Coronary Artery Bypass Graft Surgery Versus Percutaneous Coronary Intervention With First-Generation Drug-Eluting Stents A Meta-Analysis of Randomized Controlled Trials

(1)

Coronary Artery Bypass Graft Surgery Versus

Percutaneous Coronary Intervention With

First-Generation Drug-Eluting Stents

A Meta-Analysis of Randomized Controlled Trials

Juwairia Al Ali, MD,*Caroline Franck, MSC,yKristian B. Filion, PHD,yzx Mark J. Eisenberg, MD, MPHyxk

Montreal, Quebec, Canada

Objectives This study sought to compare the efﬁcacy of coronary artery bypass graft surgery (CABG) to that of

percutaneous coronary intervention (PCI) withﬁrst-generation drug-eluting stents among patients with multivessel disease (MVD), unprotected left main (LM) disease, and single-vessel proximal left anterior descending (LAD) disease.

Background The efﬁcacy and safety of CABG versus PCI with drug-eluting stents in patient subgroups remains

controversial.

Methods We systematically searched Cardiosource, Circulation,Clinicaltrials.gov, the Cochrane Library, EMBASE,

and Medline for articles published through June 2013 for randomized controlled trials comparing CABG with PCI. Primary endpoints included mortality, myocardial infarction, revascularization, and stroke. Data were meta-analyzed with random-effects models.

Results We identiﬁed 7 randomized controlled trials (N ¼ 5,835): 2 of MVD (n ¼ 2,410, 100% diabetic), 2 of LM

disease (n¼ 1,206, 29.0% diabetic), 1 of 3-vessel or LM disease (n ¼ 1,900, 25.5% diabetic), and 2 of single-vessel proximal LAD disease (n¼ 319, 36.3% diabetic). In MVD patients, CABG reduced the risk of mortality (risk ratio [RR]: 0.70, 95% conﬁdence interval [CI]: 0.57 to 0.87), myocardial infarction (RR: 0.47, 95% CI: 0.36 to 0.61), and repeat revascularization (RR: 0.36, 95% CI: 0.24 to 0.52), but increased stroke risk (RR: 1.72, 95% CI: 1.02 to 2.90). In patients with LM disease, CABG reduced revascularization risk (RR: 0.60, 95% CI: 0.46 to 0.78) and increased stroke risk (RR: 2.89, 95% CI: 1.15 to 7.27). Data for patients with single-vessel proximal LAD disease were inconclusive.

Conclusions CABG is more efﬁcacious than is PCI with ﬁrst-generation drug-eluting stents in patients with LM

and MVD, at the cost of increased rates of stroke. No conclusion can be drawn for patients with single-vessel proximal LAD disease. (J Am Coll Cardiol Intv 2014;7:497–506) ª 2014 by the American College of Cardiology Foundation

From the *Division of Cardiology, McGill University Health Center, Montreal, Quebec, Canada;yCenter for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada;zDivision of Clinical Epidemiology, McGill University, Montreal, Quebec, Canada;xDepartment of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada; and the kDivision of Cardiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. Dr. Filion is a Canadian Institutes of Health Research (CIHR) New Investigator. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received November 25, 2013; accepted December 5, 2013.

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 7 , N O . 5 , 2 0 1 4 ª 2 0 1 4 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N I S S N 1 9 3 6 - 8 7 9 8 / $ 3 6 . 0 0 P U B L I S H E D B Y E L S E V I E R I N C . h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j c i n . 2 0 1 3 . 1 2 . 2 0 2

(2)

The efﬁcacy and safety of coronary artery bypass graft surgery (CABG) versus percutaneous coronary intervention (PCI) with ﬁrst-generation drug-eluting stents (DES) remains controversial for the treatment of various patient subgroups.

Although this topic has been researched in many observa-tional studies (1–5), the recommended procedural choice for patients within subgroups of vessel disease remains un-clear due to a lack of data from randomized controlled trials (RCTs). Therefore, our objective was to conduct a meta-analysis of RCTs comparing the efﬁcacy and safety of CABG to that of PCI with ﬁrst-generation DES among patients with multivessel disease (MVD), unprotected left main (LM) dis-ease, and single-vessel proximal left anterior descending artery (LAD) disease.

