stents,” “zotarolimus-eluting stents,” “coronary artery disease,” “unprotected left main coronary artery disease,” and “multivessel disease.” Then we manually searched the conference abstracts, relevant reviews, reference lists, and relevant journals to identify additional studies. We contacted the author via e-mail for studies that did not report outcomes of interest.

Data Extraction and Quality Assessment

Studies were retrieved by our searching electronic and manual databases. Three independent reviewers (L.G., Y.D., and W.Z.) assessed the reports independently for their eligibility on the basis of the title or the abstract. In the case of discrepancies, issues were resolved through discussion or supervised by a fourth investigator (X.J.) if needed. Data extraction was standardized, and all disagreements were resolved by consensus. Pertinent data were extracted according to the prespecified forms: journal, first author, year of publication, country, location of the study group, source of controls, baseline clinical and interventional features. We assessed the quality of NRCT studies following the methodological standards of the Newcastle-Ottawa scale [16] and the quality of RCT studies following the methodological standards of the Cochrane Collaboration [17].

Risk of Bias and Consistency Test

Two independent reviewers (L.G. and Y.D.) assessed the risk of bias to determine the quality of the studies included. The risk of bias was determined according to the risk of publication bias assessment tool developed by the Cochrane Collaboration. Heterogeneity of the studies included was quantified by the I² statistic. According to Higgins’s method, I²≤25% indicated low heterogeneity, I² greater than 25% but not greater than 50% indicated intermediate heterogeneity, and I²>50% indicated high heterogeneity. A fixed-effects model analysis was used when I²≤50%, and if I²>50%, a random-effects model was used. In this regard, the results should be interpreted cautiously. Sensitivity analysis was performed on the primary end points by our changing the effects model and adjusting the inclusion criteria. A funnel plot was used to examine potential publication bias for the outcomes.

Statistical Analysis

The data were extracted from applicable articles and were calculated with RevMan 5.3 from the Cochrane Collaboration (The Nordic Cochrane Center, Rigshospitalet, Denmark, http://ims.cochrane.org/revman). As the pooled I²≤50%, we used the fixed-effects model to assess the occurrence risk of the primary end points. The risk ratio (RR) and corresponding 95% confidence interval (CI) were calculated, and statistical significance was set at P≤0.05.

Results

Search Results and Study Characteristics

As shown in Figure 1, 2815 potentially relevant articles were identified, 2801 of which were excluded after we read the titles and abstracts. Then the full-length texts of 14 potentially relevant publications were assessed for eligibility. Of these, six articles [10, 11, 13–15, 18] fulfilled our eligibility criteria, and 6604 CAD patients treated with second-generation DESs (total number of participants 3295) or treated with CABG (total number of participants 3309) were included in the meta-analysis (Figure 1). No additional studies were found during our manual search of relevant reviews, published studies, and conference abstracts. Among the studies included, two were RCTs and four were NRCTs. Two of the four NRCT studies used propensity score matching to assemble a cohort of patients with similar baseline characteristics for statistical adjustment. Patients in four studies were treated with EESs, in one study patients were treated with ZESs, and in one study the type of second-generation DES was not mentioned. The basic characteristics of each of the studies included are summarized in Table 1. The reporting quality of the studies was globally acceptable; RCT studies were evaluated according to the methodological standards of the Newcastle-Ottawa scale [16] and NRCT studies were evaluated according to the methodological standards of the Cochrane Collaboration [17].

Figure 1

Overview of the Search Strategy.

This is an overview of the number of articles included during each stage of the systematic review process

Table 1

General Characteristics of All Studies Included in the Meta-analysis.

Reference	Mean age, years	Number of participants	Follow-up, years	Period of cohort	Type of study	Origin	Propensity score used	Diabetes, %	No. of diseased vessels	Type of second-generation DES
Bangalore et al. [11] (2015)	65.1	1816	2.9	January 1, 2008 to December 31, 2011	NRCT	New York	Yes	39.2	2–3*	EES
Kim et al. [10] (2012)	62.7	606	2.0	May 2009 to September 2010	NRCT	Korea (multicenter)	No	32.4	ULMCAD	EES
Park et al. [14] (2015)	64.5	880	1.5	July 2008 to September 2013	RCT	Asia (multicenter)	No	41.2	2–3†	EES
Yi et al. [13] (2013)	65.0	1294	1.9	January 2008 to December 2011	NRCT	Korea	Yes	42.1	3	NA
Sim et al. [18] (2013)	66.0	103	1.0	November 2005 to January 2008	NRCT	Korea	No	35.0	ULMCAD	ZES
Stone et al. [19] (2016)	66.0	1816	3.0	September 2010 to March 2014	RCT	USA (multicenter)	No	29.0	ULMCAD	EES

