ijcs International Journal of Cardiovascular Sciences Int. J. Cardiovasc. Sci. 2359-4802 2359-5647 Sociedade Brasileira de Cardiologia vVZZFVb5g6K9cp6SgFx7rXk S2359-56472018000200152 10.5935/2359-4802.20180005 Original Articles Drug-eluting stents Versus Coronary Artery Bypass Grafting in Multivessel Disease and Left Main Obstruction: Meta-analysis of Randomized Clinical Trials Andrade Pedro José Negreiros de 1 2 Rocha Hermano Alexandre Lima 1 3 Falcão João Luiz de Alencar Araripe 1 2 Andrade Antonio Thomaz de 1 Falcão Breno de Alencar Araripe 1 4 Hospital Dr. Carlos Alberto Studart Gomes Fortaleza CE Brazil Hospital Dr. Carlos Alberto Studart Gomes, Messejana, Fortaleza, CE – Brazil Universidade Federal do Ceará Fortaleza CE Brazil Universidade Federal do Ceará (UFC), Fortaleza, CE – Brazil Universidade Federal do Ceará Centro Universitário Christus Fortaleza CE Brazil Centro Universitário Christus, Fortaleza, CE – Brazil Centro Universitário Christus Universidade Estadual do Ceará Fortaleza CE Brazil Universidade Estadual do Ceará (UECE), Fortaleza, CE – Brazil Universidade Estadual do Ceará Mailing Address: Pedro José Negreiros de Andrade, Francisco Holanda, 992, Ap.: 1101. Postal Code 60130-040, Dionisio Torres, Fortaleza, CE – Brazil. E-mail: pedroneg@gmail.com; pedroneg@gmail.com

Author contributions

Conception and design of the research: Andrade PJN. Acquisition of data: Andrade PJN, Falcão JLAA, Andrade AT, Falcão BAA. Analysis and interpretation of the data: Andrade PJN, Rocha HAL, Falcão JLAA, Andrade AT. Statistical analysis: Rocha HAL. Writing of the manuscript: Andrade PJN, Rocha HAL, Falcão JLAA, Falcão BAA. Critical revision of the manuscript for intellectual content: Andrade PJN, Falcão BAA. Supervision / as the major investigador: Andrade PJN.

Potential Conflict of Interest

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

 Mar-Apr 2018 31 2 152 162 13 2 2017 25 5 2017 11 7 2017 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:

The choice between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) remains controversial.

 Objective:

To conduct a meta-analysis of randomized studies comparing drug-eluting stents (DES) and CABG in multivessel disease or obstruction of the left main coronary artery.

 Method:

Electronic databases were searched systematically to evaluate results of randomized trials comparing PCI with DES versus CABG in multivessel disease and obstruction of the left main coronary artery. Ten studies were identified.

 Results:

In the aggregated results (n = 9268), mortality at 30 days and incidence of stroke favored PCI (0.8% versus 1.5%, p = 0.005; 0.4% versus 1.5%, p < 0.0001, respectively). There was no difference in mortality at 1 year (3.4% versus 3.5%, p = 0.50). The late mortality favored CABG (10.1% versus 8.5%, p = 0.01). In patients with diabetes derived from four studies (n = 3830), late mortality favored CABG (12.5% versus 9.7%, p < 0.0001). In six studies of left main coronary artery obstruction (n = 4700), the incidence of stroke favored PCI (0.3% versus 1.5%, p < 0.001) and there was no difference in mortality at 30 days (0.8% versus 1.3%, p = 0.15), mortality at 1 year, or late mortality (8.1% versus 8.1%). The subgroups with high SYNTAX score and diabetes were those influencing most strongly and adversely the PCI results.

 Conclusion:

When compared with PCI, CABG was superior in regards to late mortality and inferior in regards to 30-day mortality and incidence of stroke. Diabetes and SYNTAX score strongly impacted the results.

 Keywords: Myocardial Revascularization Drug Eluting Stents Randomized Controlled Trials as Topic Meta-Analysis Introduction

Percutaneous coronary intervention (PCI or angioplasty) and coronary artery bypass grafting (surgery or CABG) are well-accepted, safe, and effective alternatives in the treatment of coronary insufficiency. A large number of randomized clinical trials has been published comparing both procedures.1-12 In light of these studies, there seems to be a slight superiority of surgery over PCI in the ability to reduce anginal symptoms and a significant difference in its ability to prevent new revascularization procedures. Such studies are generally undersized to evaluate outcomes like death, stroke, and acute myocardial infarction (AMI).

The objective of this study was to perform a meta-analysis of randomized clinical trials comparing PCI and CABG in multivessel disease and obstruction of the left main coronary artery in the era of drug-eluting stents, with emphasis on mortality and stroke.

 Methods

Randomized studies comparing PCI with drug-eluting stents versus CABG in multivessel lesions and/or obstruction of the left main coronary artery published between January 2002 and November 2016 were searched in the databases MEDLINE and Cochrane Library, and in bibliographical references of reviews published on the subject. The date of January 2002 was chosen as the initial period since drug-eluting stents began to be established as a therapeutic method after that. Clinical trials were included in the review if they were randomized, had compared surgery and coronary angioplasty, used drug-eluting stents, involved exclusively multivessel disease or left main coronary artery obstruction, had a minimum follow-up of 1 year, and were published in international journals with an impact factor > 2.0. We used the following terms in the search: coronary artery bypass surgery, coronary stents, and randomized controlled trials. Studies exclusively using balloon or bare-metal stents, or which assessed predominantly one-vessel disease were not included. Studies using drug-eluting and bare-metal stents1,4 were included as studies of the drug-eluting stent era. Works resulting from observational studies (registries) or only published as meetings proceedings were not considered.

We identified 10 randomized studies that satisfied the requirements: LE MANS,1 SYNTAX,2-3 CARDia,4 Boudriot et al.,5 PRECOMBAT,6 VA CARDS,7 FREEDOM,8 BEST,9 NOBLE,10 and EXCEL.11 Three authors (PJNA, BAAF, and JLAAF) evaluated the studies, which were all considered to be of high quality.

The main outcomes of interest were mortality and stroke. The incidence of AMI was not evaluated because the definition of this event varied widely in the studies. We also did not evaluate the incidence of new revascularization, because the superiority of surgery on this outcome is well established. Mortality was divided into early mortality, mortality at 1 year, and late mortality. Early mortality was defined as death occurring up to 30 days after the procedure, including deaths occurring after randomization but before the procedure. This mortality was obtained from seven studies, whereas three studies did not provide this information.2,4,7 Mortality at 1 year was defined as death occurring up to 1 year after the procedure, including early mortality. This mortality was obtained from nine studies, while one study did not provide such information.9 Late mortality was defined as death recorded at the end of follow-up, after at least 3 years. This mortality was obtained from eight studies, six of which performed a follow-up for 5 years, one for 3 years2 and one for 10 years.1 We were unable to obtain this information from two studies.5,7 For the incidence of stroke, we considered the events occurring up to 1 year after the procedure. In eight studies, we obtained the results up to 30 days and in one of them,2 up to 1 year, while in one of the studies, this information was unavailable.9 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.2,4,6,8,9 Combined MACCE comprised death, AMI, and new revascularization in two of these trials,6,9 and death, AMI, and stroke in the remaining ones.

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 drug-eluting stent and the surgery groups, we performed a meta-analysis using the Mantel-Haenszel method, with a fixed-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. The differences between the results in the stent 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).

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. We refrained from using odds ratio or relative risk due to the inclusion of some clinical trials with zero or near zero events.