Methods

Search strategy. We systemati-cally searched the Cochrane Library, EMBASE, and Medline for articles published through June 2013, with the terms “cor-onary angiography” and “coro-nary artery bypass surgery” and “coronary artery bypass graft” and “drug-eluting stents”. The search was restricted to RCTs conducted in humans and pub-lished in English. In addition, we searched Cardiosource, Circula-tion, and Clinicaltrials.gov, and we hand-searched the bibliogra-phies of previous studies, relevant reviews, and previous meta-analyses to identify additional studies not found by our initial search. We conducted and reported our meta-analysis according to guidelines described in the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)(6)statement.

Study selection. We restricted inclusion to RCTs that compared the efﬁcacy and safety of CABG to that of PCI with ﬁrst-generation DES, as well as reported outcomes of mortality, myocardial infarction (MI), revascularization, or stroke. In addition, we only included trials in which the majority of patients who underwent PCI received DES. All studies not published in English were excluded. Data extraction. Data extraction was performed by 2 re-viewers, with disagreements resolved by consensus or by

a third reviewer. Extracted data included study design, enrollment period, duration of follow-up, vessel subtypes (MVD, LM disease, proximal LAD disease), and the num-ber of patients assigned to each group. Baseline participant characteristics included age, sex, body mass index, type 2 diabetes mellitus, systemic hypertension, dyslipidemia, previous MI, mean ejection fraction, and smoking. Extracted outcomes of interest were all-cause mortality, MI, revascu-larization, and stroke. Outcome data were extracted as count data following an intention-to-treat approach at the maximum available follow-up for all trials but FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease), where 5-year results were extracted.

Quality assessment. We used the Cochrane Collaboration tool for assessing risk of bias to determine the quality of included RCTs (7). This tool assesses the risk of selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias. Each RCT is categorized on the basis of criteria determining the likelihood of potential threats to validity. Quality assessment was independently performed by 2 reviewers.

Data analysis. We used DerSimonian-Laird random-effects meta-analysis models with inverse variance weighting to cal-culate relative risks and corresponding 95% conﬁdence in-tervals (CIs). In our primary analyses, we restricted inclusion to trials in which all patients in the PCI group received DES. In sensitivity analyses, we included RCTs in which the ma-jority of patients received DES rather than bare-metal stents. The amount of heterogeneity present was estimated using the I2statistic. To examine potential sources of heterogeneity, we stratiﬁed our analyses by the following 3 types of coronary disease: MVD, LM disease, and proximal LAD disease. We visually inspected funnel plots and used the Egger test to assess publication bias. All analyses were conducted using Stata (version 11.2, Stata Corp., College Station, Texas).

Results

Search results. A total of 6,431 potentially relevant studies were identiﬁed in our initial literature search (Fig. 1). After screening the titles and abstracts of these studies, the full-length texts of 68 potentially relevant publications were retrieved and assessed for eligibility. Of these, 7 studies met our inclusion criteria and were included in our meta-analysis. No additional studies were identiﬁed through our manual search of references of published studies, relevant reviews, and previous meta-analyses.

Study characteristics. The earliest RCT we identiﬁed comparing CABG with PCI withﬁrst-generation DES was published in 2005. Included studies had sample sizes ranging from 130 to 1,900 patients and had follow-up durations ranging from 6 to 60 months (Table 1). Three RCTs(8–10) and a subgroup analysis (11)from the SYNTAX (Synergy See page 507

Abbreviations and Acronyms

CABG= coronary artery bypass graft surgery

CI= conﬁdence interval

DES= drug-eluting stent(s)

EES= everolimus-eluting stent(s)

HR= hazard ratio

LAD= left anterior descending

LM= left main

MI= myocardial infarction

MIDCAB= minimally invasive direct coronary artery bypass graft surgery

MVD= multivessel disease

PES= paclitaxel-eluting stent(s)

PCI= percutaneous coronary intervention RCT= randomized controlled trial(s) RR= risk ratio SES= sirolimus-eluting stent(s) Al Ali et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 7 , N O . 5 , 2 0 1 4

CABG Versus PCI With DES M A Y 2 0 1 4 : 4 9 7 – 5 0 6

(3)

Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial compared CABG with PCI with

DES in patients with MVD (n ¼ 4,210). Of note, the

MVD subgroup of the SYNTAX trial included only patients with 3-vessel disease. Two RCTs(12,13)and another sub-group (14) of patients from SYNTAX examined patients with LM disease (n¼ 801). Two RCTs(15,16) examined patients with single-vessel proximal LAD disease (n¼ 319). All included RCTs had a low risk of bias according to the Cochrane criteria (Online Appendix 1).