DES, drug-eluting stent; EES, everolimus-eluting stent; NA, not available; NRCT, nonrandomized controlled trial; RCT, randomized controlled trial;

ULMCAD ,unprotected left main coronary artery disease; ZES, zotarolimus-eluting stent.

^*26.1% of patients have two diseased vessels with involvement of the territory of the proximal left anterior descending artery, 29.4% of patients have two diseased vessels without involvement of the territory of the proximal left anterior descending artery, 15.2% of patients have three diseased vessels with involvement of the territory of the proximal left anterior descending artery, and 29.3% of patients have three diseased vessels without involvement of the territory of the proximal left anterior descending artery.

^†77.2% of patients have two diseased vessels, and 22.8% of patients have three diseased vessels.

Meta-analysis

In our current meta-analysis, the RR and its 95% CI in each study are presented in Figure 2. There was no significant heterogeneity among the studies included (all I²<50%). Therefore all of the RRs and 95% CIs were pooled with use of a fixed-effects model in our meta-analysis.

Figure 2

Forest Plot for Comparative Analysis of the Occurrence of All-cause Death, Cardiovascular Death, Myocardial Infarction, Revascularization, and Stroke in Coronary Artery Disease Patients Treated with Second-generation Drug-eluting Stents (DES) or Coronary Artery Bypass Grafting (CABG).

CI, confidence interval; df, degrees of freedom; MACCEs, major adverse cardiac and cerebrovascular events; M-H, Mantel-Haenszel; MI, myocardial infarction.

All-Cause Death

Six studies reported the outcome of all-cause death that occurred in 393 patients [10, 11, 13, 14, 18, 19]. In the pooled results, the risk of all-cause death in the CAD patients treated with second-generation DESs was similar to that of patients treated with CABG (RR 1.18, 95% CI 0.98–1.43, P=0.09, Figure 2).

Cardiovascular Death

Four studies reported cardiovascular death in 3494 CAD patients [10, 14, 18, 19]. The pooled risk for cardiovascular death in the second-generation DES group showed no significant difference from that in the CABG group (RR 1.14, 95% CI 0.81–1.59, P=0.45, Figure 2).

Myocardial Infarction

Six studies reported the outcome of MI in 6604 patients [10, 11, 13, 14, 18, 19]. After we had pooled the data, the risk of MI in the second-generation DES group was not significantly different from that in the CABG group (RR 1.22, 95% CI 0.98–1.54, P=0.08, Figure 2).

Revascularization

Six studies met all the inclusion criteria [10, 11, 13, 14, 18, 19]. Of these, one study [18] showed no significant difference between the second-generation DES group and the CABG group for revascularization. The other five studies [10, 11, 13, 14, 19] had a significant reduction of revascularization risk in the CABG group. As a result, the pooled risk for the incidence of revascularization in the second-generation DES group was 1.95-fold higher than that of the CABG group (RR 1.95, 95% CI 1.66–2.03, P<0.001, Figure 2).

Stroke

Data on the risk of stroke were available from five studies [10, 11, 13, 14, 19]. At the mean follow-up time, the pooled RR values demonstrated that there was no difference in the risk of stoke associated with second-generation DESs and that associated with CABG (RR 0.83, 95% CI 0.59–1.17, P=0.29, Figure 2).

Major Adverse Cardiac and Cerebrovascular Events

Four studies (total number of patients 2603) were evaluated to compare the occurrence of MACCEs between second-generation DESs and CABG for treating CAD patients [10, 13, 14, 18]. There were no significant differences between second-generation DESs and CABG in relation to MACCEs in three of those studies [10, 14, 18]. In the other study, the second-generation DES group showed a higher risk of MACCEs than the CABG group [13]. After pooling the data, we found that the risk of MACCEs in the second-generation DES group was higher than in the CABG group (RR 1.72, 95% CI, 1.31–2.26, P<0.0001, Figure 2).

