Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC gYqpBsfVTtdtmbsX6PZww5m S0066-782X2019000500511 S0066-782X2019005003103 10.5935/abc.20190027 Original Article Stent versus Coronary Artery Bypass Surgery in Multi-Vessel and Left Main Coronary Artery Disease: A Meta-Analysis of Randomized Trials with Subgroups Evaluation Andrade Pedro José Negreiros de 1 2 Falcão João Luiz de Alencar Araripe 1 2 Falcão Breno de Alencar Araripe 1 2 Rocha Hermano Alexandre Lima 1 2 Hospital Dr. Carlos Alberto Studart Gomes de Messejana Fortaleza CE Brazil Hospital Dr. Carlos Alberto Studart Gomes de Messejana, Fortaleza, CE - Brazil Universidade Federal do Ceará Fortaleza CE Brazil Universidade Federal do Ceará, Fortaleza, CE - Brazil Mailing Address: Pedro José Negreiros de Andrade, Rua Francisco Holanda, 992 apt. 1101. Postal Code 60130-040, Dionísio Torres, Fortaleza, CE - Brazil. E-mail: pedroneg@gmail.com, pedroneg@gmail.com

Author contributions

Conception and design of the research and critical revision of the manuscript for intellectual content: Andrade PJN; acquisition of data: Andrade PJN, Falcão JLAA, Falcão BAA; analysis and interpretation of the data and writing of the manuscript: Andrade PJN, Falcão JLAA, Falcão BAA, Rocha HAL; statistical analysis: Rocha HAL.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 21 02 2019 05 2019 112 5 511 523 05 03 2018 06 08 2018 05 09 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Abstract Background:

Comparison between percutaneous coronary intervention (PCI) using stents and Coronary Artery Bypass Grafting (CABG) remains controversial.

 Objective:

To conduct a systematic review with meta-analysis of PCI using Stents versus CABG in randomized controlled trials.

 Methods:

Electronic databases were searched to identify randomized trials comparing PCI using Stents versus CABG for multi-vessel and unprotected left main coronary artery disease (LMCAD). 15 trials were found and their results were pooled. Differences between trials were considered significant if p < 0.05.

 Results:

In the pooled data (n = 12,781), 30 days mortality and stroke were lower with PCI (1% versus 1.7%, p = 0.01 and 0.6% versus 1.7% p < 0.0001); There was no difference in one and two year mortality (3.3% versus 3.7%, p = 0.25; 6.3% versus 6.0%, p = 0.5). Long term mortality favored CABG (10.6% versus 9.4%, p = 0.04), particularly in trials of DES era (10.1% versus 8.5%, p = 0.01). In diabetics (n = 3,274) long term mortality favored CABG (13.7% versus 10.3%; p < 0.0001). In six trials of LMCAD (n = 4,700) there was no difference in 30 day mortality (0.6%versus 1.1%, p = 0.15), one year mortality (3% versus 3.7%, p = 0.18), and long term mortality (8.1% versus 8.1%) between PCI and CABG; the incidence of stroke was lower with PCI (0.3% versus 1.5%; p < 0.001). Diabetes and a high SYNTAX score were the subgroups that influenced more adversely the results of PCI.

 Conclusion:

Compared with CABG, PCI using Stents showed lower 30 days mortality, higher late mortality and lower incidence of stroke. Diabetes and a high SYNTAX were the subgroups that influenced more adversely the results of PCI.

 Keywords: Myocardial Revascularization/mortality Percutaneous Coronary Intervention Drug-Eluting Stents Stents Coronary Vessels Randomized Controlled Trial Meta-Analysis Introduction

Percutaneous coronary intervention (PCI) using stents and coronary artery bypass grafting (CABG) are well-accepted alternatives for treatment of coronary artery disease (CAD). A large number of randomized controlled trials (RCT) comparing the two procedures were published.1-23 Most studies were underpowered to evaluate isolated endpoints like death, stroke and acute myocardial infarction (AMI). Several meta-analyses were subsequently carried out, pooling results in order to overcome this limitation.24-31 The largest meta-analysis included a limited number of drug-eluting stent (DES) era trials and/or included also single vessel disease and balloon era trials. On the other side, modern meta-analysis included a lower number of trials (only of DES era) and evaluated specific group of patients.28-32 The objective of this study was to perform a systematic review of RCT comparing stents (bare-metal and drug-eluting) versus CABG in multi-vessel and/or left main coronary disease (LMCAD) pooling data of mortality at different periods of time and using meta-regression analysis to evaluate sub-groups.

 Methods Search strategies

Randomized studies comparing PCI with Stents versus CABG in multivessel lesions and/or obstruction of left main CAD published between January 1990 and December 2017 were searched in the databases MEDLINE and Cochrane library and in bibliographic references published on the subject. The search terms used were: “coronary stents” and “coronary artery bypass surgery” and “randomized controlled trial”.

 Inclusion criteria

Clinical trials were included in the review if they were randomized, if had compared PCI with stents versus CABG, if included exclusively multi-vessel and/or LMCAD and if had a follow up of at least 1 year. We did not limit our search to DES trials because bare-metal stents (BMS) are still frequently used in many developing countries, had the peculiarity of evaluating patients with less complex coronary artery disease and there is no definitive evidence that BMS are inferior to DES in the outcome mortality. Figure 7 show a flow diagram of the search strategy in the databases. We identified a total of 15 RCT that satisfied the requirements: AWESOM1, ERACI II,2,3 MASS II,4-6 SOS,7,8 ARTS,9,10 LE MANS,11 SYNTAX,12-14 CÁRDia,15 Boldriot et al.,16 PRECOMBAT,17,18 Va-Cards,19 FREEDOM,20 BEST,21 NOBLE22 and EXCEL.23 Three reviewers (PJNA, ATA and JLAF) assessed the quality of the studies using the Cochrane Collaboration’s tool.

 Data extraction

Two reviewers (JLAAF and PJNA) obtained the data from the studies, examining abstracts, results, tables, appendices and figures. A third author (BAAF) checked the results.

The main outcomes evaluated were all case-mortality, stroke, AMI and new revascularization. Mortality was divided into early mortality, mortality at one year and late mortality. Early mortality was defined as percentage of deaths that occurred in the first 30 days after the procedure, including deaths after randomization but before the procedure. Late mortality was defined as percentage of deaths reported in the last publication, after at least three years of follow-up. For the incidence of stroke, we considered the events occurring up to 1 year after the procedure. In twelve studies we obtained the results up to 30 days, in 2 studies 9,12 up to 1 year and in one 21 this observation was unavailable. For the incidence of myocardial infarct, we considered the reported up to one year of the procedure. AMI were reported in 13 trials.2-5-15 We did not consider in the pooled data the results of NOBLE because it excluded perioperative myocardial infarct in the majority of the patients.

New revascularization was divided in any form of new revascularization (PCI or CABG) and new revascularization by alternative procedure (PCI for patients of the CABG group or CABG for the patients of the PCI group).

 Data synthesis

The characteristics of patients from the eligible studies were obtained through a weighted average of published data. For pooling results of mortality and stroke, the numerator was the number of events and the denominator the total of patients. The total of patients was the number of patients effectively followed, including the deaths. Trials were divided into DES era trials and BMS era trials. Trials that used both types of stents11,15 were classified as DES era trials. We evaluated separately the results of studies in the left main coronary artery and late mortality in the subgroup of patients with diabetes. We also performed analysis of combined major adverse cardiac and cerebrovascular events (MACCE) and assessed the variables age, gender, presence of diabetes, SYNTAX score, and compromised ejection fraction in subgroups based on data published in five trials. Combined MACCE comprised death, AMI, and new revascularization. In order to aggregate the outcomes of mortality and stroke, as well as those of MACCE (in subgroups), we considered whenever possible the absolute number of events and the number of patients followed up. Otherwise, percentages were transformed into absolute numbers.