Procedure characteristics. Included RCTs varied with respect to the chosen surgical revascularization technique (Table 1). Both trials in patients with LM disease(12,13)

and 1 trial of patients with MVD(8)employed standard CABG, whereas trials of patients with proximal LAD disease (15,16) employed minimally invasive direct coro-nary artery bypass graft surgery (MIDCAB). The 2 remaining trials(9,10)of patients with MVD selected the surgical revascularization technique according to surgeons’ recommendations.

All stents employed in the included trials were ﬁrst-gen-eration DES, including sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES). Bare-metal stents were used in a very small minority of patients with MVD (n¼ 31). Patient characteristics. Baseline patient characteristics were well balanced across treatment groups. Most patients were middle-aged men, one-quarter of whom were current smokers (Online Appendix 2). Mean ejection fraction ranged from 52.5% to 66.5%. Approximately two-thirds of patients had hypertension, and two-thirds were hyper-lipidemic. Among patients in both PCI and CABG groups, about one-ﬁfth had experienced a previous MI.

Trials of patients with MVD were predominantly (76.7%) composed of patients with diabetes: 2 of the 3 largest RCTs included in our meta-analysis, CARDia (Coronary Artery Revascularization in Diabetes) (8) and FREEDOM (10), both included an exclusively diabetic patient population (Online Appendix 2). Slightly over one-quarter of patients in the SYNTAX trial had diabetes. Diabetes was present in 29% of patients with LM disease and 36.3% of patients with single-vessel proximal LAD disease.

Overall meta-analysis results. Overall, when data were pooled across subgroups, CABG was superior relative to PCI for mortality (Fig. 2) and MI (Fig. 3). However, CABG, compared with PCI, resulted in increased rates of stroke. Heterogeneity may be explained by vessel disease subgroup, and these overall results were driven by the strength of beneﬁcial effect of CABG in patients with MVD (Table 2).

Meta-analysis of patient subgroups. Patients with MVD had a signiﬁcantly reduced risk of all outcomes with CABG compared with those for PCI with DES, with the exception of stroke, which was increased (Fig. 4). Speciﬁcally, patients

with MVD who underwent CABG had a lower risk of mortality (Fig. 2), MI (Fig. 3), and revascularization (Fig. 5). There was no signiﬁcant difference between CABG and PCI with DES in patients with LM disease for mortality (Fig. 2) or MI (Fig. 3). However, patients with LM disease had a lower risk of repeat revascularization (Fig. 5) and a greater risk of stroke (Fig. 4) when undergoing CABG.

Treatment effect estimates for patients with single-vessel LAD disease were accompanied by very wide CIs. Conse-quently, no signiﬁcant difference was found between pro-cedures for all outcomes.

Figure 1.Flow Chart

Flow chart describing the systematic literature search for randomized controlled trials comparing coronary artery bypass graft surgery and percutaneous coronary intervention with drug-eluting stents (DES).

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 7 , N O . 5 , 2 0 1 4 Al Ali et al.

M A Y 2 0 1 4 : 4 9 7 – 5 0 6 CABG Versus PCI With DES

(4)

Table 1.Characteristics of RCTs Comparing CABG to PCI with DES in Patients With MVD, LM Disease, and Proximal LAD Disease

Study, Year (Ref. #) Country PCI (n) CABG (n) DES (%) PES (%) SES (%) BMS (%) Type of Surgery IMA (%) Inclusion Exclusion Follow-Up (Months) MVD

FREEDOM, 2012(10) INT 953 947 100 43 51 0 Surgeons’ choice (unspeciﬁed % MIDCAB)

0 DM, MVD, eligible for both PCI and CABG

Severe CHF, previous cardiac surgery, ACS

60 CARDia, 2010(8) UK 256 254 69 0 69 31 Standard CABG 94 DM, MVD, complex SVD ACS, LM previous intervention 12 LM Disease