Publication Bias

We visually inspected the funnel plot for the outcomes of CAD patients treated with second-generation DESs and with CABG, and found that there was no potential publication bias (Figure 3).

Figure 3

Funnel Plot of the Adverse Cardiovascular Outcomes for Second-Generation Drug-Eluting Stent and Coronary Artery Bypass Grafting Treatment in Patients with Coronary Artery Disease.

MACCEs, major adverse cardiac and cerebrovascular events; MI, myocardial infarction; RR, risk ratio; SE, standard error.

Discussion

CAD is a leading cause of major adverse cardiac events, especially in industrialized nations [20]. Therefore the optimal strategy for the treatment of CAD has received considerable attention. Earlier studies suggested that CABG was more efficacious than first-generation DESs in reducing the rates of death, MI, and revascularization, although CABG increased the rate of stroke [5, 21, 22]. With the introduction of second-generation DESs, numerous studies have compared major adverse cardiac events in individuals treated with a first-generation DES or a second-generation DES [23–25]. Because second-generation DESs have thinner struts, more biocompatible polymers, and improved deliverability [26], they are more efficacious than first-generation DESs in CAD patients. Meta-analytic combinations of these cohort studies have shown that second-generation DESs have reduced risk rates of all-cause death, MI, revascularization, and stroke compared with first-generation DESs [6, 27, 28]. Therefore, because of the longer-term safety and efficacy than first-generation DESs, second-generation DESs have been widely used. Since 2012, studies comparing the effectiveness of second-generation DESs and CABG have been conducted. Our study is the first meta-analysis to compare the clinical efficacy and safety of second-generation DESs versus CABG among CAD patients in terms of adverse cardiovascular outcomes. Using data from 6604 CAD patients, our meta-analysis shows that compared with CABG, second-generation DESs were associated with no difference in the rates of all-cause death, cardiovascular death, MI, and stroke, but were associated with increased rates of revascularization and MACCEs.

The major finding of this meta-analysis is that the use of second-generation DESs for CAD patients is as safe and effective as CABG, as shown by the same incidence of all-cause death, cardiovascular death, MI, and stroke. This result disagrees with the results of studies that compared first-generation DESs with CABG [29]. The risk of revascularization and MACCEs was higher after second-generation DES treatment than after CABG treatment in this analysis. These results are driven mainly by the following reasons. First, routine angiography followup after second-generation DES treatment has been shown to increase the risk of revascularization [30], and the data on the risk of revascularization play a large role in assessing the risk of MACCEs for CAD disease in the pooled results. Second, CAD patients with diabetes mellitus treated by CABG had a significantly reduced rate of MACCEs compared with patients treated with DESs [31]. Up to 36.8% of diabetic patients were included in each study of our meta-analysis, and we speculate that these results might be affected largely by diabetes.

The results of the present study demonstrate that the optimal treatment for CAD patients still needs to be identified. As second-generation DESs were associated with no difference in the rates of all-cause death, cardiovascular death, MI, and stroke compared with CABG, and could be applied more easily and expeditiously and have the potential advantage of providing more rapid reperfusion, this method is a good alternative in patients without diabetes and with less complex disease [32]. However, in the treatment of CAD patients with diabetes mellitus or complex disease, CABG is the optimal strategy because CABG could reduce the risks of revascularization and MACCEs [31]. To obtain more definitive knowledge of the safety and efficacy of second-generation DESs and CABG for the treatment of patients with CAD, further study is needed.

Several limitations in this meta-analysis should be carefully addressed. First, our study did not obtain sufficient data to control for the type of antiplatelet drugs and the duration of antiplatelet therapy, which might have a significant impact on the results. Second, the studies included in this meta-analysis included patients with both mild and serious CAD, which might have influenced the different risks of major adverse cardiac events, therefore potential biases might exist in the clinical results. For example, we could not exclude the phenomenon that most of the patients with serious and complex disease were included in CABG groups. Third, it has been reported that diabetes might have an important role in major cardiovascular events [33]. We did not conduct a subgroup analysis of CAD patients with diabetes because of a lack of detailed information. Fourth, because of the limited number of studies and the limited availability of data, we included randomized and nonrandomized studies in this meta-analysis, although there was low heterogeneity between the studies selected.