 Results Characteristics of the trials are shown in <xref ref-type="table" rid="t1">table 1</xref> Overview of randomized studies comparing percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in the era of drug-eluting stents
Study Origin Year of publication Number of patients Disease extension Patients with diabetes(%) Unstable angina(%) Mean ejection fraction (%) Type of stent Follow-up Maximum
LEMANS1 Poland 2008 105 LMCA 25 32 53 ± 11 BMS and DES 10
SYNTAX2 International 2009 1800 LMCA and three-vessel disease 35 28 ND ‡ SF 5
CARDia4 United Kingdom 2010 510 Two- and three-vessel disease 100 22 59 ± 14 BMS and DES 5
Boudriot et al.5 Germany 2011 201 LMCA 30 ND ND DES 1
PRECOMBAT6 South Korea 2011 600 LMCA 42 45 60 ± 9 DES 5
FREEDOM8 International 2012 1900 Two- and three-vessel disease 100 30 65 ± 12 DES 5
Va-Cards7 USA 2013 198 Two- and three-vessel disease 100 ND ND† DES 2
BEST9 South Korea 2015 880 Two- and three-vessel disease 45 42 59 ± 9 DES 5
EXCEL11 International 2016 1905 LMCA 25 37 57 ± 10 DES 3
NOBLE10 Europe 2016 982 LMCA 18 18 60 ± 10 DES 5

SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; CARDia: Coronary Artery Revascularization in Diabetes; LE MANS: Left Main Coronary Artery Stenting; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; VA CARDS: Coronary Artery Revascularization in Diabetes; 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; Boudriot - study by Boudriot et al.: J Am Coll Cardiol. 2011; 57: 538-545; DES: drug-eluting stent; BMS: bare-metal stent; LMCA: left main coronary artery; USA: United States.

37% with ejection fraction < 55%

3% with ejection fraction < 30%.

The studies included a total of 9268 patients (4642 in the stent group and 4626 in the CABG group). The mean age of the patients was 64 years, 75% were male, 51% were diabetic, 24% were smokers, 64% were hypertensive, and 31% had unstable angina. The mean ejection fraction (reported in seven studies) was 59%, the mean EuroSCORE (reported in five studies) was 2.9, and the mean SYNTAX score (reported in seven studies) was 26. In regards to the number of affected vessels, 7% affected only two vessels, 43% affected only three vessels, and 50% presented obstruction of the left main coronary artery, associated or not with disease in other vessels. Some characteristics of the studies deserve special mention: the LE MANS1 used drug-eluting and bare-metal stents, reserving the drug-eluting stents for left main coronary arteries with a reference diameter < 3.8 mm; CARDia4 used initially bare-metal stents and only assessed patients with diabetes and multivessel disease; SYNTAX2 evaluated left main coronary artery obstruction and multivessel disease and used first-generation drug-eluting stents (TAXUS); FREEDOM8 and VA CARDS7 exclusively assessed patients with diabetes and multivessel disease; BEST9 evaluated patients with multivessel disease and used only everolimus-eluting stents; the study by Boudriot et al.,5 evaluated left main coronary artery obstruction and used only sirolimus-eluting stents; EXCEL11 evaluated left main coronary artery obstruction and used only everolimus-eluting stents; NOBLE10 evaluated left main coronary artery obstruction and used mostly a biolimus-eluting stent.

 Outcomes

The outcomes are summarized in Figures 1 to 6. The incidence of stroke up to 1 year had a low heterogeneity (I2 = 0). The results favored PCI (0.4% versus 1.5%, p < 0.00001). In regards to 30-day mortality, the studies showed low heterogeneity (I2 = 0) and favored the stent group (0.8% versus 1.5%, p = 0.005). As for mortality up to 1 year, the studies presented low heterogeneity (I2 = 0%) and no difference between the groups (3.4% versus 3.5%, p = 0.50). In late mortality, the studies showed low heterogeneity (I2 = 0%) and favored CABG (10.1% versus 8.5%, p = 0.01). After exclusion of patients with diabetes from four studies (SYNTAX,2 FREEDOM,8 BEST,9 and CARDIa4), the differences in late mortality tended to disappear (8.5% versus 8.1%, p = 0.6).

Mortality at 30 days: stent versus coronary artery bypass grafting.

The size of the squares is proportional to the number of patients. The bars represent 95% confidence intervals. The diamond represents the synthesis of the results.

Abbreviations: CABG: coronary artery bypass grafting; LE MANS: Left Main Coronary Artery Stenting; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; 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; Boudriot: study by Boudriot et al. : J Am Coll Cardiol. 2011; 57: 538-545. Graph obtained using the software Review Manager (RevMan), version 5.3.

Mortality at 1 year: stent versus coronary artery bypass grafting.

The size of the squares is proportional to the number of patients. The bars represent 95% confidence intervals. The diamond represents the synthesis of the results.

Abbreviations: CABG: coronary artery bypass grafting; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; CARDia: Coronary Artery Revascularization in Diabetes; LE MANS: Left Main Coronary Artery Stenting; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; VA CARDS: Coronary Artery Revascularization in Diabetes; BEST: Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease; NOBLE: Nordic-Baltic-British Left Main Revascularization; Boudriot: study by Boudriot et al.: J Am Coll Cardiol. 2011; 57: 538-545. Graph obtained using the software Review Manager (RevMan), version 5.3.

Late mortality: stent versus coronary artery bypass grafting.

The size of the boxes is proportional to the number of patients. The bars represent 95% confidence intervals. The diamond represents the synthesis of the results.

Abbreviations: CABG: coronary artery bypass grafting; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; CARDia: Coronary Artery Revascularization in Diabetes; LE MANS: Left Main Coronary Artery Stenting; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; VA CARDS: Coronary Artery Revascularization in Diabetes; 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; Boudriot: study by Boudriot et al. : J Am Coll Cardiol. 2011; 57: 538-545. Graph obtained using the software Review Manager (RevMan), version 5.3.

Stroke: stent versus coronary artery bypass grafting.

The size of the boxes is proportional to the number of patients. The bars represent 95% confidence intervals. The diamond represents the synthesis of the results.

Abbreviations: CABG: coronary artery bypass grafting; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; CARDia: Coronary Artery Revascularization in Diabetes; LE MANS: Left Main Coronary Artery Stenting; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; VA CARDS: Coronary Artery Revascularization in Diabetes; 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; Boudriot: study by Boudriot et al. : J Am Coll Cardiol. 2011; 57: 538-545. Graph obtained using the software Review Manager (RevMan), version 5.3.

Studies including the left main coronary artery. Mortality at 1 year: Stent versus coronary artery bypass grafting.

The size of the boxes is proportional to the number of patients. The bars represent 95% confidence intervals. The diamond represents the synthesis of the results.

Abbreviations: CABG: coronary artery bypass grafting; LE MANS: Left Main Coronary Artery Stenting; SYNTAX LM: left main coronary artery subgroup of SYNTAX (Synergy between PCI with Taxus and Cardiac 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; Boudriot: study by Boudriot et al. : J Am Coll Cardiol. 2011; 57: 538-545. Graph obtained using the software Review Manager (RevMan), version 5.3.

Studies including the left main coronary artery. Late mortality: stent versus coronary artery bypass grafting.

The size of the boxes is proportional to the number of patients in the trial. The bars represent 95% confidence intervals. The diamond represents the synthesis of the results.

Abbreviations: CABG: coronary artery bypass grafting; LE MANS: Left Main Coronary Artery Stenting; SYNTAX LM: left main coronary artery subgroup of SYNTAX (Synergy between PCI with Taxus and Cardiac 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; Boudriot: study by Boudriot et al. : J Am Coll Cardiol. 2011; 57: 538-545. Graph obtained using the software Review Manager (RevMan), version 5.3.