 Statistical analysis

We measured the relative risk and the risk difference after grouping the results of each outcome. In order to assess the statistical significance of the differences between the DES and the surgery groups, we performed a meta-analysis using the Mantel-Haenszel method, with a random-effect model. We calculated the heterogeneity of the studies using Cochran's Q test and the significance of the measure of the meta-analytic effect using the Z test. Finally, we performed a meta-regression analysis using diabetes, age, gender, ejection fraction, and syntax scores as factors. The differences between the results in the PCI and CABG groups were considered significant if p<0.05. The statistical analyses were performed using the program Review Manager (RevMan), version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) and SPSS for Windows v 23, IBM Inc. In order to represent the heterogeneity of the studies, we constructed Forest plots. We used the risk difference to plot these graphs since this is a more stable index. The possibility of publication bias was assessed by visual inspection of funnel plots.

 Results Studies Characteristics

The studies (table 1) included a total of 12,781 patients (6,382 in the CABG group and 6,399 in the PCI group). All studies were, considered of quality A or B in terms of adequate randomization, adequate concealment and inexistence of selection bias, but not in terms of adequate making. In all studies, the PCI and CABG groups were similar, with the exception of VaCards where the PCI group had a higher incidence of the previous revascularization (in most of the cases a previous PCI) and showed a higher percentage of patients with ejection fraction < 55%. The mean age of the patients was 64 years; 74% were male; 42% were diabetics; 28% were smokers; 64% were hypertensive. Unstable angina was the clinical presentation in 34%; mean ejection fraction was 58%. With the exception of AWESOME, all studies tended to exclude patients with previous CABG. The mean SYNTAX score was 26. According to number of arteries affected 20% had two vessel disease, 43% had three-vessel disease and 37% had LMCAD (alone or associated with diseases of other arteries). In the CABG group, at least one arterial graft was used in 90% of the patients. In trials of the BMS era surgery was done almost always using on-pump technique; in trials of the era, the DES off-pump technique was used in 28% of the patients. Some characteristics of the studies deserve special mention: ERACI II included more them 90% of patients with unstable angina. AWESOME included only patients with high surgical risk; MASS II included predominantly stable angina and had a clinical arm; LE MANS used drug-eluting and BMS, reserving the DESs for left main coronary arteries with a reference diameter < 3.8 mm; CARDia used initially BMS and only assessed patients with diabetes and multivessel disease; SYNTAX evaluated left main coronary artery obstruction and multivessel disease and used first-generation DESs (TAXUS); FREEDOM and VA CARDS exclusively assessed patients with diabetes and multivessel disease; BEST evaluated patients with multivessel disease and used only everolimus-eluting stents; the study by Boudriot et al. evaluated left main coronary artery obstruction and used only sirolimus-eluting stents; EXCEL evaluated left main coronary artery obstruction and used only everolimus-eluting stents; NOBLE evaluated left main coronary artery obstruction and used mostly a biolimus-eluting stent.

Overview of clinical trials
Study Origin Period of recruitment Number of Patients Disease extension Characteristics Unstable angina (%) Average ejection fraction (%) Off pump surgery (%) Diabetics (%)
AWESOME North America (USA) 1995-2000 454 Two and three vessel disease BMS. Previous CABG included 36 45 0 32
ARTS International 1997-2000 1205 Two and three vessel disease BMS. Majority two vessel disease 30 61 0 21
ERACI II South America (Argentina) 1996-1998 450 Two and three vessel disease BMS. Majority unstable angina 92 ND 0 17
SOS Europe and Canada 1995-1999 988 Two and three vessel disease BMS. Majority two vessel disease 33 ND 3 15
MASS II South America (Brazil) 1995-2000 408 Two and three vessel disease BMS. Clinical arm 36 65 0 30
LEMANS Europe (Poland) 2001-2004 105 Left main coronary disease BMS and DESDES if LM < 3.8 32 53 0 25
SYNTAX Europe and USA 2005-2007 1800 Left main and three vessel disease DES (Taxus) 28 ND 15 35
CARDia Europe (United Kingdom) 2002-2007 510 Two and three vessel disease BMS and DES. Only diabetics. 22 59 31 100
Boudriot et al Europe (Germany) 2003-2009 201 Left main coronary disease DES (Sirolimus) ND ND 46 30
PRECOMBAT Asia (Korea) 2003-2009 600 Left main coronary disease DES (Everolimus) 45 60 64 42
FREEDOM International 2005-2010 1900 Two and three vessel disease DES. Only diabetes 30 65 19 100
Va-Cards North America (USA) 2006-2010 198 Two and three vessel disease DES. Only diabetics ND ND ND 100
BEST Asia (Korea) 2008-2013 880 Two and three vessel disease DES. (Everolimus) 42 59 64 45
EXCEL International 2010-2014 1905 Left main coronary disease DES. (Everolimus) 37 57 29 25
NOBLE Europe 2008-2015 982 Left main coronary disease DES (Biolimus) 18 60 18

AWESOME: Angina with extremely severe outcomes; ERACI II: Argentine randomized study: coronary angioplasty with stenting versus coronary bypass surgery in patients with multivessel disease; MASS II: Medicine, Angioplasty, or Surgery Study; ARTS: Arterial Revascularization Therapies Study; SOS: Stent or Surgery trial. SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; CARDia: Coronary artery revascularization in diabetic; Le Mans: Left main stenting; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; Va-Cards: Coronary Artery Revascularization in Diabetes in VA Hospitals; BEST: Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease; PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; NOBLE: Nordic-Baltic-British Left Main Revascularization Study. Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545. DES: drug-eluting stent; BMS: bare-metal stent.

 Outcomes

The results are summarized in Figures 1 to 6. Regarding 30-day mortality, the results favoured PCI (1% versus CABG 1.7%, p = 0.01), but the trials showed moderate overall heterogeneity (I2= 49%). The heterogeneity was particularly higher in BMS era trials (I2= 83%) and could be attributed to the significant inferior results of surgery in ERACI II and AWESOME. The incidence of stroke was lower with PCI (0.6% versus CABG 1.7%, p < 0.0001), with trials showing low heterogeneity (I2= 0). There was no difference in mortality up to one year (PCI 3.3% versus CABG 3.7%, p = 0.25) or up to two year (PCI 6.3% versus CABG 6.0%, p = 0.5). Long-term mortality showed a trend to superiority of CABG (10.6% versus 9.4%, p = 0.04), with trials showing moderate heterogeneity (I2= 25%). The differences were significant in trials of DES era (10.1% versus 8.5%, p = 0.01). After excluding FREEDOM (that included only diabetics) the overall difference in long-term mortality between PCI and CABG became not significant (10.2% versus 9.4%, p = 0.17). The incidence of myocardial infarct was lower with CABG (PCI 6.4 % versus CABG 5.3% at one year and PCI 8,8% versus CABG 6.7 % after 3 or more years), but the trials showed high heterogeneity.

Stent versus CABG: 30 days mortality (top) and stroke (bottom). The size of each box is proportional to the number of patients of the trial. The bars represent 95% confidence interval. The diamond represents the syntheses of results. DES: trials of the drug-eluting stent era. BMS: trials of the bare-metal stent trials era. CABG: coronary artery bypass grafting. ARTS: Arterial Revascularization Therapies Study; AWESOME: Angina with extremely severe outcomes; ERACI II: Argentine randomized study: coronary angioplasty with stenting versus coronary bypass surgery in patients with multi-vessel disease; MASS II: Medicine, Angioplasty, or Surgery Study; SOS: Stent or Surgery trial; BEST: Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multi-vessel Coronary Artery; Boldriot, trial of Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545. CARDia: Coronary artery revascularization in diabetic; LE MANS: Left main coronary artery stenting; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus NOBLE, Nordic-Baltic-British Left Main Revascularization Study; PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; Va-Cards: Coronary Artery Revascularization in Diabetes in VA Hospitals.

STENT versus CABG: One-year mortality (top) and late mortality (bottom). The size of each box is proportional to the number of patients of the trial. The bars represent 95% confidence interval. The diamond represents the syntheses of results. DES: trials of the drug-eluting stent era; BMS: trials of the bare-metal stent trials era; CABG: coronary artery bypass grafting; ARTS: Arterial Revascularization Therapies Study; AWESOME: Angina with extremely severe outcomes; ERACI II: Argentine randomized study: coronary angioplasty with stenting versus coronary bypass surgery in patients with multi-vessel disease; MASS II: Medicine, Angioplasty, or Surgery Study; SOS: Stent or Surgery trial; BEST: Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multi-vessel Coronary Artery; Boldriot, trial of Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545. CARDia: Coronary artery revascularization in diabetic; LE MANS: Left main coronary artery stenting; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; NOBLE: Nordic-Baltic-British Left Main Revascularization Study; PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; Va-Cards: Coronary Artery Revascularization in Diabetes in VA Hospitals.