Conclusions

We found that second-generation DESs have no differential efficacy compared with CABG in regard to all-cause death, cardiovascular death, MI, and stroke. These results suggest that CAD patients with an intermediate or high risk of stroke are best treated with a second-generation DES. By contrast, CABG reduces the risk of revascularization and MACCEs compared with second-generation DESs. As a result, CABG remains the optimal revascularization strategy for CAD patients with complex disease or diabetes.

Acknowledgements

Xinghua Jiang oversaw the entire project and revised the draft. Linjuan Guo, Ying Ding, and Fuwei Liu performed the systematic literature review, constructed the database, and analyzed the data. Linjuan Guo and Wengen Zhu drafted the first version of the manuscript. All authors took part in the interpretation of the results and prepared the final version of the manuscript. This work was supported by the National Natural Science Foundation of China (8153000545).

Conflict of Interest

The authors have no conflicts of interest.

References

1. CostaF, AriottiS, ValgimigliM, KolhP, WindeckerS. Perspectives on the 2014 ESC/EACTS guidelines on myocardial revascularization: fifty years of revascularization: where are we and where are we heading? J Cardiovasc Transl Res 2015;8:21120.

2. HillisLD, SmithPK, AndersonJL, BittlJA, BridgesCR, ByrneJG, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:261042.

3. KandzariDE, KiniAS, KarmpaliotisD, MosesJW, TummalaPE, GranthamJA, et al. Safety and effectiveness of everolimus-eluting stents in chronic total coronary occlusion revascularization: results from the EXPERT CTO multicenter trial (Evaluation of the XIENCE Coronary Stent, Performance, and Technique in Chronic Total Occlusions). JACC Cardiovasc Interv 2015;8:7619.

4. WindeckerS, StorteckyS, StefaniniGG, DaCB, RutjesAW, Di NisioM, et al. Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis. BMJ 2014;348:g3859.

5. AlAJ, FranckC, FilionKB, EisenbergMJ. Coronary artery bypass graft surgery versus percutaneous coronary intervention with first-generation drug-eluting stents: a meta-analysis of randomized controlled trials. JACC Cardiovasc Interv 2014;7:497506.

6. DangasGD, SerruysPW, KereiakesDJ, HermillerJ, RizviA, NewmanW, et al. Meta-analysis of everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease: final 3-year results of the SPIRIT clinical trials program (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with De Novo Native Coronary Artery Lesions). JACC Cardiovasc Interv 2013;6:91422.

7. CapodannoD, CapranzanoP, La MannaA, TamburinoC: Meta-analysis of everolimus-eluting stents versus first-generation drug-eluting stents in patients with left main coronary artery undergoing percutaneous coronary intervention. Int J Cardiol 2013;168:17189.

8. AriyaratneTV, AdemiZ, YapCH, BillahB, RosenfeldtF, YanBP, et al. Prolonged effectiveness of coronary artery bypass surgery versus drug-eluting stents in diabetics with multi-vessel disease: an updated systematic review and meta-analysis. Int J Cardiol 2014;176:34653.

9. AthappanG, PatvardhanE, TuzcuME, EllisS, WhitlowP, KapadiaSR. Left main coronary artery stenosis: a meta-analysis of drug-eluting stents versus coronary artery bypass grafting. JACC Cardiovasc Interv 2013;6:121930.

10. KimYH, ParkDW, AhnJM, YunSC, SongHG, LeeJY, et al. Everolimus-eluting stent implantation for unprotected left main coronary artery stenosis. The PRECOMBAT-2 (Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease) study. JACC Cardiovasc Interv 2012;5:70817.

11. BangaloreS, GuoY, SamadashviliZ, BleckerS, XuJ, HannanEL. Everolimus-eluting stents or bypass surgery for multivessel coronary disease. N Engl J Med 2015;372:121322.

12. CamposCM, van KlaverenD, FarooqV, SimontonCA, KappeteinAP, SabikJR, et al. Long-term forecasting and comparison of mortality in the Evaluation of the Xience Everolimus Eluting Stent vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial: prospective validation of the SYNTAX Score II. Eur Heart J 2015;36:123141.

13. YiG, JooHC, YounYN, HongS, YooKJ. Stent versus off-pump coronary bypass grafting in the second-generation drug-eluting stent era. Ann Thorac Surg 2013;96:53541.

14. ParkSJ, AhnJM, KimYH, ParkDW, YunSC, LeeJY, et al. Trial of everolimus-eluting stents or bypass surgery for coronary disease. N Engl J Med 2015;372:120412.