In the six studies evaluating left main coronary artery obstruction (LE MANS,1 SYNTAX LEFT MAIN,12 PRECOMBAT,6 EXCEL,11 NOBLE,10 and the study by Boudriot et al.,5) totaling 4700 patients, there was no difference in mortality at 30 days (0.8% versus 1.4%, p = 0.15), 1 year (3.0% versus 3.7%, p = 0.18), or in late mortality (8.1% versus 8.1%). There was a significant difference in favor of the stent group in the incidence of stroke (0.3% versus 1.5%, p < 0.0001).

Four studies reported late mortality in patients with diabetes (SYNTAX,3 CARDIa,4 FREEDOM,8 and BEST9). In the combined results (n = 3223), mortality up to 5 years was 12.5% in the stent group versus 9.7% in the surgery group (p < 0.0001).

Five studies provided the outcomes of the late incidence of combined adverse events (MACCE) divided into subgroups, which are represented in Figure 7. The combined MACCE outcomes in these subgroups (Figure 7) show that a SYNTAX score in the upper tertile and the occurrence of diabetes had a strong negative influence on the PCI outcome. In patients in the lower SYNTAX tertile and in those without diabetes, there was no significant difference in terms of MACCE between the CABG and PCI groups. The elderly condition and the female gender contributed to the difference in results but to a lesser degree. An ejection fraction < 50% did not contribute significantly to the difference in results.

Combined adverse events outcomes (major adverse cardiovascular and cerebrovascular disease events, MACCE) in subgroups in five studies.

The size of each box is proportional to the number of patients in the subgroup. The bar is equal to the confidence interval. The diamonds represent the synthesis of the results. In the SYNTAX, FREEDOM, and EXCEL, the combined events were death, acute myocardial infarction (AMI), and stroke. In the remaining studies, they were death, AMI, and new revascularization.

Abbreviations: CABG: coronary artery bypass grafting; SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; 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. Graph obtained using the software Review Manager (RevMan), version 5.3.

 Discussion

Several systematic reviews, collaborative studies, and meta-analyses13-18 have been published comparing PCI and CABG. The most important ones included studies of the balloon and bare-metal stent era or left out important recent studies.14-16 The main differential of the present meta-analysis is the large number of included studies and patients and the fact that it is up-to-date and included only trials of the drug-eluting stent era.

In the evaluation of the results, it is important to highlight the superiority of PCI in the mortality at 30 days. This is in line with a prior systematic review17 and with the New York registry.19 The difference is obviously not applicable to patients with lesions of high angiographic complexity, as seen in the analysis of the survival curves of aggregated results from SYNTAX LM and PRECOMBAT.20 A greater incidence of stroke in the surgical group had already been suggested in prior systematic reviews,14,17 and in the light of the data presented here, this fact becomes indisputable. It is worth mentioning a reduced incidence of stroke in more recent studies, reflecting a greater care taken by surgeons while manipulating the aorta. The similarity of the mortality results at 1 year is aligned with a prior systematic review, which included studies of the era prior to drug-eluting stents.17 The difference favoring surgery in regards to late mortality is consistent with another meta-analysis16 and also with a recently published collaborative study.21 It should be emphasized that the difference found was due to the large number of patients with diabetes in the studies of the drug-eluting stent era, which disappeared in the aggregated results when these studies were excluded. These data confirm those of the collaborative study by Hlatki et al.,15, which demonstrated a lower overall mortality at 5 years with surgery, but no difference among nondiabetic patients. We should emphasize that the study by Hlatki et al.,15 included trials of the balloon era in which two-vessel disease predominated, while in the present review there was a predominance of three-vessel disease and obstruction of the left main coronary artery.

In regards to the results of obstruction of the left main coronary artery, it is important to remember that the group of patients with this type of obstruction comprised for a long time a forbidden territory for angioplasty. LE MANS was the first randomized study that attempted to compare stent and surgery in left main coronary artery obstruction, with results similar or even superior to those with PCI. However, this was a small study (105 patients), which has been criticized for not having used grafting of internal thoracic artery in approximately 25% of the cases. After that, emerged the results of the SYNTAX12 subgroup with left main coronary artery obstruction and of the PRECOMBAT trial and the study by Boudriot et al.,5, which led to the improvement of the recommendations of PCI in left main artery obstruction. Despite that, the American guidelines only changed the recommendation to IIA in patients with a low SYNTAX score and IIB in patients with intermediate SYNTAX scores.18 We should emphasize that such recommendations are restricted to patients with a high surgical risk. In the present study, which combined the results of six studies with 4700 patients, the outcomes of PCI with drug-eluting stents were equal or even greater than those with CABG. In light of these evidence and recent results of NOBLE and EXCEL, we believe that the American and Brazilian guidelines22,23 may be soon modified to improve the classification of PCI with drug-eluting stents, mainly in left main coronary artery obstruction.

In relation to the results in patients with diabetes, it is important to remember that the evidence contrary to PCI in diabetes has its origin in the balloon era, from occasional findings of the BARI study. The investigators of this study evaluated a subgroup of 343 patients with diabetes and found a late mortality of 34.5% for PCI with balloon and 19.4% for surgery (p = 0.03). In the era of conventional stent, studies such as SoS and ARTS have confirmed a trend toward greater mortality with PCI in patients with diabetes, even though it did not reach statistical significance. From there onwards, the presence of diabetes has become a criterion for preferential indication of surgery as a method for myocardial revascularization. There used to be a hypothesis that drug-eluting stents would eliminate the differences in mortality found in these studies, but the results presented here demonstrate that the difference in mortality between PCI and surgery in patients with diabetes continues in the era of drug-eluting stents. However, it should be noted a reduced risk difference compared with previous studies (3.5% risk difference as opposed to 7.3% in the study by Hclatki et al., and 15.1% in BARI). This should raise the hypothesis that it is not the metabolic disorder in itself, but the complexity of the lesions which is the factor leading to a higher mortality of angioplasty in patients with diabetes. This question could perhaps be explained by a meta-analysis of individual patient data involving a large number of studies. In this sense, a recent collaborative study categorizing the results of three studies (SYNTAX, BEST, and PRECOMBAT) corroborated this hypothesis.24

The MACCE outcomes in subgroups (Figure 7) in the present study demonstrate that the SYNTAX score in the upper tertile strongly and negatively influenced the PCI outcomes, similarly to the presence of diabetes. The elderly condition and the female gender had a small influence on the results; an ejection fraction < 50% did not negatively influence the PCI outcomes, but an ejection fraction < 35% had a greater impact, even though it had no statistical significance. These results are in agreement with those of the collaborative study by Cavalcante et al.,20 In that study, by aggregating the results of the SYNTAX LEFT MAIN and PRECOMBAT for combined adverse events (death, stroke, AMI, and new revascularization), a high SYNTAX score, like diabetes, had an important role. The female gender, elderly condition, ejection fraction < 50%, and renal insufficiency did not negatively affect the results compared with PCI. This same study showed that the subgroups most significantly affecting PCI-associated mortality outcomes in obstruction of the left main coronary artery were those with two- or three-vessel disease and with a SYNTAX score > 32. Diabetes had a less important role, possibly related to the fact that only patients with left main coronary artery obstruction were evaluated.

Study limitations

This study has important limitations. Because the meta-analysis included published data rather than individual patient data, we were unable to analyze the mortality outcomes in subgroups, except in those with diabetes. Additionally, the percentages had to be processed as absolute numbers, which may deserve criticism. The results apply only to patients in whom revascularization is possible by both methods and without a high surgical risk or history of prior surgical revascularization, and with the procedures carried out in institutions of excellence.