Stent versus CABG: Acute myocardial infarct at one year (top) and after three or more years (bottom). The size of each box is proportional to the number of patients of the trial. The bars represent 95% confidence interval. The diamond represents the syntheses of results. DES: trials of the drug-eluting stent era; BMS: trials of the bare-metal stent trials era; CABG: coronary artery bypass grafting; ARTS: Arterial Revascularization Therapies Study; AWESOME: Angina with extremely severe outcomes; ERACI II: Argentine randomized study: coronary angioplasty with stenting versus coronary bypass surgery in patients with multi-vessel disease; MASS II: Medicine, Angioplasty, or Surgery Study; SOS: Stent or Surgery trial; BEST: Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multi-vessel Coronary Artery; Boldriot, trial of Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545. CARDia: Coronary artery revascularization in diabetic; LE MANS: Left main coronary artery stenting; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; NOBLE: Nordic-Baltic-British Left Main Revascularization Study; PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; Va-Cards: Coronary Artery Revascularization in Diabetes in VA Hospitals.

Stent versus CABG in left main coronary artery disease: one-year mortality (top) and long-term mortality (bottom). The size of each box is proportional to the number of patients of the trial. The bars represent 95% confidence interval. The diamond represents the syntheses of results. ULMCAD: unprotected left main coronary artery disease. CABG: coronary artery bypass graft. LE MANS: Left Main coronary artery stenting study; SYNTAX LEMANS: subgroup of ULMCAD of SYNTAX (Synergy between PCI with Taxus and Surgery); PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; NOBLE: Nordic-Baltic-British Left Main Revascularization Study. Boldriot: Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545.

Stent versus CABG: risk difference of long-term major composite adverse outcomes (MACCE) in subgroups. The size of each box is proportional to the number of patients of the subgroups. The bars represent 95% confidence interval. The diamond represents the syntheses of results. CABG: coronary artery bypass grafting. LEE = Lee et al, J Am Coll Cardiol Intv 2016; 9:2481–9 (Meta-analysis of individual patient data of SYNTAX, PRECOMBAT and BEST); EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus. Low ejection Fraction was defined as < 50% in EXCEL and as < 40% in FREEDOM and LEE.

Stent versus CABG: new revascularization (top) and new revascularization by alternative procedure (bottom). The size of each box is proportional to the number of patients of the trial. The bars represent 95% confidence interval. The diamond represents the syntheses of results. DES: trials of the drug-eluting stent era; BMS: trials of the bare-metal stent trials era; CABG: coronary artery bypass grafting; ARTS: Arterial Revascularization Therapies Study; AWESOME: Angina with extremely severe outcomes; ERACI II: Argentine randomized study: coronary angioplasty with stenting versus coronary bypass surgery in patients with multi-vessel disease; MASS II: Medicine, Angioplasty, or Surgery Study; SOS: Stent or Surgery trial; BEST: Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multi‑vessel Coronary Artery; Boldriot, trial of Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545. CARDia: Coronary artery revascularization in diabetic; LE MANS: Left main coronary artery stenting; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; NOBLE: Nordic-Baltic-British Left Main Revascularization Study; PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; Va‑Cards: Coronary Artery Revascularization in Diabetes in VA Hospitals.

Study Flow Diagram. RCT: randomized controlled trial; CABG: coronary artery bypass grafting; LAD: left anterior descending; PCI: percutaneous coronary intervention.

In 6 studies of LMCAD (n = 4700), there was no difference in 30 days mortality (0.6% versus 1.1%, p = 0.15) between PCI and CABG, but the incidence of stroke was significantly lower after PCI (0.3% versus 1.1%, p = 0.007). There was no difference in one-year mortality (3% versus 3.7%, p = 0.18) or long-term mortality (8.1% versus 8.1%) between PCI and CABG.

Nine trials (n = 4394) reported long-term mortality in diabetics (AWESOME, ARTS, ERACII, MASS II, SOS, SYNTAX, CARDia, FREEDOM and BEST). After pooling of results, CABG was associated with significantly lower long-term mortality (13.7% versus 10.3% CABG, p < 0.0001); After excluding the diabetic patients of these nine trials the overall difference in long-term mortality between PCI and CABG was no longer significant (9.2% versus 9.2%).

The data regarding new revascularization are shown in figure 5. The superiority of surgery over PCI was consistent in all 15 trials. However, if we consider the risk of new revascularization by alternative procedure there was a trend to superiority of PCI in ARTS and in all studies of DES era.

 Subgroups results

Five trials reported long-term results of major Adverse Composite Events (death, myocardial infarct and stroke) in subgroups. In three of them (SYNTAX, PRECOMBAT and BEST) the results were obtained through the collaborative meta-analysis of Lee et al.24 (Figure 4). The pooled data showed that CABG, compared to PCI, was associated with a lower incidence of MACCE (18.4% vs 14.4%, p < 0.0001). The subgroups in which PCI had worse results, when compared with CABG, by meta-regression analysis were presence of diabetes (23% versus 17.5, p < 0.0001) and a high SYNTAX score (22.7 vs. 16.3%, p = 0.001). There was no difference between PCI and CABG in non-diabetics (14.1% versus 12.3%, p = 0.11), low SYNTAX score patients (14.1% vs. 13.3% scores, p = 0.4) and LMCAD patients (14.7% vs 14.1%, p = 0.5). Female sex and old age less significantly influenced the results. Left ventricular dysfunction did not influence the results. Figure 5 shows that the meta-Adjusted value of p for diabetes was 0.03 (adjusted for age or sex) and 0.09 (adjusted for SYNTAX score). The same figure shows that the meta-adjusted value of p for SYNTAX score was 0.03 (adjusted for diabetes).

 Discussion

To our knowledge this meta-analysis is the most comprehensive and up to date overview of randomized trials that compared coronary stents (DES and BMS) versus CABG. It is also the only major meta-analysis of the stent era that evaluated mortality at different times (up to 30 days, up to one year and after three or more years of follow-up). Another peculiarity of the present meta-analysis was the statistical meta-regression analysis of sub-groups.

The superiority of PCI on 30 days mortality is in accord with the New York state Registry33 and with the meta-analysis of Palmerini et al.32 This superiority should be seen with caution considering the heterogeneity of the trials and cannot be extended to patients with high SYNTAX score, considering the mortality curve of the study of Cavalcante et al.30 The significant difference, favoring PCI found in the incidence of stroke is a relevant finding. A recent study showed that, after death (relative weight 0.23), stroke is the most feared event for patients (relative weight 0.18), being considered more important them longevity (relative weight 0.17), myocardial infarct (relative weight 0.14) and risk of repeat revascularization (relative weight 0.11).34The lack of difference in intermediate mortality was an expected finding, having been reported in almost all trials.

The trend superiority of surgery in long-term mortality was shown in other meta-analysis26,29,31 and is probably related to the higher percentage of diabetics in recent trials. Our results of long-term mortality (HR 1.13) were similar to the results of Smit el al.26 (HR 1.11) and Lee et at.29 (HR 1.18). They were much less unfavourable to PCI them the reported by Benedetto et al (HR 1.5).31 The reason for this is that Benedetto et al excluded LMCAD (that presented similar results of mortality with the two methods of revascularization) and BMS trials (that involved patients with less complex CAD), did not include AWESOME and included two years results of VaCards. Another reason for the significant worse comparative results of PCI-stent in the meta-analysis of Benedetto et al. was that diabetics represented 66% of their population. Recently a pooled analysis of an individual database from 11 trials was published by Head et al.35 and their overall results are similar to ours. Small differences can be explained by the fact that they included late results of VACards and did not include AWESOME, CARDia, Boldriot and LEMANS.