PRECOMBAT, 2011(13) Korea 300 300 100 0 100 0 Standard CABG 0 LM ACS, previous intervention, EF<30%

24 Boudriot, 2011(12) Germany 100 101 100 2 98 0 Standard CABG 50 LM ACS, previous surgical

intervention, severe PVD

12

3-Vessel or LM Disease*

SYNTAX, 2009(9) USA, Europe 903 897 100 100 0 0 Surgeons’ choice (15% MIDCAB)

0 MVD and/or LM Previous intervention, acute MI 48 Proximal LAD Artery Disease

Hong, 2005(16) Korea 119 70 100 20 80 0 MIDCAB 37 Isolated LAD stenosis ACS, previous intervention 6 Thiele, 2009(15) Germany 65 65 100 0 100 0 MIDCAB 50 Isolated LAD stenosis ACS, previous intervention 36

*SYNTAX included patients with 3-vessel or LM disease. Secondary analyses were conducted in which patients were stratiﬁed by type of underlying coronary disease. Where possible, we present the results of these subgroup analyses in the current meta-analysis, which were reported at the end of follow-up (48 months).

ACS¼ acute coronary syndrome; BMS ¼ bare-metal stent; CABG ¼ coronary artery bypass graft surgery; CARDia ¼ Coronary Artery Revascularization in Diabetes; CHF ¼ congestive heart failure; DES ¼ drug-eluting stent; DM ¼ diabetes mellitus; EF ¼ ejection fraction; FREEDOM¼ Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease; IMA ¼ internal mammary artery; INT ¼ international; LAD ¼ left anterior descending; LM ¼ left main; MI ¼ myocardial infarction; MIDCAB¼ minimally invasive direct coronary artery bypass graft surgery; MVD ¼ multivessel disease; PCI ¼ percutaneous coronary intervention; PES ¼ paclitaxel-eluting stent; PRECOMBAT ¼ Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; PVD¼ peripheral vascular disease; RCT ¼ randomized controlled trial; SES ¼ sirolimus-eluting stent; SVD ¼ single-vessel disease; SYNTAX ¼ Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery.

Al Ali et al . JACC: C A R D IOVA SC ULA R INTERVE N TIONS, V O L . 7, NO. 5 , 2014 CABG Versus PCI With DES MAY 2014: 497 – 506 500

(5)

Visual inspection of the funnel plot (Online Appendix 3) and Egger test (p ¼ 0.025) suggested the presence of publication bias.

Discussion

Our study was designed to compare the efﬁcacy and safety

of CABG with that of PCI with ﬁrst-generation DES

across subgroups of coronary artery vessel disease in terms of mortality, MI, revascularization, and stroke. Our results suggest that in patients with MVD, CABG reduces mor-tality, MI, and repeat revascularization, but increases the risk of stroke when compared with first-generation DES. In patients with LM disease, CABG was associated with a reduced risk of revascularization, with an increased risk of stroke, and no significant differences in death or MI. Available data were insufficient to draw meaningful conclu-sions regarding the relative efficacies of CABG and PCI with DES in patients with single-vessel proximal LAD disease.

As an important caveat, both the FREEDOM and CARDia trials were conducted in diabetic patients. Diabetes is a well-known risk factor for cardiovascular disease, and several studies have concluded that CABG is preferable to PCI in diabetics (17,18). Two of the 3 largest RCTs examining patients with MVD included an exclusively dia-betic population; as a result, our findings showing a signif-icant benefit of CABG versus DES in MVD may be driven by this effect. A recent study stratifying the results of the SYNTAX trial by diabetes status found that diabetic pa-tients with 3-vessel disease had a marked clinical benefit with CABG versus PCI with DES (18). This benefit was

also present among nondiabetic patients, albeit less pro-nounced. Among both diabetic and nondiabetic patients, the rates of all-cause death were similar with both CABG and PCI, whereas cardiac death occurred more frequently with PCI than with CABG (nondiabetic hazard ratio [HR]: 1.62, 95% CI: 1.03 to 2.55; diabetic HR: 2.01, 95% CI: 1.04 to 3.88). Both diabetic and nondiabetic patients Figure 2.Forest Plot of RCTs Comparing the Effect of CABG on All-Cause Mortality to That of PCI With DES

CABG¼ coronary artery bypass graft surgery; CI ¼ conﬁdence interval; DES ¼ drug-eluting stents; FREEDOM ¼ Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease; LAD¼ left anterior descending; LM ¼ left main; MVD ¼ multivessel disease; PCI ¼ percutaneous coronary intervention; PRECOMBAT¼ Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; RCT¼ randomized controlled trial; RR ¼ risk ratio; SYNTAX ¼ Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery.