 Conclusion

In combined results of randomized studies involving multivessel disease or obstruction of the left main coronary artery, PCI with drug-eluting stent was associated with a lower incidence of stroke, lower mortality at 30 days, and increased late mortality when compared with CABG. There was no difference in early, intermediate, or late mortality in the subgroup with left main coronary obstruction, but there was a difference in favor of PCI in regards to the incidence of stroke. The presence of diabetes and a high SYNTAX score were factors most strongly and negatively impacting PCI outcomes in terms of combined adverse results.

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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Boudriot E Thiele TW Liebetrau C Boeckstegers P Pohl T Reichart B Randomized comparison of percutaneous coronary intervention with Sirolimus eluting stents versus coronary artery bypass grafting in unprotected in unprotected left main stenosis J Am Coll Cardiol 2011 57 5 538 545 10.1016/j.jacc.2010.09.038 6 Park SJ, Kim YH, Park DW, Yun SC, Ahn JM, Song HG, et al. Randomized trial of stents versus bypass surgery for left main coronary artey disease. N Engl J Med. 2011;364(18):1718-27. doi: 10.1056/NEJMoa1100452. Park SJ Kim YH Park DW Yun SC Ahn JM Song HG Randomized trial of stents versus bypass surgery for left main coronary artey disease N Engl J Med 2011 364 18 1718 1727 10.1056/NEJMoa1100452 7 Kamalesh M, Shap TG, Tamg XC, Shunk K, Ward HB, Walsh J, et al. Percutaneous coronary intervention versus coronary artery bypass surgery in United States veterans with diabetes. J Am Coll Cardiol. 2013;61(8):808-16. doi: 10.1016/j.jacc.2012.11.044. Kamalesh M Shap TG Tamg XC Shunk K Ward HB Walsh J Percutaneous coronary intervention versus coronary artery bypass surgery in United States veterans with diabetes J Am Coll Cardiol 2013 61 8 808 816 10.1016/j.jacc.2012.11.044 8 Farkouh ME, Dornanski M, Sleeper LA, Siami FS, Dangas G, Mack M, et al; FREEDOM Trial Investigators. Strategies for multivessel revascularization in diabetes. N Engl J Med. 2012;367(25):2375-84. doi: 10.1056/NEJMoa1211585. Farkouh ME Dornanski M Sleeper LA Siami FS Dangas G Mack M FREEDOM Trial Investigators Strategies for multivessel revascularization in diabetes N Engl J Med 2012 367 25 2375 2384 10.1056/NEJMoa1211585 9 Park SJ, Ahn KM, Kim YH, Park DW, Yun SC, Lee JY, et al: BEST Trial Investigators. Trial of everolimus-eluting stents or bypass surgery for coronary artery disease. N Engl J Med. 2015; 372(13):1204-12. doi: 10.1056/NEJMoa1415447. Park SJ Ahn KM Kim YH Park DW Yun SC Lee JY BEST Trial Investigators Trial of everolimus-eluting stents or bypass surgery for coronary artery disease N Engl J Med 2015 372 13 1204 1212 10.1056/NEJMoa1415447 10 Makikallio T, Holm NR, Liundsay M, Sprnce MS, Erglis A, Menown IB, et al; NOBLE study investigators. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE) a prospective, randomized, open-label, non-inferiority trial. Lancet. 2016;388(10061):2743-2752. doi: 10.1016/S0140-6736(16)32052-9. Makikallio T Holm NR Liundsay M Sprnce MS Erglis A Menown IB NOBLE study investigators Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE) a prospective, randomized, open-label, non-inferiority trial Lancet 2016 388 10061 2743 2752 10.1016/S0140-6736(16)32052-9 11 Stone GW, Sabik JF, Serruys PW, Simonton CA, Genereux P, Puskas J, et al; EXCEL Trial Investigators. Everolimus-stenting or bypass surgery for left main coronary artery disease. N Engl J Med. 2016;375(23):2223-35. doi: 10.1056/NEJMoa1610227. Stone GW Sabik JF Serruys PW Simonton CA Genereux P Puskas J EXCEL Trial Investigators Everolimus-stenting or bypass surgery for left main coronary artery disease N Engl J Med 2016 375 23 2223 2235 10.1056/NEJMoa1610227 12 Morice MC, Serruys PW, Kappetein AP, Feldman TE, Ståhle E, Colombo A, et al. Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial. Circulation. 2014;129(23):2388-94. doi: 10.1161/CIRCULATIONAHA.113.006689. Morice MC Serruys PW Kappetein AP Feldman TE Ståhle E Colombo A Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial Circulation 2014 129 23 2388 2394 10.1161/CIRCULATIONAHA.113.006689 13 Daemen J, Boersma E, Flather M, Bonth J, Stables R, Rodrigues A, et al. Long-term safety and efficacy of percutaneous coronary intervention with stenting and coronary artery bypass surgery for multivessel coronary artery disease: a meta-analysis with 5-year patient-level data from the ARTS, ERACI-II, MASS-II, and SoS trials. Circulation. 2008;118(11):1146-54. doi: 10.1161/CIRCULATIONAHA.107.752147. Daemen J Boersma E Flather M Bonth J Stables R Rodrigues A Long-term safety and efficacy of percutaneous coronary intervention with stenting and coronary artery bypass surgery for multivessel coronary artery disease: a meta-analysis with 5-year patient-level data from the ARTS, ERACI-II, MASS-II, and SoS trials Circulation 2008 118 11 1146 1154 10.1161/CIRCULATIONAHA.107.752147 14 Bravata DM, Gienger AL, McDonad KM, Vandana S, Perez MV, Varguese R, et al. Sistematic review: the comparative effectiveness of percutaneous coronary intervention and coronary artery bypass surgery. Ann Intern Med. 2007;147(10):703-6. PMID: 17938385. Bravata DM Gienger AL McDonad KM Vandana S Perez MV Varguese R Sistematic review: the comparative effectiveness of percutaneous coronary intervention and coronary artery bypass surgery Ann Intern Med 2007 147 10 703 706 17938385 15 Hlatky MA, Boothroyd DB, Bravata DM, Buersma E, Bonth E, Brooks MM, et al Coronary angioplasty compared with percutaneous coronary interventions for multivessel diseases: a colaborative analysis of individual patient data from ten randomized trials. Lancet. 2009;373(9670):1190-7. doi: 10.1016/S0140-6736(09)60552-3. Hlatky MA Boothroyd DB Bravata DM Buersma E Bonth E Brooks MM Coronary angioplasty compared with percutaneous coronary interventions for multivessel diseases: a colaborative analysis of individual patient data from ten randomized trials Lancet 2009 373 9670 1190 1197 10.1016/S0140-6736(09)60552-3 16 Smit Y, Valyen J, Kopennaal H, Edfting F, Kappetein P, Mariani MA. Percutaneous coronary invervention versus coronary artery bypass grafting: a Meta-analysis. J Thorac Cardiovasc Surg. 2015;149(3):831-8.e1-13. doi: 10.1016/j.jtcvs.2014.10.112. Smit Y Valyen J Kopennaal H Edfting F Kappetein P Mariani MA Percutaneous coronary invervention versus coronary artery bypass grafting: a Meta-analysis J Thorac Cardiovasc Surg 2015 149 3 831 838 10.1016/j.jtcvs.2014.10.112 17 Andrade PJ, Medeiros, MM, Andrade AT, Lima AA. Coronary Angioplasty versus CABG: review of randomized trials. Arq Bras Cardiol. 2011;97(3):e60-9. doi: http://dx.doi.org/10.1590/S0066-782X2011001200021 Andrade PJ Medeiros MM Andrade AT Lima AA Coronary Angioplasty versus CABG: review of randomized trials Arq Bras Cardiol 2011 97 3 e60 e69 http://dx.doi.org/10.1590/S0066-782X2011001200021 18 Andrade PJ, Silva RP, Lima AA, Andrade AT, Rodrigues Sobrinho CR. Drug-eluting stents versus coronary artery bypass-graft surgery: meta-analysis of prospective clinical trials. Rev Bras Cardiol. 2013;25(3):210-7. Andrade PJ Silva RP Lima AA Andrade AT Rodrigues CR Sobrinho Drug-eluting stents versus coronary artery bypass-graft surgery: meta-analysis of prospective clinical trials Rev Bras Cardiol 2013 25 3 210 217 19 Bangalore S, Guo Y, Samadashvili Z, Blecker S, Xu J, Hannan EL. Everolimus-eluting stents or bypass surgery for multivessel coronary disease. N Engl J Med. 2015;372(13):1213-22. doi: 10.1056/NEJMoa1412168. Bangalore S Guo Y Samadashvili Z Blecker S Xu J Hannan EL Everolimus-eluting stents or bypass surgery for multivessel coronary disease N Engl J Med 2015 372 13 1213 1222 10.1056/NEJMoa1412168 20 Cavalcante R, Sotomi Y, Lee CW, Ahn JM, Farooq V, Tateishi H. Outcomes after percutaneous coronary intervention and bypass surgery in patients with unprotected left main disease. J Am Coll Cardiol. 2016;68(10):999-1009. doi: 10.1016/j.jacc.2016.06.024. Cavalcante R Sotomi Y Lee CW Ahn JM Farooq V Tateishi H Outcomes after percutaneous coronary intervention and bypass surgery in patients with unprotected left main disease J Am Coll Cardiol 2016 68 10 999 1009 10.1016/j.jacc.2016.06.024 21 Lee CW, Ahn JM, Cavalcante R, Sotomi Y, Onuma Y. Coronary artery bypass surgery versus drug-eluting stent implantation for left main or multivessel coronary artery disease. A meta-analysis of individual patient data. JACC Cardiovasc Interv. 2016;9(24):2481-2489. doi: 10.1016/j.jcin.2016.10.008. Lee CW Ahn JM Cavalcante R Sotomi Y Onuma Y Coronary artery bypass surgery versus drug-eluting stent implantation for left main or multivessel coronary artery disease. A meta-analysis of individual patient data JACC Cardiovasc Interv 2016 9 24 2481 2489 10.1016/j.jcin.2016.10.008 22 Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, et al. Special Articles: 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Anesth Analg. 2012;114(1):11-45. doi: 10.1213/ANE.0b013e3182407c25. Hillis LD Smith PK Anderson JL Bittl JA Bridges CR Byrne JG Special Articles: 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Anesth Analg 2012 114 1 11 45 10.1213/ANE.0b013e3182407c25 23 Mattos LA, Lemos Neto PA, Rassi A Jr, Marin-Neto JA, Sousa AG, Devito FS, et al; Sociedade Brasileira de Cardiologia. Diretrizes sobre intervenção percutânea e métodos adjuntos diagnósticos em cardiologia intervencionista (II Edição). Arq Bras Cardiol. 2008;91(6 supl 1):1-58. Mattos LA Lemos PA Neto Rassi A Jr Marin-Neto JA Sousa AG Devito FS Sociedade Brasileira de Cardiologia Diretrizes sobre intervenção percutânea e métodos adjuntos diagnósticos em cardiologia intervencionista (II Edição) Arq Bras Cardiol 2008 91 6 Suppl 1 1 58 24 Cavalcante R, Sotomi Y, Mancone M, Whan Lee C, Ahn JM, Onuma Y, et al. Impact of the SYNTAX scores I and II in patients with diabetes and multivessel coronary disease: a pooled analysis of patient level data from the SYNTAX, PRECOMBAT, and BEST trials. Eur Heart J. 2017;38(25):1969-77. doi: 10.1093/eurheartj/ehx138. Cavalcante R Sotomi Y Mancone M Whan Lee C Ahn JM Onuma Y Impact of the SYNTAX scores I and II in patients with diabetes and multivessel coronary disease: a pooled analysis of patient level data from the SYNTAX, PRECOMBAT, and BEST trials Eur Heart J 2017 38 25 1969 1977 10.1093/eurheartj/ehx138 Artigos Originais Stents farmacológicos versus Cirurgia de Revascularização Miocárdica em Multiarteriais e Obstrução de Tronco: Meta-Análise de Ensaios Clíncos Aleatorizados Andrade Pedro José Negreiros de 1 2 Rocha Hermano Alexandre Lima 1 3 Falcão João Luiz de Alencar Araripe 1 2 Andrade Antonio Thomaz de 1 Falcão Breno de Alencar Araripe 1 4 Hospital Dr. Carlos Alberto Studart Gomes, Messejana, Fortaleza, CE – Brasil Universidade Federal do Ceará (UFC), Fortaleza, CE – Brasil Centro Universitário Christus, Fortaleza, CE – Brasil Universidade Estadual do Ceará (UECE), Fortaleza, CE – Brasil Correspondência: Pedro José Negreiros de Andrade, Rua Francisco Holanda, 992, Ap.: 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: Andrade PJN. Obtenção de dados: Andrade PJN, Falcão JLAA, Andrade AT, Falcão BAA. Análise e interpretação dos dados: Andrade PJN, Rocha HAL, Falcão JLAA, Andrade AT. Análise estatística: Rocha HAL. Redação do manuscrito: Andrade PJN, Rocha HAL, Falcão JLAA, Falcão BAA. Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Andrade PJN, Falcão BAA. Supervisão / como investigador principal: Andrade PJN.