LMCAD was, for a long time, an indication type III for PCI, but this concept began to change after four trials showed similar results in mortality.11,12,16,17 However, AHA/ACC guidelines have accepted PCI only as class IIA or IIB indication for LMCAD and yet, only for patients at high surgical risk. In the present study, we found results similar in mortality, while the incidence of stroke was lower, favouring PCI. Our findings are similar to the collaborative study of Head et al and to the meta-analysis of Palmerini et al.32 This study provided also mortality results in subgroups, showing that in patients with low SYNTAX SCORE there was a trend to higher long-term mortality with CABG (HR, 0.68, CI 0.43-1.08; p = 0.09); intermediate SYNTAX score patients had similar results (HR 1.16, CI 0.51-264, p = 0.49). Considering this, we believe that PCI indications for LMCAD in AHA/ACC guidelines may be modified in near future.

Diabetic patients are a present challenge for PCI. A more diffuse atherosclerotic disease is a possible explanation for the worse comparative results of PCI in this population. Our results suggest that there is still a superiority of surgery over PCI in long-term mortality, even in the DES era. There is a hypothesis that the greater mortality of PCI compared to CABG in diabetic patients may be attributed to the presence of more complex lesions in diabetic patients and, not to the metabolic disturbance. The fact that in the subgroup analysis of MACCE results (Figure 5) the meta-Adjusted value was 0.09 (adjusted for SYNTAX score) supports this hypothesis.

This review was not aimed to compare the results of BMS and DES for several reasons: in BMS trials patients had less complex angiographic lesions (average of 2.3 stents per patient in ARTS and SOS trials versus 3.8 stents per patient in SYNTAX, FREEDOM, BEST, PRECOMBAT and CARDia trials) and had a small percentage of diabetic patients. Otherwise, medical adjunctive treatment and results of surgery for patients with failed PCI also evolved. But the good comparative results of PCI in BMS era trials suggest that for patients with less complex lesions, or patients with unstable angina (ERACI II trial) or high surgical risk (AWESOME trial) initial PCI is a good alternative to CABG.

In terms of major adverse composite events, the analysis of subgroups showed that diabetes and a high SYNTAX score were the most important factors to influence adversely the results of PCI. Presence of left ventricular dysfunction did not influence the results, but the number of patients with this finding was small. A high SYNTAX score was an independent risk factor for adverse outcomes, even when adjusted for diabetes, but diabetes was not an independent risk factor for adverse outcomes when adjusted for SYNTAX score.

In the present review despite the clear superiority of CABG in the outcome of new revascularization, it is possible to notice the progressive improvement of PCI results. This was particularly striking when we consider the outcome “new revascularization by alternative procedures”, in which there was a tendency to superiority of PCI in the DES era.

The evidence presented here should be used to inform patients, helping them in choosing the more adequate form of revascularization in multi-vessel and LMCAD. Some patients may prefer having PCI to avoid the higher morbidity and short-term mortality of surgery. Other patients may put greater emphasis on the superiority of surgery regarding long-term mortality. However, PCI using second generation DES may still be considered as an alternative to CABG, having similar mortality results, for patients with LMCAD of low or intermediate complexity (SYNTAX score < 33). This may also be the case for multi-vessel disease patients with lesions of low complexity (SYNTAX score < 23). For all other patients, particularly if diabetics, surgery remains the best form of revascularization. There is the possibility that second-generation DES and a more functional strategy, using free fractional reserve and avoiding unnecessary revascularizations will improve the comparative results of PCI in the future. The one year results of the SYNTAX II36 study suggests that this will be true, but long-term follow-up is waited and a randomized trial with contemporary CABG is warranted.

The present study presents important limitations. It is a meta-analysis of published data and not a collaborative meta-analysis with access to individual data of patients. The inclusion of BMS era trials can also be criticized. It should also be noted that 30 days mortality and late mortality showed moderate heterogeneity, reducing the robustness of our results. Otherwise, our findings apply only to patients for whom revascularization may be performed using either method, without high surgical risk, no history of prior surgical revascularization, normal or near-normal ejection fraction and with the procedures carried out in institutions of excellence.

 Conclusion

PCI using stents when compared to CABG was associated with a trend to lower mortality at 30 days, similar one-year mortality, lower incidence of stroke up to one-year, and a trend to higher long-term mortality. There was no long-term mortality difference in non-diabetics and in LMCAD patients. In terms of composite adverse outcomes, the SYNTAX score and diabetes were the most important factors to consider when choosing between the two methods of revascularization.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

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Tong BC Huber JC Ascheim DD Puskas JD Ferguson TB Jr Blackstone EH Weighting composite events endpoints in clinical trials: essential evidence for the heart team Ann Thorac Surg 2012 94 6 1908 1913 35 Head SJ, Milojevic M, Daemen J, Ahn JM, Boersma E, Christiansen EH, et al. Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a polled analysis of individual patient data. Lancet. 2018;391(10124):939-48. Head SJ Milojevic M Daemen J Ahn JM Boersma E Christiansen EH Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a polled analysis of individual patient data Lancet 2018 391 10124 939 948 36 Escaned J, Collet C, Ryan N, De Maria GL, Walsh S, Sabate M, et al. Clinical outcomes of state-of-the-art percutaneous coronary revascularization in patients with de novo three vessel disease: 1-year results of the SYNTAX II study. Eur Heart J. 2017;38(42):3124-34. Escaned J Collet C Ryan N De Maria GL Walsh S Sabate M Clinical outcomes of state-of-the-art percutaneous coronary revascularization in patients with de novo three vessel disease: 1-year results of the SYNTAX II study Eur Heart J 2017 38 42 3124 3134 Artigo Original Uso de Stent vs. Cirurgia de Revascularização Miocárdica em Multiarteriais e Doença de Tronco de Coronária Esquerda: Uma Metanálise de Estudos Randomizados com Avaliação de Subgrupos Andrade Pedro José Negreiros de 1 2 Falcão João Luiz de Alencar Araripe 1 2 Falcão Breno de Alencar Araripe 1 2 Rocha Hermano Alexandre Lima 1 2 Hospital Dr. Carlos Alberto Studart Gomes de Messejana, Fortaleza, CE - Brasil Universidade Federal do Ceará, Fortaleza, CE - Brasil Correspondência: Pedro José Negreiros de Andrade, Rua Francisco Holanda, 992 apt. 1101. CEP 60130-040, Dionísio Torres, Fortaleza, CE - Brasil. E-mail: pedroneg@gmail.com, pedroneg@gmail.com

Contribuição dos autores

Concepção e desenho da pesquisa e revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Andrade PJN; obtenção de dados: Andrade PJN, Falcão JLAA, Falcão BAA; análise e interpretação dos dados e redação do manuscrito: Andrade PJN, Falcão JLAA, Falcão BAA, Rocha HAL; análise estatística: Rocha HAL.

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

 Resumo Fundamento:

A comparação entre a intervenção coronária percutânea (ICP) utilizando stents e cirurgia de revascularização do miocárdio (CRM) permanece controversa.

 Objetivo:

Realizar uma revisão sistemática com metanálise da ICP utilizando stents vs. CRM em estudos clínicos randomizados.

 Métodos:

Foram pesquisadas bases de dados eletrônicas para identificar estudos randomizados comparando a ICP com stents vs. CRM em multiarteriais e lesão de tronco de coronária esquerda desprotegida (LTCED). Foram encontrados quinze estudos, e seus resultados foram agrupados. As diferenças entre os estudos foram consideradas significativas com valor de p < 0,05.

 Resultados:

Nos dados agrupados (n = 12.781), a mortalidade em 30 dias e o acidente vascular cerebral (AVC) tiveram menor incidência com a ICP (1% versus 1,7%, p = 0,01; 0,6% versus 1,7%, p < 0,0001); não houve diferença na mortalidade em um e dois anos (3,3% versus 3,7%, p = 0,25; 6,3% versus 6,0%, p = 0,5). A mortalidade em longo prazo favoreceu a CRM (10,6% versus 9,4%, p = 0,04), particularmente nos estudos realizados na era do stent farmacológico (SF) (10,1% versus 8,5%, p = 0,01). Nos diabéticos (n = 3.274), a mortalidade em longo prazo favoreceu a CRM (13,7% versus 10,3%; p < 0,0001). Em seis estudos de LTCED (n = 4.700) não houve diferença na mortalidade em 30 dias (0,6% versus 1,1%, p = 0,15), mortalidade em um ano (3% versus 3,7%, p = 0,18) e mortalidade em longo prazo (8,1% versus 8,1%) entre ICP e CRM; a incidência de AVC foi menor com a ICP (0,3% versus 1,5%; p < 0,001). Diabetes e um escore SYNTAX elevado foram os subgrupos que influenciaram de maneira mais adversa os resultados da ICP.

