Cardiovascular Revascularization Medicine 15 (2014) 421–423
Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
Coronary artery bypass surgery or coronary stenting in diabetic patients: too soon to make a statement?☆ Alfredo E. Rodriguez ⁎ Head Cardiac Unit, Otamendi Hospital, Buenos Aires School of Medicine
a r t i c l e
i n f o
Article history: Received 29 June 2014 Received in revised form 29 September 2014 Accepted 7 October 2014 Keywords: Diabetes Coronary artery bypass surgery Drug eluting stent Multiple vessel disease
a b s t r a c t Diabetic patients have been associated with poor procedural and long term outcome if they were treated either with percutaneous coronary interventions or coronary artery bypass surgery. Recently several randomized clinical trials (RCT) in this subset of patients have been published showing a greater incidence of major adverse cardiovascular events, death/myocardial infarction/stroke, if they were treated with first generation drug eluting stents (DES) which was not observed previously in the bare metal stent era. However, almost simultaneously with this data, several RCT demonstrated better safety profile with new generation DES including biocompatible polymers, biodegradable polymers and lately complete absorbable DES, all of them showed reduction in adverse cardiac events compared to 1st generation DES in patients with diabetes. In this editorial we review the old and new randomized data in diabetic patients and conclude that there are many unresolved issues to make a definitive statement regarding which is the best revascularization preference in diabetic patients and the measured final efficacy of PCI and CABG will not be reached until the arrival of RCT using next generation DES, including complete absorbable scaffolds. © 2014 Elsevier Inc. All rights reserved.
Percutaneous coronary intervention (PCI) in diabetic patients has been associated with poorer outcomes compared to coronary artery by-pass graft (CABG) since the beginning of this therapeutic option for the treatment of coronary artery disease (CAD). This fact was not modified by the introduction of 1st generation drug eluting stents (DES) [1,2]. Furthermore, the largest trial ever performed in this cohort of patients, FREEDOM Trial (comparison of two treatments for multivessel coronary artery disease in individuals with diabetes), showed a significant lower incidence of the primary endpoint—the composite of death, myocardial infarction (MI) and cerebrovascular accident (CVA)—at 4-year follow-up if patients were treated with CABG [3,4]. In an accompanying editorial in the journal where the trial was published, the author stated that all diabetic patients had to be treated with CABG and all patients were to be aware of the benefits of the surgical procedure, signing an informed consent after a coronary angiography [5]. We recognize that diabetic patients with coronary artery disease were and are a therapeutic challenge to PCI. However, in spite of negative long term results from large randomized clinical trials (RCT), we consider that we still do not have enough data to close the door on PCI; furthermore, there are certain clinical situations where PCI with stent implantation should be a revascularization option. Briefly, we will expound the data in which we base our assumptions and contextualize when and on whom PCI could be performed: ☆ No conflict of interest to report. ⁎ Corresponding author. Sanatorio Otamendi y Miroli, Cardiac Unit, Azcuenaga 870 PB, Argentina, C1024AAA Buenos Aires, Argentina. Tel./fax: +541149648721. E-mail address: [email protected] (A. E. Rodriguez). http://dx.doi.org/10.1016/j.carrev.2014.10.003 1553-8389/© 2014 Elsevier Inc. All rights reserved.
1. Results on diabetics in the youngest tertile are similar between PCI and CABG A meta-analysis from 10 RCT [6] showed that, over a median followup of 5.9 years, the effect of CABG vs. PCI on mortality varied according to age with an adjusted CABG:PCI hazard ratios of 1.23 (0.95–1.59) in the youngest tertile, 0.89 (0.73–1.10) in the middle tertile, and 0.79 (0.67–0.94) in the oldest tertile, with a CABG:PCI HR b 1 (favor to CABG) for patients aged 59 and older. In such analysis, younger diabetic patients had similar 5.9-year survival independently to revascularization treatment, 19% with CABG and PCI: HR. 0.89 (0.55–1.46) p = 0.65 unadjusted and 0.93 (0.55–1.55) p = 0.77 adjusted. 