(6)

experienced higher rates of repeat revascularization after PCI relative to CABG (diabetic HR: 2.75, 95% CI: 1.78 to 4.24, p< 0.001; nondiabetic HR: 1.82, 95% CI: 1.39 to 2.38). Nondiabetic patients had a higher rate of MI following PCI relative to CABG (HR: 2.90, 95% CI: 1.70 to 4.70), whereas no such difference was found among diabetic pa-tients (HR: 1.62, 95% CI: 0.77 to 3.41). Neither diabetic nor nondiabetic patients had signiﬁcantly different risks of stroke across CABG or PCI. Together, these results suggest that a protective effect conferred by CABG to patients with

3-vessel disease exists for both diabetic and nondiabetic individuals.

CABG may also be beneﬁcial for patients with high disease complexity and severity. The 3-vessel disease patient subgroup in the SYNTAX trial also reported that patients with more severe disease (as determined by the SYNTAX score[19]) who received PCI had a signiﬁcantly higher risk

of mortality than did patients with high scores who received CABG. Similarly, a recent meta-analysis of observational and randomized studies found that, compared with patients Figure 3.Forest Plot of RCTs Comparing the Effect of CABG on MI to That of PCI With DES

Abbreviations as inFigure 2.

Table 2.Treatment Effects Obtained From the Meta-Analysis of RCTs Comparing CABG to PCI With DES Overall and in Patients With MVD, LM Disease, and Proximal LAD Disease*

Outcome Mortality MI Revascularization Stroke

MVD 0.73 (0.56–0.96) 0.45 (0.34–0.60) 0.36 (0.26–0.51) 1.72 (1.02–2.90)

Unprotected LM disease 1.08 (0.75–1.57) 0.69 (0.41–1.16) 0.60 (0.46–0.78) 2.89 (1.15–7.27)

Single-vessel proximal LAD disease 2.34 (0.57–9.64) 1.85 (0.46–7.40) 0.55 (0.05–6.24) 5.07 (0.21–122.80)

Overall 0.85 (0.64–1.12) 0.58 (0.40–0.84) 0.51 (0.39–0.67) 1.79 (1.23–2.62)

Values are risk ratio (95% conﬁdence interval). *Data were pooled across trials using random-effects meta-analytic models. Abbreviations as inTable 1.

Al Ali et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 7 , N O . 5 , 2 0 1 4

(7)

with low SYNTAX scores, those with high scores had significantly higher rates of major adverse cardiovascular and cerebrovascular events with PCI than with CABG at 12, 24, and 36 months of follow-up (20). That is, the benefits of CABG versus PCI differ across disease severity. Additional support is lent to this reasoning based on the recent release of the 5-year follow-up data from the SYNTAX trial: after 5 years, patients with severe disease (as indicated by a high SYNTAX score) had lower mor-tality rates among the CABG treatment group, relative to the PCI group(21). Among patients with a low or inter-mediate SYNTAX score, mortality rates were similar across both treatment groups. However, patients with an inter-mediate SYNTAX score had significantly higher rates of MI and repeat revascularization with PCI than with CABG. Overall, the 5-year SYNTAX results show that approximately two-thirds of patients with complex coro-nary disease derive greater benefit from CABG than from PCI with first-generation DES, whereas the remaining patients may derive comparable benefit from PCI. These findings support the use of CABG in patients with MVD, particularly among those with complex or severe disease.