 Conclusão:

Comparada à CRM, a ICP com stent apresentou menor mortalidade em 30 dias, maior mortalidade tardia e menor incidência de AVC. Diabetes e escore SYNTAX elevado foram os subgrupos que influenciaram de maneira mais adversa os resultados da ICP.

 Palavras-chave: Revascularização Miocárdica/mortalidade Intervenção Coronária Percutânea Stents Farmacológicos Stents Vasos Coronários Ensaio Clínico Controlado Aleatório Metanálise Introdução

A intervenção coronária percutânea (ICP) com stent e a cirurgia de revascularização do miocárdio (CRM) são alternativas bem aceitas para o tratamento da doença arterial coronariana (DAC). Um grande número de estudos clínicos randomizados (ECRs) comparando os dois procedimentos foram publicados.1-23 Os estudos foram, em sua maioria, subdimensionados para avaliar desfechos isolados como morte, acidente vascular cerebral (AVC) e infarto agudo do miocárdio (IAM). Diversas metanálises foram subsequentemente realizadas, agrupando os resultados para superar essa limitação.24-31 A maior metanálise incluiu um número limitado de estudos na era do stent farmacológico (SF) e/ou incluiu também doença monoarterial e estudos na era do balão farmacológico. Em contrapartida, uma metanálise mais recente incluiu um menor número de estudos (apenas da era do SF), e avaliou um grupo específico de pacientes.28-32 O objetivo deste estudo foi realizar uma revisão sistemática de ECRs comparando stents (não farmacológicos e farmacológicos) vs. CRM em pacientes multiarteriais e/ou na lesão do tronco da coronária esquerda desprotegida (LTCED), agrupando dados sobre a mortalidade em diferentes períodos de tempo e utilizando análise de meta-regressão para avaliar subgrupos.

 Métodos Estratégias de busca

Estudos randomizados comparando a ICP com stent vs. CRM em pacientes multiarteriais e/ou com LTCED, publicados entre janeiro de 1990 e dezembro de 2017, foram pesquisados nas bases de dados MEDLINE, Cochrane e em referências bibliográficas publicadas sobre o assunto. Os termos de busca utilizados foram: “coronary stents” and “coronary artery bypass surgery” e “randomized controlled trial”.

 Critérios de inclusão

Foram incluídos na revisão estudos clínicos que: fossem randomizados, comparassem a ICP com stent vs. a CRM, considerassem exclusivamente pacientes multiarteriais e/ou com LTCED, e tivessem um seguimento de pelo menos um ano. Não limitamos nossa pesquisa aos estudos com SF porque os stents não farmacológicos (SNF) ainda são usados com frequência em muitos países em desenvolvimento, observando que os estudos com SNF tinham a peculiaridade de avaliar pacientes com doença arterial coronariana menos complexa e que não há evidências definitivas de que os SNF são inferiores aos SF no desfecho mortalidade. A Figura 7 mostra o diagrama de fluxo da estratégia de pesquisa nos bancos de dados. Identificamos um total de 15 ECRs que satisfaziam os requisitos: AWESOM1, ERACI II,2,3 MASS II,4-6 SOS,7,8 ARTS,9,10 LE MANS,11 SYNTAX,12-14 CÁRDia,15 Boldriot et al.,16 PRECOMBAT,17,18 Va-Cards,19 FREEDOM,20 BEST,21 NOBLE22 e EXCEL.23 Três revisores (PJNA, ATA e JLAF) avaliaram a qualidade dos estudos utilizando a ferramenta Cochrane Collaboration.

 Extração de dados

Dois revisores (JLAAF e PJNA) obtiveram os dados dos estudos, examinando resumos, resultados, tabelas, apêndices e figuras. Um terceiro autor (BAAF) verificou os resultados.

Os principais desfechos avaliados foram mortalidade, acidente vascular cerebral, infarto agudo do miocárdio (IAM) e nova revascularização. A mortalidade foi dividida em mortalidade precoce, mortalidade em um ano e mortalidade tardia. A mortalidade precoce foi definida como a porcentagem de mortes que ocorreram nos primeiros 30 dias após o procedimento, incluindo as mortes ocorridas depois da randomização mas antes do procedimento. A mortalidade tardia foi definida como a porcentagem de mortes relatadas na última publicação, depois de pelo menos três anos de seguimento. Para a incidência de AVC, foram considerados os eventos ocorridos até um ano após o procedimento. Em doze estudos foram obtidos os resultados em até 30 dias, em 2 estudos9,12 até um ano e para um deles21 esta observação não estava disponível. Para a incidência de infarto do miocárdio, consideramos o que foi relatado até um ano após o procedimento. O IAM foi relatado em 13 estudos.2-5-15 Nos dados agrupados não foram considerados os resultados do estudo NOBLE (Nordic-Baltic-British Left Main Revascularization Study) porque o mesmo excluiu o infarto do miocárdio perioperatório na maioria dos pacientes.

Uma nova revascularização foi dividida em qualquer forma de nova revascularização (ICP ou CRM) ou nova revascularização por procedimento alternativo (ICP para pacientes do grupo CRM ou CRM para os pacientes do grupo ICP).

 Síntese de dados

As características dos pacientes dos estudos elegíveis foram obtidas através de uma média ponderada dos dados publicados. Para agrupar os resultados de mortalidade e acidente vascular cerebral, o numerador foi o número de eventos e o denominador o total de pacientes. O total de pacientes foi o número de pacientes efetivamente em seguimento, incluindo as mortes. Os estudos foram divididos em estudos da era SF e estudos da era SNF. Estudos que usaram os dois tipos de stents11,15 foram classificados como estudos da era SF. Foram avaliados separadamente os resultados de estudos de tronco de coronária esquerda e mortalidade tardia no subgrupo de diabéticos. Também foi feita uma análise de eventos cardíacos e cerebrovasculares adversos maiores (ECCAM), analisando as variáveis idade, sexo, presença de diabetes, escore SYNTAX e fração de ejeção comprometida em subgrupos com base nos dados publicados em cinco estudos. Os eventos adversos combinados incluíram morte, IAM e nova revascularização. Para agregar os desfechos de mortalidade e AVC, bem como de ECCAM (em subgrupos), foram considerados, sempre que possível, o número absoluto de eventos e de pacientes em seguimento. Caso contrário, as porcentagens foram transformadas em números absolutos.

 Análise estatística

Foram medidos o risco relativo e a diferença de risco após agrupar os resultados de cada um dos desfechos. Para avaliar a significância estatística das diferenças entre o grupo SF e o grupo cirurgia, foi realizada uma metanálise pelo método de Mantel-Haenszel, com modelo de efeito randomizado. Foram calculadas a heterogeneidade dos estudos utilizando o teste Q de Cochran e a significância da medida de efeito meta-analítico através do teste Z. Finalmente, foi realizada uma análise de meta-regressão utilizando diabetes, idade, sexo, fração de ejeção e escore SYNTAX como fatores. As diferenças entre os resultados nos grupos ICP e CRM foram consideradas significativas se p < 0,05. As análises estatísticas foram realizadas utilizando-se o programa Review Manager (RevMan), versão 5.3 (Copenhague: The Nordic Cochrane Center, The Cochrane Collaboration, 2014) e o software SPSS for Windows v. 23, IBM Inc. Para representar a heterogeneidade dos estudos, foram construídos gráficos em floresta (forest plots). A diferença de risco foi utilizada para construção desses gráficos, pois é um índice mais estável. A possibilidade de viés da publicação foi avaliada por inspeção visual de gráficos de funil (funnel plots).