Potencial Conflito de Interesse

Declaro não haver conflito de interesses pertinentes.

 Resumo Fundamento:

A escolha entre intervenção coronária percutânea (ICP) e cirurgia de revascularização miocárdica (CRM) continua controversa.

 Objetivo:

Realizar uma meta-análise dos estudos randomizados que compararam stents farmacológicos (SF) a cirurgia de revascularização miocárdica (CRM) em multiarteriais ou obstrução de tronco de coronária esquerda.

 Método:

Bases de dados eletrônicas foram pesquisadas sistematicamente com objetivo de avaliar resultados de estudos aleatorizados que compararam ICP com uso de SF a CRM em multiarteriais e obstrução de tronco de coronária esquerda. Dez estudos foram identificados.

 Resultados:

Na agregação de resultados (n = 9268) a mortalidade em 30 dias e a incidência de acidente vascular encefálico (AVE) favoreceram a ICP (0,8% versus 1,5%, p = 0,005; 0,4% versus 1,5%, p < 0,0001). Não houve diferença na mortalidade em um ano (3,4% versus 3,5%. p = 0,50). A /mortalidade tardia favoreceu a CRM (10,1% versus 8,5%, p = 0,01). Em diabéticos de quatro estudos (n = 3830); a mortalidade tardia favoreceu a CRM (12,5% versus 9,7% p < 0,0001). Em seis estudos de obstrução de tronco (n = 4700) a incidência de AVE favoreceu a ICP (0,3% versus 1,5%; p < 0,001); não houve diferença na mortalidade em 30 dias (0,8% versus 1,3%. p = 0,15), na mortalidade em um ano nem na mortalidade tardia (8,1% versus 8,1%). Escore de SYNTAX elevado e diabete foram os subgrupos que influenciaram mais fortemente de forma adversa os resultados da ICP.