Evidence for the optimal treatment of LM disease is less clear. Results from our meta-analysis suggest a possible

benefit favoring CABG, albeit statistically inconclusive. These inconclusive results may be due in part to the rela-tively smaller sample size of patients with LM disease. However, results from a large retrospective multinational registry comparing CABG and PCI with first-generation DES in patients with LM disease also showed no difference between procedures for death, MI, and cerebrovascular ac-cidents at a median follow-up of 1,295 days(22). Our an-alyses show that in patients with LM disease, CABG results in a decreased risk of revascularization (Fig. 5) and an increased risk of stroke (Fig. 4). Increasingly, however, revascularization is not being considered as clinically sig-nificant as death, MI, or stroke(20,23). Thus, the evidence favoring CABG over PCI with first-generation DES for patients with LM disease is not as strong as for patients with MVD.

Our study had insufﬁcient power to draw clinically directive conclusions for patients with single-vessel proximal LAD disease. There are only 2 trials in patients with proximal LAD disease, and these had a substantially shorter duration of follow-up relative to all other included RCTs. Although the evidence comparing CABG with PCI with ﬁrst-generation DES is limited, a previous trial comparing PCI with bare-metal stents found that patients undergoing Figure 4.Forest Plot of RCTs Comparing the Effect of CABG on Stroke to That of PCI With DES

(8)

PCI had a higher risk of major adverse cardiovascular events after 5 years(24). However, with the exception of a higher risk of repeat revascularization with PCI, the risk of death and MI was similar in both groups. Although theseﬁndings suggest PCI may be comparable to CABG in patients with proximal LAD disease, statistically inconclusive results highlight the need to rely on additional clinical consider-ations to aid in procedural choice.

Results from a recent study validating the SYNTAX score II (25), an enhanced version of the SYNTAX score with prognostically important clinical variables, confirmed the importance of considering clinical characteristics in weighing the benefits of CABG against those of PCI. The investigators demonstrated that the low, intermediate, and high anatomical complexity SYNTAX score categories incorrectly categorized lower-risk patients in high SYNTAX score groups and higher-risk patients in low SYNTAX score groups. To correct for this misclassification, the SYNTAX score II considered additional patient factors including age, creatinine clearance, left ventricular ejection fraction, sex, chronic obstructive pulmonary disease, and peripheral vascular disease. The presence of these clinical characteristics

modiﬁed the threshold of the SYNTAX score at which 4-year mortality rates were similar between CABG and PCI. Among patients with LM disease who underwent PCI, higher anatomical SYNTAX scores were required to achieve similar long-term prognosis as for patients who received CABG. By contrast, among patients with 3-vessel disease, the SYNTAX score was representative of greater disease complexity than that for patients with LM disease with identical SYNTAX scores. Thus, patients with 3-vessel disease would have better long-term outcomes with CABG. These ﬁndings highlight the importance of considering all patient factors, particularly in the event where the choice of procedure is not straightforward.

There is suggestive evidence that first- and second-gen-eration stents may have differential efficacy profiles, which in turn could affect the optimal procedural choice between CABG and PCI with DES. Results from the SPIRIT IV (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System IV) trial(26)revealed that, at 1 year after PCI, patients treated with everolimus-eluting stents (EES), compared with patients treated with PES, had a lower occurrence of MI (EES: 1.9%, PES: 3.1%, p¼ 0.02), Figure 5.Forest Plot of RCTs Comparing the Effect of CABG on Repeat Revascularization to That of PCI With DES

(9)

deﬁnite stent thrombosis (EES: 0.3%, PES: 1.1%, p ¼ 0.004), target lesion revascularization (EES: 2.5%, PES: 4.6%, p ¼ 0.001), target vessel revascularization (EES: 3.9%, PES: 5.9%, p ¼ 0.009), and major adverse cardiovascular events (EES: 4.2%, PES: 6.9%, p < 0.001). Similarly, 1-year post-PCI, results from the XAMI (Xience V Stent vs. Cypher Stent in Primary PCI for Acute Myocardial Infarction) trial (27) showed major adverse cardiovascular event rates were signiﬁcantly lower among patients treated with EES relative to SES (RR: 0.52, 95% CI: 0.27- to 1.00, p ¼ 0.048). Although there may be clinical differences attributable to stent type and generation, it remains unclear to what extent these affect the choice between second-generation DES and CABG.