 Resultados Características de estudos

Os estudos (tabela 1) incluíram um total de 12.781 pacientes (6.382 no grupo CRM e 6.399 no grupo ICP). Todos os estudos foram considerados de qualidade A ou B em termos de randomização adequada, ocultação adequada e inexistência de viés de seleção, embora não em termos de realização adequada. Em todos os estudos, os grupos ICP e CRM foram semelhantes, com a exceção do estudo VaCards, onde o grupo ICP apresentou maior incidência de revascularização prévia (na maioria dos casos uma ICP prévia) e maior porcentagem de pacientes com fração de ejeção <55%. A média de idade dos pacientes foi de 64 anos; 74% eram do sexo masculino; 42% eram diabéticos; 28% fumantes; 64% hipertensos; 34% apresentavam angina instável; a fração de ejeção média foi de 58%. Com exceção do estudo AWESOME, todos os estudos tenderam a excluir pacientes com CRM prévia. O escore SYNTAX médio foi 26. De acordo com o número de vasos comprometidos, 20% eram biarteriais, 43%, triarteriais e 37% tinham LTCED (isoladamente ou associada a doenças de outros vasos). No grupo CRM, pelo menos um enxerto arterial foi utilizado em 90% dos pacientes. Nos estudos da era do SNF, a cirurgia foi executada quase sempre com a técnica de circulação extracorpórea (CEC); nos estudos da época, a técnica sem CEC com SF foi utilizada em 28% dos pacientes. Algumas características dos estudos merecem destaque: o estudo ERACI II incluiu mais de 90% dos pacientes com angina instável. O estudo AWESOME incluiu apenas pacientes com alto risco cirúrgico; o MASS II incluiu predominantemente angina estável e tinha um braço clínico; o estudo LE MANS utilizou SF e SNF, reservando os SF para o tronco de coronária esquerda com diâmetro de referência < 3,8 mm; o estudo CARDia usou inicialmente o SNF, e avaliou apenas pacientes diabéticos multiarteriais; o estudo SYNTAX avaliou a obstrução do tronco de coronária esquerda e doença multiarterial, utilizando SF de primeira geração (TAXUS); os estudos FREEDOM e VaCards avaliaram exclusivamente pacientes diabéticos multiarteriais; o estudo BEST avaliou pacientes multiarteriais e utilizou apenas stents farmacológicos eluidores de everolimus; o estudo de Boudriot et al. avaliou a obstrução do tronco de coronária esquerda utilizando apenas stents farmacológicos eluidores de sirolimus; o estudo EXCEL avaliou obstrução do tronco de coronária esquerda e utilizou apenas stents farmacológicos eluidores de everolimus; o estudo NOBLE avaliou obstrução do tronco de coronária esquerda e utilizou principalmente stents eluidores de biolimus.

Visão geral dos estudos clínicos
Estudo Origem Período de recrutamento Número de pacientes Extensão da doença Características Angina instável (%) Fração de Ejeção média (%) Cirurgia sem circulação extracorpórea (%) Diabéticos (%)
AWESOME América do Norte (EUA) 1995-2000 454 Doença biarterial e triarterial SNF. CRM prévia incluída 36 45 0 32
ARTS Internacional 1997-2000 1205 Doença biarterial e triarterial SNF. Predominância de doença biarterial 30 61 0 21
ERACI II América do Sul (Argentina) 1996-1998 450 Doença biarterial e triarterial SNF. Predominância de angina instável 92 ND 0 17
SOS Europa e Canadá 1995-1999 988 Doença biarterial e triarterial SNF. Predominância de doença biarterial 33 ND 3 15
MASS II América do Sul (Brasil) 1995-2000 408 Doença biarterial e triarterial SNF. Braço clínico 36 65 0 30
LEMANS Europa (Polônia) 2001-2004 105 Lesão do tronco da coronária esquerda e doença triarterial SNF e SFSF se LM < 3.8 32 53 0 25
SYNTAX Europa e EUA 2005-2007 1800 Lesão do tronco da coronária esquerda e doença triarterial SF (Taxus) 28 ND 15 35
CARDia Europa (Reino Unido) 2002-2007 510 Doença biarterial e triarterial SNF and SF. Apenas diabéticos 22 59 31 100
Boudriot et al Europa (Alemanha) 2003-2009 201 Lesão do tronco da coronária esquerda SF (Sirolimus) ND ND 46 30
PRECOMBAT Ásia (Coréia) 2003-2009 600 Lesão do tronco da coronária esquerda SF (Everolimus) 45 60 64 42
FREEDOM Internacional 2005-2010 1900 Doença biarterial e triarterial SF. Apenas diabetes 30 65 19 100
VaCards América do Norte (EUA) 2006-2010 198 Doença biarterial e triarterial SF. Apenas diabéticos ND ND ND 100
BEST Ásia (Coréia) 2008-2013 880 Doença biarterial e triarterial SF. (Everolimus) 42 59 64 45
EXCEL Internacional 2010-2014 1905 Lesão do tronco da coronária esquerda SF. (Everolimus) 37 57 29 25
NOBLE Europa 2008-2015 982 Lesão do tronco da coronária esquerda SF (Biolimus) 18 60 16 18

AWESOME: Angina with extremely severe outcomes; ERACI II: Argentine randomized study: coronary angioplasty with stenting versus coronary bypass surgery in patients with multivessel disease; MASS II: Medicine, Angioplasty, or Surgery Study; ARTS: Arterial Revascularization Therapies Study; SOS: Stent or Surgery trial. SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; CARDia: Coronary artery revascularization in diabetic; Le Mans: Left main stenting; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; Va-Cards: Coronary Artery Revascularization in Diabetes in VA Hospitals; BEST: Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease; PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; NOBLE: Nordic-Baltic-British Left Main Revascularization Study. Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545. SF: stent farmacológico; SNF: stent não-farmacológico.

 Desfechos

Os resultados estão resumidos nas Figuras 1 a 6. Com relação à mortalidade em 30 dias, os resultados favoreceram a ICP (1% vs. CRM 1,7% p = 0,01), mas os estudos mostraram uma heterogeneidade geral moderada (I2=49%). A heterogeneidade foi particularmente mais elevada nos estudos da era dos SNF (I2= 83%) e pode ser atribuída aos resultados significativamente inferiores da cirurgia nos estudos ERACI II e AWESOME. A incidência de AVC foi menor com a ICP (0,6% vs. CRM 1,7%, p < 0,0001), com os estudos mostrando baixa heterogeneidade (I2= 0). Não houve diferença na mortalidade até um ano (ICP 3,3% vs. CRM 3,7%, p = 0,25) ou em até dois anos (ICP 6,3% vs. CRM 6,0%, p = 0,5). A mortalidade em longo prazo mostrou uma tendência ao favorecimento da CRM (10,6% vs. 9,4%, p = 0,04), com estudos mostrando heterogeneidade moderada (I2= 25%). As diferenças foram significativas nos estudos da era SF (10,1% vs. 8,5%, p = 0,01). Após a exclusão do estudo FREEDOM (que incluía apenas pacientes diabéticos), a diferença global na mortalidade em longo prazo entre ICP e CRM tornou-se não significativa (10,2% vs. 9,4%, p = 0,17). A incidência de infarto do miocárdio foi menor com a CRM (ICP 6,4% vs. CRM 5,3% em um ano e ICP 8,8% vs. CRM 6,7% após três anos ou mais), mas os estudos mostraram alta heterogeneidade.

Stent vs. CRM: mortalidade em 30 dias (topo) e acidente vascular cerebral (base). O tamanho das caixas é proporcional ao número de pacientes do estudo. As barras representam 95% de intervalo de confiança. Os diamantes representam a síntese dos resultados. SF: estudos da era stent farmacológico. SNF: estudos da era stents não-farmacológicos. CRM: cirurgia de revascularização do miocárdio. ARTS: Arterial Revascularization Therapies Study; AWESOME: Angina with extremely severe outcomes; ERACI II: Argentine randomized study: coronary angioplasty with stenting versus coronary bypass surgery in patients with multi-vessel disease; MASS II: Medicine, Angioplasty, or Surgery Study; SOS: Stent or Surgery trial; BEST: Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multi-vessel Coronary Artery; Boldriot, estudo de Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545. CARDia: Coronary artery revascularization in diabetic; LE MANS: Left main coronary artery stenting; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; NOBLE, Nordic-Baltic-British Left Main Revascularization Study; PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; Va-Cards: Coronary Artery Revascularization in Diabetes in VA Hospitals.