2. Meta-analysis of RCT comparing bare metal stents (BMS) vs. CABG—such as ARTS, ERACI II, MASS II and SoS—showed similar findings at 5 years, even in diabetic patients In this meta-analysis performed by Daemen et al [7], for the composite end point of death, MI and CVA, no heterogeneity in treatment was found between patients with diabetes and those without diabetes (p for interaction = 0.65). In diabetics, the cumulative incidence of death was not significantly higher in the PCI group, 12.4% compared to 7.9% in the CABG group (p = 0.09), and the cumulative incidence of death, MI or CVA, the primary end point, was similar after PCI with BMS vs. CABG (21.4% vs. 20.9%, respectively; p = 0.9). The only significant difference was a threefold incidence of repeat revascularization in the PCI group; HR increase for repeat revascularization was 0.18 (95% CI, 0.11 to 0.29) in the PCI group [7–11]. Additionally, if we compare
422
A.E. Rodriguez / Cardiovascular Revascularization Medicine 15 (2014) 421–423
results from this meta-analysis with those obtained in RCT between 1st generation DES vs. CABG, such as SYNTAX and FREEDOM, an indirect comparison suggested that 1st generation DES had a greater number of death/MI rate than BMS in spite of a significant reduction of repeat revascularization procedures. Moreover, this lack of benefit with 1st generation DES was seen in diabetic and non-diabetic population, in fact, the observed incidence in the composite of death, MI and CVA in FREEDOM was 20% higher than previously seen in diabetic patients randomized in BMS/CABG trials [3,7,12,13]. These findings imply that if we used a wrong stent device to treat diabetic patients in the above mentioned trials it would be, perhaps, the main limitation to search potential benefits of PCI in these trials. 3. Threefold increased incidence of CVA with CABG CABG was associated with higher incidence of CVA at 5-year followup in all randomized trials, RR 1.72 (1.18–2.53). This finding was particularly observed in diabetics [16,17]. In the FREEDOM trial, diabetics had a significant greater incidence of CVA:RR 2.16 (1.27–3.69). Furthermore, in FREEDOM, the 5-year increased CVA rate following CABG compared to PCI was independent of diabetic status 7.5% vs. 3.7% for CABG and PCI in insulin treated diabetics (ITDM) and 4.3% vs. 1.7% for CABG and PCI in non-insulin treated diabetic patients (non-ITDM) [18]. Similarly, at 5 years, the SYNTAX trial nonITDM patients had a 5.2% non-fatal stroke rate which was higher than the 1.6% incidence seen in the DES arm (p = 0.09), although it is not significant due to the small sample size [17]. Therefore, due to the reduced sample size of ITDM patients in both FREEDOM and SYNTAX, it would be impossible to determine significant differences between the outcomes of PCI and CABG in those patients; in FREEDOM composite of death/MI/CVA, PCI vs. CABG HR was 1.21 [0.87–1.69] [18]. 4. FREEDOM showed significant differences in favor to CABG only in USA and Canada sites This is a crucial point: not all centers performed either PCI or CABG in the same fashion. This is also true in other RCT such as SYNTAX where there were also large differences among sites [19]. In FREEDOM, primary end point was reached in favor of CABG only in USA and Canada sites, death/MI/CVA was 16% and 28% with DES and CABG respectively, from a population of 770 patients. Conversely, non-USA and Canada sites, from a population of 1130 patients, primary end point was 25% with DES and 21% with CABG, not statistically significant, with p = 0.05 for interaction between North American and outside North American sites [3]. In the past, certain RCT showed lower incidence of death with PCI at one year compared to CABG, and this difference was less significant but remained in favor of PCI at 5-year follow-up [8]. In fact, two studies from South America—ERACI II and MASS II— showed similar mortality with both revascularization strategies in diabetic patients treated either with BMS or CABG [RR 1 (0.27–3.72) and 0.95 (0.41–2.22) in ERACI II and MASS II, respectively] [8,10,15]. In contrast, other trials conducted in Great Britain and Europe showed significant survival advantage with CABG at 6 years: RR 0.13 (0.02–1.04) [11], and the advantage in the latter was driven for an incidence of inhospital mortality with CABG less than 1%. Thus, old—ERACI, MASS and SoS—and new RCT—FREEDOM and SYNTAX—are consistent to show geographic disparities in the results between PCI and CABG. 5. 1st generation DES were largely replaced with latest ones In the past few years several RCT either comparing 2nd or 3rd generation DES versus the 1st ones were conducted.