15. ParkSJ, KimYH, ParkDW, YunSC, AhnJM, SongHG, et al. Randomized trial of stents versus bypass surgery for left main coronary artery disease. N Engl J Med 2011;364:171827.

16. StangA. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:6035.

17. RobertsonC, RamsayC, GurungT, MowattG, PickardR, SharmaP. Practicalities of using a modified version of the Cochrane Collaboration risk of bias tool for randomised and non-randomised study designs applied in a health technology assessment setting. Res Synth Methods 2014;5:20011.

18. SimDS, AhnY, JeongMH, KimYJ, ChaeSC, HongTJ, et al. Clinical outcome of unprotected left main coronary artery disease in patients with acute myocardial infarction. Int Heart J 2013;54:18591.

19. StoneGW, SabikJF, SerruysPW, SimontonCA, GenereuxP, PuskasJ, et al. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med 2016;375:222335.

20. DavierwalaPM, MohrFW. Surgical versus percutaneous revascularization in patients with multivessel coronary artery disease. Curr Atheroscler Rep 2014;16:461.

21. KappeteinAP, FeldmanTE, MackMJ, MoriceMC, HolmesDR, StahleE, et al. Comparison of coronary bypass surgery with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the SYNTAX trial. Eur Heart J 2011;32:212534.

22. SaMP, FerrazPE, EscobarRR, NunesEO, SoaresAM, AraujoESF, et al. Five-year outcomes following PCI with DES versus CABG for unprotected LM coronary lesions: meta-analysis and meta-regression of 2914 patients. Rev Bras Cir Cardiovasc 2013;28:8392.

23. PendyalaL, LohJ, KitabataH, MinhaS, ChenF, TorgusonR, et al. Clinical impact of second-generation everolimus-eluting stents compared with first-generation drug-eluting stents in diabetic patients undergoing multivessel percutaneous coronary intervention. J Invasive Cardiol 2015;27:2638.

24. StoneGW, RizviA, NewmanW, MastaliK, WangJC, CaputoR, et al. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med 2010;362:166374.

25. KedhiE, GomesM, JoesoefKS, WassingJ, GoedhartD, McFaddenE, et al. Everolimus-eluting stents and paclitaxel-eluting stents in patients presenting with myocardial infarction: insights from the two-year results of the COMPARE prospective randomised controlled trial. Eurointervention 2012;7:137685.

26. KolandaiveluK, SwaminathanR, GibsonWJ, KolachalamaVB, Nguyen-EhrenreichKL, GiddingsVL, et al. Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 2011;123:14009.

27. LankaV, PatelVG, SaeedB, KotsiaA, ChristopoulosG, RanganBV, et al. Outcomes with first- versus second-generation drug-eluting stents in coronary chronic total occlusions (CTOs): a systematic review and meta-analysis. J Invasive Cardiol 2014;26:30410.

28. GorlaR, LoffiM, VernaE, MargonatoA, Salerno-UriarteJ. Safety and efficacy of first-generation and second-generation drug-eluting stents in the setting of acute coronary syndromes. J Cardiovasc Med (Hagerstown) 2014;15:53242.

29. SmitY, VlayenJ, KoppenaalH, EeftingF, KappeteinAP, MarianiMA. Percutaneous coronary intervention versus coronary artery bypass grafting: a meta-analysis. J Thorac Cardiovasc Surg 2015;149:8318.

30. YuXP, WuCY, RenXJ, YuanF, SongXT, LuoYW, et al. Very long-term outcomes and predictors of percutaneous coronary intervention with drug-eluting stents versus coronary artery bypass grafting for patients with unprotected left main coronary artery disease. Chin Med J (Engl) 2016;129:76370.

31. QiX, XuM, YangH, ZhouL, MaoY, SongH, et al. Comparing mortality and myocardial infarction between coronary artery bypass grafting and drug-eluting stenting in patients with diabetes mellitus and multivessel coronary artery disease: a meta-analysis. Arch Med Sci 2014;10:4118.

32. MohrFW, MoriceMC, KappeteinAP, FeldmanTE, StahleE, ColomboA, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381:62938.

33. MartinDM, BoyleFJ. Drug-eluting stents for coronary artery disease: a review. Med Eng Phys 2011;33:14863.