STENT versus CABG: Mortalidade em 1 ano (topo) e mortalidade tardia (base). O tamanho das caixas é proporcional ao número de pacientes do estudo. As barras representam 95% de intervalo de confiança. O diamante representa a síntese dos resultados. SF: estudos da era stent farmacológico. SNF: estudos da era stents não farmacológicos. CRM: cirurgia de revascularização do miocárdio. ARTS: Arterial Revascularization Therapies Study; AWESOME: Angina with extremely severe outcomes; ERACI II: Argentine randomized study: coronary angioplasty with stenting versus coronary bypass surgery in patients with multi-vessel disease; MASS II: Medicine, Angioplasty, or Surgery Study; SOS: Stent or Surgery trial; BEST: Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multi-vessel Coronary Artery; Boldriot, estudo de Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545. CARDia: Coronary artery revascularization in diabetic; LE MANS: Left main coronary artery stenting; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; NOBLE, Nordic-Baltic-British Left Main Revascularization Study; PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; VaCards: Coronary Artery Revascularization in Diabetes in VA Hospitals.

Stent vs. CRM: Infarto agudo do miocárdio em um ano (topo) e após três ou mais anos (base). O tamanho das caixas é proporcional ao número de pacientes do estudo. As barras representam 95% de intervalo de confiança. O diamante representa a síntese dos resultados. SF: estudos da era stent farmacológico. SNF: estudos da era de stents não farmacológicos. CRM: cirurgia de revascularização do miocárdio. ARTS: Arterial Revascularization Therapies Study; AWESOME: Angina with extremely severe outcomes; ERACI II: Argentine randomized study: coronary angioplasty with stenting versus coronary bypass surgery in patients with multi-vessel disease; MASS II: Medicine, Angioplasty, or Surgery Study; SOS: Stent or Surgery trial; BEST: Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multi-vessel Coronary Artery; Boldriot, estudo de Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545. CARDia: Coronary artery revascularization in diabetic; LE MANS: Left main coronary artery stenting; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; NOBLE, Nordic-Baltic-British Left Main Revascularization Study; PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; VaCards: Coronary Artery Revascularization in Diabetes in VA Hospitals.

Stent vs. CRM na lesão do tronco de coronária esquerda: mortalidade em um ano (topo) e mortalidade em longo prazo (base). O tamanho das caixas é proporcional ao número de pacientes do estudo. As barras representam 95% de intervalo de confiança. O diamante representa a síntese dos resultados. LTCED: lesão do tronco de coronária esquerda desprotegida. CRM: cirurgia de revascularização do miocárdio. LE MANS: Left Main coronary artery stenting study; SYNTAX LEMANS: subgoupo de LTCED do estudo SYNTAX (Synergy between PCI with Taxus and Surgery); PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; NOBLE: Nordic-Baltic-British Left Main Revascularization Study. Boldriot: Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545.

Stent vs. CRM: diferença de risco de resultados de desfechos adversos combinados maiores (ECCAM) em longo prazo em subgrupos. O tamanho das caixas é proporcional ao número de pacientes do estudo. As barras representam 95% de intervalo de confiança. O diamante representa a síntese dos resultados. CRM: cirurgia de revascularização do miocárdio. LEE: Lee et al, J Am Coll Cardiol Intv 2016; 9:2481–9 (Meta-análise de dados individuais do paciente dos estudos SYNTAX, PRECOMBAT and BEST); EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus. A fração de ejeção baixa foi definida como <50% no estudo EXCEL e como < 40% nos estudos FREEDOM e LEE.

Stent versus CRM: nova revascularização (topo) e nova revascularização por procedimento alternativo (base). O tamanho das caixas é proporcional ao número de pacientes do estudo. As barras representam 95% de intervalo de confiança. O diamante representa a síntese dos resultados. SF: estudos da era stent farmacológico. SNF: estudos da era stents não farmacológicos. CRM: cirurgia de revascularização do miocárdio. ARTS: Arterial Revascularization Therapies Study; AWESOME: Angina with extremely severe outcomes; ERACI II: Argentine randomized study: coronary angioplasty with stenting versus coronary bypass surgery in patients with multi-vessel disease; MASS II: Medicine, Angioplasty, or Surgery Study; SOS: Stent or Surgery trial; BEST: Bypass Surgery and Everolimus‑Eluting Stent Implantation in the Treatment of Patients with Multi-vessel Coronary Artery; Boldriot, estudo de Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545. CARDia: Coronary artery revascularization in diabetic; LE MANS: Left main coronary artery stenting; EXCEL: Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; NOBLE, Nordic-Baltic-British Left Main Revascularization Study; PRECOMBAT: Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; Va-Cards: Coronary Artery Revascularization in Diabetes in VA Hospitals.

Diagrama do Fluxo do Estudo. ECR: estudo controlado randomizado; CRM: cirurgia de revascularização do miocárdio; ADA: artéria descendente anterior esquerda; ICP: intervenção coronária percutânea.

Em 6 estudos que avaliaram a LTCED (n = 4700), não houve diferença na mortalidade em 30 dias (0,6% vs. 1,1%, p = 0,15) entre ICP e CRM, mas a incidência de AVC foi significativamente menor após a ICP (0,3% vs. 1,1%, p = 0,007). Não houve diferença na mortalidade em um ano (3% vs. 3,7%, p = 0,18) ou na mortalidade em longo prazo (8,1% vs. 8,1%) entre ICP e CRM. Nove estudos (n = 4394) relataram mortalidade em longo prazo em diabéticos (AWESOME, ARTS, ERACII, MASS II, SOS, SYNTAX, CARDia, FREEDOM e BEST). Após o agrupamento dos resultados, a CRM foi associada com mortalidade significativamente menor em longo prazo (13,7% vs. CRM 10,3%, p < 0,0001). Depois de excluir os pacientes diabéticos desses nove estudos, a diferença global na mortalidade em longo prazo entre ICP e CRM deixou de ser significativa (9,2% versus 9,2%).

Os dados referentes à nova revascularização são mostrados na figura 5. A superioridade da cirurgia sobre a ICP foi consistente em todos os 15 estudos. No entanto, se considerarmos o risco de uma nova revascularização por procedimento alternativo, houve uma tendência à superioridade da ICP nos estudos ARTS e em todos os estudos da era dos SF.

 Resultados dos subgrupos

Cinco estudos forneceram resultados da incidência em longo prazo de eventos adversos combinados (morte, infarto do miocárdio e acidente vascular cerebral) em subgrupos. Em três deles (SYNTAX, PRECOMBAT e BEST), os resultados foram obtidos através da metanálise colaborativa de Lee et al.24 (Figura 4). Os dados agrupados mostraram que a CRM, em comparação com a ICP, foi associada a uma menor incidência de ECCAM (18,4% vs. 14,4%, p < 0,0001). Os subgrupos nos quais a ICP apresentou piores resultados, quando comparados com a CRM por análise de meta-regressão, foram: presença de diabetes (23% vs. 17,5, p < 0,0001) e escore SYNTAX elevado (22,7 vs. 16,3%, p = 0,001). Não houve diferença entre a ICP e a CRM em não-diabéticos (14,1% versus 12,3%, p = 0,11), pacientes com escore SYNTAX baixo (14,1% vs. 13,3%, p = 0,4) e pacientes com LTCED (14,7% vs. 14,1% p = 0,5). Pacientes idosos e o sexo feminino influenciaram de forma menos significativa os resultados. A disfunção ventricular esquerda não influenciou os resultados. A Figura 5 mostra que o valor meta-ajustado de p para diabetes foi de 0,03 (ajustado para idade ou sexo) e 0,09 (ajustado para o escore SYNTAX). A mesma figura mostra que o valor meta-ajustado de p para o escore SYNTAX foi de 0,03 (ajustado para diabetes).

 Discussão

Que seja de nosso conhecimento, essa metanálise é a visão geral mais abrangente e atualizada de estudos randomizados que compararam os stents coronarianos (SF e SNF) vs. a CRM. É também a única grande metanálise da era stent que avaliou a mortalidade em diferentes momentos (em até 30 dias, um ano e após três ou mais anos de seguimento). Outra peculiaridade da presente metanálise foi a análise estatística de meta-regressão de subgrupos.