Study limitations. First, the included RCTs varied in study design, patient characteristics, procedural differences, and duration of follow-up. To account for this between-study heterogeneity, we used random-effects models. We also stratified our analyses by type of coronary disease to explicitly examine the impact of this source of heterogeneity. Second, we found evidence of publication bias, which may have resulted in an overestimate of the protective effects of CABG. Although this may have affected our results for LM or proximal LAD patients, it is unlikely to have biased our MVD analyses as all trials in this patient subpopulation were large (i.e., >500 patients) and thus likely to be published regardless of statistical significance. Third, diabetic patients were over-represented in trials conducted in patients with MVD. In addition, CABG and PCI with DES were only compared in patients with single-vessel proximal LAD disease in 2 relatively small RCTs to date; analyses con-ducted in this subpopulation, therefore, had only modest statistical power. Despite the varying duration of follow-up across studies, the absence of reported event rates necessi-tated the calculation of pooled relative risks. Among patients with LAD disease, surgical outcomes referred solely to MIDCAB, limiting our ability to comment on the efficacy of standard CABG for LAD disease. Finally, only first-generation DES were employed in all included RCTs, limiting our ability to draw conclusions for second-genera-tion devices.

Conclusions

We found that CABG has superior efficacy when compared to PCI with first-generation DES in patients with MVD but results in an increased risk of stroke. Among patients with LM disease, CABG reduces the risk of revasculariza-tion and increases the risk of stroke. Results were incon-clusive in patients with single-vessel proximal LAD disease. Our observed treatment benefits in patients with MVD but not others is consistent with the need to consider risk profiles and disease complexity in selecting the optimal revascularization procedure.

Acknowledgment

The authors thank Jennifer Reoch for her help with data extraction and the reviewers for their thoughtful suggestions. Reprint requests and correspondence: Dr. Mark J. Eisenberg, Divisions of Cardiology and Clinical Epidemiology, Jewish Gen-eral Hospital/McGill University, 3755 Côte Ste. Catherine Road, Suite H-421.1, Montreal, Quebec H3T 1E2, Canada. E-mail: mark.eisenberg@mcgill.ca.

REFERENCES

1.Luo Y, Yu X, Chen F, et al. Impact of diabetes mellitus on patients with unprotected left main coronary artery lesion disease treated with either percutaneous coronary intervention or coronary-artery bypass grafting. Coron Artery Dis 2012;23:322–9.

2.Lee SW, Kim SH, Kim SO, et al. Comparative long-term efﬁcacy and safety of drug-eluting stent versus coronary artery bypass grafting in ostial left main coronary artery disease: analysis of the MAIN-COMPARE registry. Catheter Cardiovasc Interv 2012;80:206–12. 3.Kawecki D, Morawiec B, Fudal M, Milejski W, Jachec W,

Nowalany-Kozielska E. Comparison of coronary artery bypass grafting with percutaneous coronary intervention for unprotected left main coronary artery disease. Yonsei Med J 2012;53:58–67.

4.Head SJ, Bogers A, Kappetein AP. Drug-eluting stent implantation for coronary artery disease: current stents and a comparison with bypass surgery. Curr Opin Pharmacol 2012;12:147–54.

5.Ahmed K, Jeong MH, Chakraborty R, et al., for the Korea Acute Myocardial Infarction Registry Investigators. Percutaneous coronary intervention with drug-eluting stent implantation vs. coronary artery bypass grafting for multivessel coronary artery disease in metabolic syndrome patients with acute myocardial infarction. Circ J 2012;76: 721–8.

6.Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339: b2700.

7.Higgins J, Green S, Cochrane Collaboration. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken, NJ: John Wiley & Sons, 2008.

8.Kapur A, Hall RJ, Malik IS, et al. Randomized comparison of percu-taneous coronary intervention with coronary artery bypass grafting in diabetic patients: 1-year results of the CARDia (Coronary Artery Revascularization in Diabetes) trial. J Am Coll Cardiol 2010;55:432–40. 9.Serruys PW, Morice MC, Kappetein AP, et al., for the SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009; 360:961–72.

10.Farkouh ME, Domanski M, Sleeper LA, et al., for the FREEDOM Trial Investigators. Strategies for multivessel revascularization in pa-tients with diabetes. N Engl J Med 2012;367:2375–84.