 Conclusão:

CRM foi superior a ICP na mortalidade tardia e inferior na mortalidade em 30 dias e na incidência de AVE. Diabete e escore de SYNTAX impactaram fortemente nos resultados.

 Palavras-chave: Revascularização Miocárdica Stents Farmacológicos Ensaios Clínicos Aleatórios como Assunto Metanálise Introdução

Intervenção coronária percutânea (ICP ou angioplastia) e cirurgia de revascularização miocárdica (cirurgia ou CRM) são alternativas bem aceitas, seguras e efetivas de tratamento da insuficiência coronariana. Grande número de ensaios clínicos aleatorizados foi publicado comparando os dois procedimentos.1-12 À luz desses estudos parece haver ligeira superioridade da cirurgia sobre a ICP na capacidade de reduzir sintomas anginosos e significativa diferença na capacidade de evitar novos procedimentos de revascularização. Tais estudos são geralmente subdimensionados para avaliar desfechos como morte, acidente vascular encefálico (AVE) e infarto agudo do miocárdio (IAM). O objetivo do presente trabalho foi realizar uma meta análise dos ensaios clínicos aleatorizados que compararam ICP a CRM em multiarteriais e em obstrução de tronco de coronária esquerda na era stent farmacológico com ênfase em mortalidade e AVE.

 Métodos

Foram pesquisados nas bases de dados MEDLINE, Cochrane Library e em referências bibliográficas de trabalhos de revisão sobre o assunto estudos aleatorizados comparando ICP com stents farmacológicos a CRM em multiarteriais e/ou obstrução de tronco de coronária esquerda que tivessem sido publicados no período entre janeiro de 2002 e novembro de 2016. Janeiro de 2002 foi escolhido como período inicial devido a stents farmacológicos terem começado a se estabelecer como método terapêutico a partir dessa data. Os critérios para o ensaio clínico entrar na revisão foram: ele deveria ser aleatorizado, deveria comparar cirurgia a angioplastia coronariana, ter utilizado stents farmacológicos, ter envolvido exclusivamente multiarteriais ou obstrução de tronco, ter seguimento de pelo menos um ano e ter sido publicado em revistas internacionais com impacto superior a 2,0. Na busca foram utilizados os seguintes termos: coronary artery bypass surgery , coronary stents e randomized controlled trials. Estudos que usaram apenas balão apenas balão ou exclusivamente stents não farmacológicos, ou que avaliaram predominantemente uni-arteriais não foram considerados. Estudos que utilizaram stents farmacológicos e não farmacológicos1,4 foram aceitos como estudos da era stent farmacológico. Trabalhos resultantes de estudos observacionais (registros) ou publicados apenas em anais de Congressos não foram considerados.

Foram identificados 10 estudos randomizados que satisfaziam as exigências: LE MANS,1 SYNTAX,2,3 CÁRDia,4 Boldriot et al., 5 PRECOMBAT,6 Va-Cards,7 FREEDOM,8 BEST,9 NOBLE10 e EXCEL.11

Os principais desfechos de interesse foram mortalidade e AVE. Não foi avaliada a incidência de infarto agudo do miocárdio (IAM) porque sua definição variou amplamente nos estudos, nem de nova revascularização, por ser evidente a superioridade da cirurgia neste desfecho. A mortalidade foi dividida em mortalidade precoce, mortalidade em um ano e mortalidade tardia. A mortalidade precoce foi definida como a que ocorreu até 30 dias após o procedimento, incluindo as mortes ocorridas depois da randomização mas, antes do procedimento. Ela foi obtida em 7 estudos. Em três estudos não foi possível obter essa informação.2,4,7 A mortalidade em um ano foi definida como a que ocorreu até um ano pós-procedimento, incluindo a mortalidade precoce. Ela foi obtida em 9 estudos. Em um não foi possível obter essa informação.9 A mortalidade tardia foi definida como a registrada ao fim do seguimento, depois de um acompanhamento de pelo menos três anos. Ela foi obtida em 8 estudos. Em seis estudos o acompanhamento foi de cinco anos , em um de três anos2 e em um de dez anos.1 Em dois estudos não foi possível obter essa informação.5,7 Para a incidência de AVE foram considerados os ocorridos até um ano pós-procedimento. Em oito estudos foram obtidos os resultados até 30 dias e em um2 os de até um ano. Em um não foi possível obter essa informação.9 Foram avaliados separadamente os resultados de estudos de tronco de coronária esquerda e a mortalidade tardia no subgrupo de diabéticos Foi feita também análise de eventos adversos combinados maiores(MACCE) e realizada análise para as variáveis idade, sexo, presença de diabetes, escore SYNTAX e fração de ejeção comprometida em subgrupos a partir de dados publicados em cinco ensaios2,4,6,8,9 Em dois deles,6,9 os eventos adversos combinados foram morte, IAM e nova revascularização e nos demais morte, IAM e AVE.

Na agregação de resultados de mortalidade e AVE, assim como de MACCE em subgrupos sempre que possível foram considerados o número absoluto de eventos e de pacientes acompanhados. Caso contrário, percentuais foram transformados em números absolutos.

Análise estatística

Foram medidos o risco relativo e a diferença de risco no agrupamento de resultados de cada um dos desfechos. Para avaliação do significado estatístico das diferenças entre o grupo stent farmacológico e o grupo cirurgia foi realizada meta-análise pelo método de Mantel-Haenszel, com modelo de efeitos fixos. Foram calculadas a heterogeneidade dos estudos através do teste Q de Cochran e a significância da medida de efeito meta-analitíco através do teste Z. As diferenças entre os resultados do grupo stent e do grupo CRM foram consideradas significativas se p < 0,05.

As análises estatísticas foram feitas através do programa Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Para a representação da heterogeneidade dos estudos foram construídos gráficos tipo Forest Plot. Na construção desses gráficos foi utilizada a diferença de risco por ser um índice mais estável. Não foram utilizadas a razão de chances nem o risco relativo devido a existência de alguns ensaios clínicos com número de eventos zero ou próximo de zero.

 Resultados Características dos estudos são mostradas na <xref ref-type="table" rid="t2">tabela 1</xref>

Os estudos envolveram um total de 9268 pacientes, 4642 no grupo stent e 4626 no grupo CRM. A média de idade foi de 64 anos; 75% eram do sexo masculino; 51% eram diabéticos; 24% eram tabagistas; 64% hipertensos; 31% apresentavam angina instável; a fração de ejeção média (reportada em sete estudos) foi de 59%; o Euroscore médio (reportado em cinco estudos) foi de 2,9; o SYNTAX escore médio (reportado em sete estudos) foi 26. No que toca ao numero de vasos comprometidos cerca de 7% eram bi arteriais apenas, 43% eram tri arteriais apenas e 50 % tinham obstrução de tronco de coronária esquerda, associado ou não a doença de outros vasos. Algumas características dos estudos merecem destaque: o LE MANS,1 utilizou stents farmacológicos e não farmacológicos, reservando os stents farmacológicos para tronco < 3.8 mm; o CARDia4 usou inicialmente stents não farmacológicos e avaliou apenas diabéticos multiarteriais. O SINTAX2 avaliou tronco e multiarteriais e usou stents farmacológicos de primeira geração (Taxus); o FREEDOM8 e o VaCards7 avaliaram exclusivamente diabéticos multiarteriais; o BEST9 avaliou multiarteriais e usou apenas stents farmacológicos do tipo everolimus. O estudo de Boldriot et al.,5 avaliou tronco e usou apenas Stents Sirolimus. O EXCEL11 avaliou tronco e usou apenas stents farmacológicos do tipo everolimus; o NOBLE10 avaliou tronco e usou na maioria dos casos stents do tipo Biolimus.