A superioridade da ICP considerando a mortalidade no período de 30 dias está de acordo com o registro do Estado de Nova York33 (New York State Registry) e com a metanálise de Palmerini et al.32 Essa superioridade deve ser vista com cautela, considerando a heterogeneidade dos estudos, e não deve ser estendida a pacientes com escore SYNTAX elevado, considerando a curva de mortalidade do estudo de Cavalcante et al.30 A diferença significativa favorecendo a ICP, encontrada na incidência de AVC, é um achado relevante. Um estudo recente mostrou que, após a morte (peso relativo 0,23), o AVC é o evento mais temido pelos pacientes (peso relativo 0,18), sendo considerado mais importante que a longevidade (peso relativo 0,17), infarto do miocárdio (peso relativo 0,14) e risco de nova revascularização (peso relativo 0,11).34 A falta de diferença na mortalidade intermediária foi um achado esperado, tendo sido relatado em quase todos os estudos.

A tendência de superioridade da cirurgia na mortalidade em longo prazo foi demonstrada em outras metanálises,26,29,31 e provavelmente está relacionada à maior porcentagem de diabéticos em estudos recentes. Nossos resultados de mortalidade em longo prazo (HR 1,13) foram semelhantes aos resultados de Smit el al.26 (HR 1,11) e Lee et al.29 (HR 1,18). Eles foram muito menos desfavoráveis à ICP do que aqueles relatados por Benedetto et al. (HR 1.5).31 A razão para isto é que Benedetto et al. excluíram a LTCED (que apresentou resultados semelhantes de mortalidade com os dois métodos de revascularização) e estudos de SNF (que envolveram pacientes com DAC menos complexa), não incluíram o estudo AWESOME e incluíram dois anos de resultados do estudo VaCards. Outra razão para os resultados comparativos significativamente piores da ICP com stent na metanálise de Benedetto et al. foi que os diabéticos representaram 66% da população estudada. Recentemente, uma análise conjunta de um banco de dados individual de 11 estudos foi publicada por Head et al.,35 e seus resultados gerais são semelhantes aos nossos. Pequenas diferenças podem ser explicadas pelo fato de que eles incluíram resultados tardios do estudo VaCards, e não incluíram os estudos AWESOME, CARDia, Boldriot e LEMANS.

A LTCED foi, por muito tempo, uma indicação de classe III para ICP, mas esse conceito começou a mudar depois que quatro estudos mostraram resultados semelhantes em relação à mortalidade.11,12,16,17 No entanto, as diretrizes da AHA/ACC (American College of Cardiology/American Heart Association) aceitaram a ICP somente como indicação de classe IIA ou IIB para LTCED e, ainda assim, apenas para pacientes com alto risco cirúrgico. No presente estudo, encontramos resultados semelhantes na mortalidade, enquanto a incidência de AVC foi menor, favorecendo a ICP. Nossos achados são semelhantes aos do estudo colaborativo de Head et al. e à metanálise de Palmerini et al.32 Esse estudo forneceu também resultados de mortalidade em subgrupos, mostrando que em pacientes com escores SYNTAX baixos, havia uma tendência a maior mortalidade em longo prazo com a CRM (HR 0,68, IC 0,43-1,08; p = 0,09); pacientes com escore SYNTAX intermediário apresentaram resultados semelhantes (HR 1,16; IC 0,51-264, p = 0,49). Portanto, acreditamos que as indicações de ICP para LTCED nas diretrizes da AHA/ACC podem ser modificadas no futuro próximo.

Pacientes diabéticos são um desafio atual para a ICP. Uma doença aterosclerótica mais difusa é uma possível explicação para os piores resultados comparativos da ICP nessa população. Nossos resultados sugerem que ainda há uma superioridade da cirurgia sobre a ICP em relação à mortalidade em longo prazo, mesmo na era dos SF. Existe a hipótese de que a maior mortalidade da ICP em relação à CRM em pacientes diabéticos possa ser atribuída à presença de lesões mais complexas em pacientes diabéticos e, não ao distúrbio metabólico. O fato de que na análise do subgrupo dos resultados de ECCAM (Figura 5), o valor meta-ajustado foi de 0,09 (ajustado para o escore SYNTAX) apoia essa hipótese.

Esta revisão não teve como objetivo comparar os resultados dos SNF e SF por várias razões: nos estudos com SNF, os pacientes apresentaram lesões angiográficas menos complexas (média de 2,3 stents por paciente nos estudos ARTS e SOS versus 3,8 stents por paciente nos estudos SYNTAX, FREEDOM, BEST, PRECOMBAT e CARDia), com uma pequena porcentagem de pacientes diabéticos. Em contrapartida, os tratamentos médicos adjuvantes e os resultados da cirurgia para os pacientes com falha na ICP também evoluíram. Mas os bons resultados comparativos da ICP nos estudos da era SNF sugerem que, para pacientes com lesões menos complexas, ou pacientes com angina instável (estudo ERACI II) ou alto risco cirúrgico (estudo AWESOME), a ICP inicial é uma boa alternativa à CRM.

Em relação aos eventos adversos maiores compostos, a análise de subgrupos mostrou que o diabetes e um escore SYNTAX elevado foram os fatores mais importantes para influenciar negativamente os resultados da ICP. A presença de disfunção ventricular esquerda não influenciou os resultados, mas o número de pacientes com esse achado foi pequeno. Um escore SYNTAX alto foi um fator de risco independente para desfechos adversos, mesmo quando ajustado para a presença de diabetes, mas a diabetes não foi um fator de risco independente para desfechos adversos quando ajustado para o escore SYNTAX.

Na presente revisão, apesar da clara superioridade da CRM no desfecho de uma nova revascularização, é possível perceber a melhora progressiva dos resultados da ICP. Isso foi particularmente impressionante quando consideramos o desfecho “nova revascularização por procedimentos alternativos”, no qual houve uma tendência à superioridade da ICP na era dos SF.

As evidências apresentadas aqui devem ser utilizadas como informação aos pacientes, ajudando-os na escolha da forma mais adequada de revascularização em pacientes multiarteriais e aqueles com LTCED. Alguns pacientes podem preferir a ICP para evitar a maior morbidade e mortalidade em curto prazo da cirurgia. Outros pacientes podem colocar maior ênfase na superioridade da cirurgia na mortalidade em longo prazo. No entanto, a ICP utilizando SF de segunda geração ainda pode ser considerada uma alternativa à CRM, com resultados de mortalidade semelhantes, para pacientes com LTCED de baixa ou intermediária complexidade (escore SYNTAX < 33). Este também pode ser o caso de pacientes multiarteriais com lesões de baixa complexidade (escore SYNTAX <23). Para todos os outros pacientes, particularmente os diabéticos, a cirurgia continua sendo a melhor forma de revascularização. Existe a possibilidade de que os SF de segunda geração e uma estratégia mais funcional, utilizando a reserva de fluxo fracionada e evitando revascularizações desnecessárias, melhorem os resultados comparativos da ICP no futuro. Os resultados de um ano do estudo SYNTAX II36 sugerem que isso de fato ocorrerá; no entanto, espera-se um seguimento em longo prazo, um estudo randomizado com revascularização miocárdica atual é necessário.

O presente estudo apresenta limitações importantes. É uma metanálise de dados publicados e não uma metanálise colaborativa com acesso a dados individuais de pacientes. A inclusão dos estudos da era SNF também pode ser criticada. Também deve-se observar que a mortalidade em 30 dias e a mortalidade tardia apresentaram heterogeneidade moderada, reduzindo a robustez de nossos resultados. Por outro lado, nossos achados aplicam-se apenas aos pacientes para os quais a revascularização pode ser realizada por qualquer método, sem alto risco cirúrgico, sem histórico de revascularização cirúrgica prévia, com fração de ejeção normal ou quase normal e com os procedimentos realizados em instituições de excelência.

 Conclusão

A ICP com stent quando comparada à CRM foi associada à uma tendência de redução de mortalidade em 30 dias, mortalidade semelhante em um ano, menor incidência de AVC em até um ano e tendência a maior mortalidade em longo prazo. Não houve diferença de mortalidade em longo prazo em não-diabéticos e em pacientes com LTCED. Em termos de desfechos adversos combinados, o escore SYNTAX e a diabetes foram os fatores mais importantes a serem considerados na escolha entre os dois métodos de revascularização.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Aprovação ética e consentimento informado

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.