11.Mohr F, Redwood S, Venn G, et al. Finalﬁve-year follow-up of the SYNTAX trial: optimal revascularization strategy in patients with three-vessel disease (abstr). J Am Coll Cardiol 2012;60:B13.

12.Boudriot E, Thiele H, Walther T, et al. Randomized comparison of percutaneous coronary intervention with sirolimus-eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis. J Am Coll Cardiol 2011;57:538–45.

13.Park SJ, Kim YH, Park DW, et al. Randomized trial of stents versus bypass surgery for left main coronary artery disease. N Engl J Med 2011; 364:1718–27.

14.Serruys P, Religa G, Ruzyllo W, et al. Long-term safety and efficacy of percutaneous coronary intervention with stenting and coronary artery bypass surgery for left main disease:final five-year follow-up of the SYNTAX trial (abstr). J Am Coll Cardiol 2012;60:B13.

15.Thiele H, Neumann-Schniedewind P, Jacobs S, et al. Randomized comparison of minimally invasive direct coronary artery bypass surgery

(10)

versus sirolimus-eluting stenting in isolated proximal left anterior descending coronary artery stenosis. J Am Coll Cardiol 2009;53: 2324–31.

16.Hong SJ, Lim DS, Seo HS, et al. Percutaneous coronary intervention with drug-eluting stent implantation vs. minimally invasive direct coronary artery bypass (MIDCAB) in patients with left anterior descending coronary artery stenosis. Catheter Cardiovasc Interv 2005; 64:75–81.

17.Ellis SG. Coronary revascularization for patients with diabetes: updated data favor coronary artery bypass grafting. J Am Coll Cardiol 2013;61: 817–9.

18.Kappetein AP, Head SJ, Morice MC, et al., for the SYNTAX In-vestigators. Treatment of complex coronary artery disease in patients with diabetes: 5-year results comparing outcomes of bypass surgery and percutaneous coronary intervention in the SYNTAX trial. Eur J Car-diothorac Surg 2013;43:1006–13.

19.Serruys PW, Onuma Y, Garg S, et al., for the ARTS II Investigators. 5-year clinical outcomes of the ARTS II (Arterial Revascularization Therapies Study II) of the sirolimus-eluting stent in the treatment of patients with multivessel de novo coronary artery lesions. J Am Coll Cardiol 2010;55:1093–101.

20.Alam M, Huang HD, Shahzad SA, et al. Percutaneous coronary intervention vs. coronary artery bypass graft surgery for unprotected left main coronary artery disease in the drug-eluting stents eradan aggregate data meta-analysis of 11,148 patients. Circ J 2013;77: 372–82.

21.Mohr FW, Morice MC, Kappetein AP, 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;381:629–38. 22.Chieffo A, Meliga E, Latib A, et al. Drug-eluting stent for left main

coronary artery disease: the DELTA registry: a multicenter registry evaluating percutaneous coronary intervention versus coronary artery

bypass grafting for left main treatment. J Am Coll Cardiol Intv 2012;5: 718–27.

23.Jang JS, Choi KN, Jin HY, et al. Meta-analysis of three randomized trials and nine observational studies comparing drug-eluting stents versus coronary artery bypass grafting for unprotected left main coronary artery disease. Am J Cardiol 2012;110:1411–8.

24.Thiele H, Oettel S, Jacobs S, et al. Comparison of bare-metal stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery: a 5-year follow-up. Circulation 2005;112: 3445–50.

25.Farooq V, van Klaveren D, Steyerberg EW, et al. Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX. score II. Lancet 2013;381:639–50.

26.Stone GW, Rizvi A, Newman W, et al. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med 2010; 362:1663–74.

27.Hofma SH, Brouwer J, Velders MA, et al. Second-generation everolimus-eluting stents versusﬁrst-generation sirolimus-eluting stents in acute myocardial infarction: 1-year results of the randomized XAMI (XienceV Stent vs. Cypher Stent in Primary PCI for Acute Myocardial Infarction) trial. J Am Coll Cardiol 2012;60:381–7.

Key Words: coronary artery bypass graft-drug-eluting stent(s)-meta-analysis.

APPENDIX

For supplemental information, please see the online version of this paper.