Visão geral dos estudos aleatorizados que compararam ICP a CRM na era stent farmacológico
Estudo Origem Ano de publicação Número de pacientes Extensão da doença Diabeticos% Angina instável% Fração de ejeção média% Tipo de stent Seguimento Máximo
LEMANS1 Polônia 2008 105 Tronco de CE 25 32 53 ± 11 SNFe SF 10
SYNTAX2 Internacional 2009 1800 Tronco de CE e doença de 3 vasos. 35 28 ND ‡ SF 5
CARDia4 Reino Unido 2010 510 Doença de 2 e 3 vasos 100 22 59 ± 14 SNF e SF 5
Boudriot et al.5 Alemanha 2011 201 Tronco de CE 30 ND ND SF 1
PRECOMBAT6 Coréia 2011 600 Tronco de CE 42 45 60 ± 9 SF 5
FREEDOM8 Internacional 2012 1900 Doença de 2 e 3 vasos 100 30 65 ± 12 SF 5
Va-Cards7 EEUU 2013 198 Doença de 2 e 3 vasos 100 ND ND† SF 2
BEST9 Coréia 2015 880 Doença de 2 e 3 vasos 45 42 59 ± 9 SF 5
EXCEL11 Internacional 2016 1905 Tronco de CE 25 37 57 ± 10 SF 3
NOBLE10 Europa 2016 982 Tronco de CE 18 18 60 ± 10 SF 5

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: trabalho de Boldriot et al: J Am Coll Cardiol. 2011; 57: 538-545. SF: stent farmacológico. SNF: stent não farmacológico. CE: coronária esquerda. EEUU: Estados Unidos.

37% with ejection fraction < 55%.

3% with ejection fraction < 30%.

 Desfechos

Os desfechos estão sintetizados nas figuras 1 a 6. Na incidência de AVE até um ano a heterogeneidade foi baixa (I2 = 0). Os resultados favoreceram a ICP (0,4% versus 1,5%, p < 0,00001); Na mortalidade em 30 dias os estudos mostraram baixa heterogeneidade (I2 = 0) e favoreceram o grupo stent (0,8% versus 1,5%, p = 0,005). Na mortalidade até um ano os estudos apresentaram baixa heterogeneidade (I2 = 0%) e não mostraram diferença entres os grupos (3,4% versus 3,5%. p = 0,50). Na mortalidade tardia os estudos mostraram baixa heterogeneidade (I2 = 0%) e favoreceram a CRM (10,1% versus 8,5%, p = 0,01). Ao excluir os pacientes diabéticos de quatro estudos (SYNTAX,2 FREEDOM,8 BEST9 e Cardia4) as diferenças na mortalidade tardia tenderam a desaparecer (8,5% versus 8,1%, p = 0,6).

Mortalidade em 30 dias: Stent versus cirurgia de revascularização miocárdica.

O tamanho dos quadrados é proporcional ao numero de pacientes. As barras representam 95% de intervalo de confiança. O diamante representa a síntese dos resultados. CRM: cirurgia de revascularização miocárdica . Le Mans: Left main stenting; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; 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. Fonte: Boldriot et al.,5 Gráfico obtido através do programa Review Manager (RevMan). Version 5.3.

Mortalidade em um ano: stent versus cirurgia de revascularização miocárdica.

O tamanho das caixas é proporcional ao numero de pacientes. As barras representam 95% de intervalo de confiança. O diamante representa a síntese dos resultados CRM: cirurgia de revascularização miocárdica . 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: 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.,5 Gráfico obtido através do programa Review Manager (RevMan). Version 5.3.

Mortalidade tardia: Stent versus cirurgia de revascularização miocárdica.

O tamanho das caixas é proporcional ao numero de pacientes. As barras representam 95% de intervalo de confiança. O diamante representa a síntese dos resultados. CRM: cirurgia de revascularização miocárdica. 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., 5 Gráfico obtido através do programa Review Manager (RevMan). Version 5.3.

Acidente vascular encefálico: stent versus cirurgia de revascularização miocárdica.

O tamanho das caixas é proporcional ao numero de pacientes. As barras representam 95% de intervalo de confiança. O diamante representa a síntese dos resultados. CRM: cirurgia de revascularização miocárdica. 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.,5 Gráfico obtido através do programa Review Manager (RevMan). Version 5.3.

Estudos de tronco de coronária esquerda. Mortalidade em um ano: stent versus cirurgia de revascularização miocárdica.

O tamanho das caixas é proporcional ao numero de pacientes. As barras representam 95% de intervalo de confiança . O diamante representa a síntese dos resultados. CRM: cirurgia de revascularização miocárdica. Le Mans: Left main stenting trial; SYNTAX LM: subgrupo de tronco do SYNTAX (Synergy between PCI with Taxus and Cardiac 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 et al.,5 Gráfico obtido através do programa Review Manager (RevMan). Version 5.3.

Estudos de tronco de coronária esquerda. Mortalidade tardia: stent versus cirurgia de revascularização miocárdica

O tamanho das caixas é proporcional ao numero de pacientes do ensaio. As barras representam 95% de intervalo de confiança. O diamante representa a síntese dos resultados. CRM: cirurgia de revascularização miocárdica. Le Mans: Left main stenting trial; SYNTAX LM: subgrupo de tronco do SYNTAX (Synergy between PCI with Taxus and Cardiac 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 et al.,5. Gráfico obtido através do programa Review Manager (RevMan).

Nos seis estudos que avaliaram obstrução de tronco (LE MANS,1 SYNTAX LEFT MAIN,12 PRECOMBAT,6 EXCEL,11 NOBLE10 e o estudo de Boldriot et al.,5), totalizando 4700 pacientes, não houve diferença na mortalidade em 30 dias (0,8% versus 1,4%, p = 0,15), um ano (3% versus 3,7%, p = 0,18), ou na mortalidade tardia (8,1% versus 8,1%). Houve diferença significativa favorável ao grupo stent na incidência de AVE (0,3% versus 1,5%, p < 0,0001).

Quatro estudos reportaram a mortalidade tardia em diabéticos (SYNTAX,3 Cardia,4 FREEDOM8 e BEST9). No agrupamento de resultados (n = 3223) a mortalidade até cinco anos foi de 12,5% no grupo stent versus 9,7% no grupo cirurgia (p < 0,0001).

Cinco estudos forneceram os resultados da incidência tardia de eventos adversos combinados (MACCE) em subgrupos, os quais estão representados na figura 7. O agrupamento dos resultados de MACCE desses subgrupos (Figura 7) mostra que escore de SYNTAX no tercil superior e a condição de diabético influíram fortemente de maneira negativa nos resultados da ICP. Em pacientes no tercil inferior do SYNTAX e em não diabéticos não houve diferença significativa em termos de MACCE entre o grupo CRM e o grupo ICP. A condição de idoso e o sexo feminino contribuíram em menor grau para a diferença de resultados. Fração de ejeção de menos de 50% não contribuiu de forma significativa para a diferença de resultados.

Resultados MACCE em subgrupos de cinco estudos.

O tamanho de cada caixa é proporcional ao numero de pacientes do subgrupo. A barra é igual ao intervalo de confiança. Os diamantes representam a síntese dos resultados. No SYNTAX, FREEDOM E EXCEL os eventos combinados foram morte, IAM e AVE. Nos demais morte, IAM e nova revascularização. CRM: cirurgia de revascularização miocárdica. SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery; FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus; 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; Gráfico obtido através do programa Review Manager (RevMan). Version 5.3.

Discussão

Várias revisões sistemáticas, estudos colaborativos e meta-análises13-18 foram publicados comparando ICP com CRM. Os mais importantes incluíram estudos da era balão e da era stent não farmacológico ou deixaram de fora importantes estudos recentes.14-16 O principal diferencial da presente meta-análise é o grande número de estudos e pacientes avaliados, o seu caráter atualizado e o fato de ter incluído exclusivamente ensaios clínicos da era stent farmacológico.

Na avaliação dos resultados é importante destacar a superioridade da ICP na mortalidade em 30 dias. Isso está em consonância com revisão sistemática prévia17 e com o registro de Nova York.19 Obviamente a diferença não se aplica aos pacientes com lesões de alta complexidade angiográfica como pode ser percebido na análise de curvas de sobrevida da agregação de resultados do SYNTAX LM e do PRECOMBAT.20 A maior incidência de AVE no grupo cirúrgico já havia sido sugerida em revisões sistemáticas prévias.14,17 À luz dos dados aqui apresentados ela é indiscutível. Ressalte-se que podemos notar uma redução da incidência de AVE em estudos mais recentes, refletindo o maior cuidado atual dos cirurgiões na manipulação da aorta. A similaridade de resultados na mortalidade até um ano está de acordo com revisão sistemática prévia, que incluiu estudos da era pré stent farmacológico.17 A diferença favorável à cirurgia na mortalidade tardia está de acordo com outra meta-análise16 e também com estudo colaborativo recentemente publicado.21 Deve ser ressaltado que a diferença encontrada deveu-se ao grande número de diabéticos nos estudos da era SF, desaparecendo na agregação de resultados quando esses foram excluídos. Esses dados confirmam o do estudo colaborativo de Hlatki et al.,15 que demonstrou mortalidade global em cinco anos menor com a cirurgia mas ausência de diferença em pacientes não diabéticos. Ressalte-se que o estudo de Hlatki et al.,15 incluiu ensaios da era balão e nele predominavam os bi arteriais enquanto na presente revisão predomina a doença tri arterial e a obstrução de tronco de coronária esquerda.

Em relação aos resultados em obstrução de tronco de coronária é importante lembrar que esse grupo de pacientes constituiu durante muito tempo um território proibido para a angioplastia. O LE MANS foi primeiro estudo aleatorizado a tentar comparar stent a cirurgia em obstrução de tronco, com resultados semelhantes ou mesmo superiores com a ICP. Mas era um pequeno estudo (105 pacientes) tendo sido criticado por ter não ter usado mamaria em aproximadamente 25% dos casos. Depois vieram os resultados do subgrupo de tronco do SYNTAX12 e os do estudo de Boldriot et al.,5 e do PRECOMBAT que levaram a melhora das indicações de ICP em obstrução de tronco. Mesmo assim nas diretrizes norte-americanas ela evoluiu apenas para indicação IIA nos com baixo escore de SYNTAX e IIB nos com escore de SYNTAX intermediário.18 Ressalte-se ainda que tais indicações são restritas a pacientes de elevado risco cirúrgico. No presente estudo, em que agrupamos resultados de seis estudos, com 4700 pacientes, os resultados da ICP com stent farmacológico foram iguais, ou mesmo superiores aos da CRM. À luz deles e dos recentes resultados do NOBLE e do EXCEL, acreditamos que as diretrizes norte-americanas e brasileiras22,23 poderão brevemente serem modificadas, melhorando a classificação da ICP com stent farmacológico, principalmente em obstrução de tronco.

Em relação aos resultados em diabéticos é importante lembrar que as evidências contrárias à ICP em diabéticos tem origem na era balão, a partir dos achados ocasionais do estudo BARI. Seus investigadores avaliaram um subgrupo de 343 diabéticos e encontraram uma mortalidade tardia de 34,5% para a ICP com balão e 19,4% para a cirurgia (p = 0,03). Na era stent convencional estudos como o SOS e o ARTS confirmaram uma tendência a maior mortalidade da intervenção percutânea em diabéticos, ainda que não tenham atingido significância estatística. A partir daí presença de diabetes passou a ser critério para indicação preferencial da cirurgia como método de revascularização miocárdica. Havia a hipótese de que stents farmacológicos viriam eliminar as diferenças de mortalidade encontradas nesses estudos. Os resultados aqui apresentados demonstram que a diferença em mortalidade entre ICP e cirurgia em diabéticos persiste na era Stent farmacológico. Nota-se no entanto, uma redução da diferença de risco em relação a estudos mais antigos (3,5% de diferença de risco em contraposição a 7,3% no estudo de Hclatki e 15,1% no BARI). A hipótese de que não seja o distúrbio metabólico em si, mas a complexidade das lesões o fator que leva à maior mortalidade da angioplastia em diabéticos merece ser levantada. Essa dúvida talvez possa ser esclarecida por uma meta-análise de dados individuais dos pacientes envolvendo grande número de estudos. Nesse sentido, estudo colaborativo recente que agrupou os resultados de três estudos (SYNTAX, BEST e PRECOMBAT) corrobora essa hipótese.24

Os resultados de MACCE em subgrupos (Figura 7) no presente estudo demonstram que escore de SYNTAX no tercil superior influenciou fortemente de maneira negativa os resultados da ICP, da mesma maneira que presença de diabetes. A condição de idoso e o sexo feminino influenciaram de forma menor nos resultados; fração de ejeção < 50% não influiu negativamente nos resultados da ICP, mas fração de ejeção menor que 35% teve um impacto maior, ainda que sem significância estatística. Esses resultados estão de acordo com os do estudo colaborativo de Cavalcante et al.,20 Nele, ao agregar os resultados do SYNTAX LEFT MAIN e do PRECOMBAT para eventos adversos compostos (morte, AVE, IAM e nova revascularização) escore de SYNTAX elevado teve papel importante assim como diabetes. Sexo feminino, condição de idoso, fração de ejeção < 50% e insuficiência renal não afetaram negativamente os resultados comparativos da ICP. Esse mesmo estudo mostrou que os subgrupos que mais significantemente afetaram os resultados de mortalidade da ICP em obstrução de tronco foram a associação com doença de dois ou três vasos e o escore de SYNTAX > 32. Diabete teve um papel menos importante, possivelmente relacionado ao fato de terem sido a avaliados exclusivamente pacientes com obstrução de tronco.

Limitações do estudo

Esse estudo apresenta importantes limitações. È uma meta-análise de dados publicados e não de dados individuais de pacientes. Sendo assim não foi possível analisar resultados de mortalidade em subgrupos, com exceção de diabéticos e fomos obrigados a transformar percentuais em números absolutos, o que pode merecer críticas. Além disso, os resultados aplicam-se apenas a pacientes em que a revascularização possa ser feita por ambos os métodos, sem elevado risco cirúrgico, sem história de revascularização cirúrgica prévia e com os procedimentos realizados em instituições de excelência.

 Conclusão

Na agregação de resultados de estudos aleatorizados envolvendo multiarteriais ou obstrução de tronco de coronária esquerda, ICP usando SF mostrou uma menor incidência de AVE, uma menor mortalidade em 30 dias e uma maior mortalidade tardia quando comparada a CRM. Não houve diferença de mortalidade precoce, intermediária ou tardia no subgrupo de obstrução de tronco, mas houve diferença na incidência de AVE favorável à ICP. A presença de diabete e o alto escore de SYNTAX foram os fatores que mais fortemente impactaram negativamente nos resultados da ICP em termos de desfechos adversos compostos.

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.