All of them consistently showed a significant reduction in the incidence of cardiac late events including cardiac death and/or MI death/ MI and very late stent thrombosis with the latest generations DES [20–24]. Randomized studies with the everolimus eluted stents (EES) with durable polymer, compared to paclitaxel eluted stents (PES/Taxus, Boston Scientific Corp.) showed a significant reduction in death/MI (p b 0.02), stent thrombosis and target lesion revascularization (TLR) (p b 0.001 for both) in the non-diabetic population. In the randomized SPIRIT V diabetic study, late lumen loss and 1-year cardiac death or MI was significantly reduced with EES, although, incidence of ischemic driven target lesion revascularization (ID-TLR) rate on ITDM was higher with EES than with paclitaxel eluted stents (PES), and differences in therapeutic responses with these two drugs in hyperglycemic status can be linked to these findings [25]. However, the more recent ESSENCE-DIABETES study found an extremely low IDTLR rate with EES [26] which is in agreement from last Bern-Rotterdam registry [27] in diabetic patients. In addition, with the introduction of absorbable polymer or complete bioabsorbable stents (BVS), we are observing promising results in the diabetic patient cohort. Pooled results [24] from individual patient-level data from 3 RCT— ISAR-TEST 3, ISAR-TEST 4 and LEADERS—comparing biodegradable polymer DES with durable polymer SES, reported at 4 years a significant reduction of stent thrombosis, definite or probable, in diabetic patients treated with biodegradable polymer DES (hazard ratio = 0.52, 95% CI = 0.28–0.96, p = 0.04), and the difference was driven by significantly lower stent thrombosis rates with biodegradable polymer DES between 1 and 4 years (0.4% vs. 2.8%; hazard ratio = 0.15, 95% CI = 0.03–0.70, p = 0.02). Furthermore, a pooled analysis from one year-follow up of diabetic patients from several trials using a 2nd generation permanent polymer EES: SPIRIT FIRST, SPIRIT II, SPIRIT III, SPIRIT IV compared with a 3rd generation complete absorbable DES (BVS): ABSORB Cohort B and ABSORB EXTEND trial, showed that on patients with diabetes treated with BSV, the incidence of target lesion failure (TLF), cardiac death, MI, and IDTLR was—for the first time in the stent era—lower when compared with non-diabetic population. The cumulative incidence of adverse events at one year did not differ between diabetic and non-diabetic patients treated with BVS (3.7% vs. 5.1%, p = 0.64), whereas incidence of stent thrombosis between diabetics and non-diabetics was also equal (0.7%) [28]. Of course, these promising data are preliminary, longer follow-up will be necessary and potential bias with presence of co-founding factors in this retrospective analysis cannot be excluded. Nevertheless, role of restoration of vasomotor function, one of the advantages of BSV, might be of particular interest to diabetics in which endothelial dysfunction is a rule. The very low incidence of very late stent thrombosis rate with all these new devices with either biocompatible, bioabsorbable polymers or complete absorbable stents (1.0%/0.4%/0.7% respectively) are far from the unacceptable high stent thrombosis numbers reported with 1st generation DES in patients with multiple vessel disease at 5-year follow-up, 9% in ARTS 2, 6.2% in ERACI III and 15.4% in SYNTAX [14,15,29–31]32. On the same wave length, recent data from ERACI IV registry with patients with multiple vessel disease and left main, treated with 2nd generation DES, showed, at mid-term follow-up, a remarkable low incidence of death/MI/CVA, 1.8%, either in comparison with CABG, p b 0.001, or first generation DES, p = 0.004, and these advantages were also seen in diabetics, p = 0.04 vs. CABG and p = 0.02 vs. 1st generation DES. 33 In summary, 1st generation DES used in FREEDOM and SYNTAX have been largely replaced by the safer and newer generations of DES, therefore, measured final efficacy of PCI and CABG will not be reached until the arrival of RCT using next generation DES, including BSV scaffolds.
A.E. Rodriguez / Cardiovascular Revascularization Medicine 15 (2014) 421–423
In conclusion, after the analysis from new and old RCT between PCI with stents vs. CABG, at 5-year follow-up, diabetic patients were at higher risk of death, MI and stroke when they were treated with 1st generation DES. Nevertheless and taking into account some of the observations mentioned above, like the higher risk of stroke with CABG, large geographic disparities in the results with PCI and CABG, similar survival in diabetic young patients treated with either CABG or PCI and finally the significant improvement in safety with newer generation DES, it appears to be too soon to make a definite statement regarding revascularization preference for diabetic patients. References [1] Bari Investigators. The final 10-years follow-up results from the BARI randomized trial. J Am Coll Cardiol 2007;49:1600–6 [2]. [2] Hlatky MA, Boothroyd DB, Bravata DM, Boersma E, Booth J, Brooks MM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet 2009;373(9670):1190. [3] Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367 (25):2375–84. [4] Farkouh ME, Dangas G, Leon MB, Smith C, Nesto R, Buse JB, et al. Design of the future revascularization evaluation in patients with diabetes mellitus: optimal management of multivessel disease (FREEDOM) trial. Am Heart J 2008;155:215–23. [5] Hlatky MA. Compelling evidence for coronary-bypass surgery in patients with diabetes. N Engl J Med 2012;367(25):2437–8. [6] Flather M, Rhee JW, Boothroyd DB, Boersma E, Brooks MM, Carrié D, et al. The effect of age on outcomes of coronary artery bypass surgery compared with balloon angioplasty or bare-metal stent implantation among patients with multivessel coronary disease. A collaborative analysis of individual patient data from 10 randomized trials. J Am Coll Cardiol 2012;60(21):2150–7 [En el punto de edad, punto primero]. [7] Daemen J, Boersma E, Flather M, Booth J, Stables R, Rodriguez 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. [8] Rodriguez AE, Baldi J, Fernández Pereira C, Navia J, Rodriguez Alemparte M, Delacasa A, et al. Five-year follow-up of the Argentine randomized trial of coronary angioplasty with stenting versus coronary bypass surgery in patients with multiple vessel disease (ERACI II). J Am Coll Cardiol 2005;46(4):582–6. [9] Serruys PW, Ong AT, van Herwerden LA, Sousa JE, Jatene A, Bonnier JJ, et al. Five-year outcomes after coronary stenting versus bypass surgery for the treatment of multivessel disease: the final analysis of the Arterial Revascularization Therapies Study (ARTS) randomized trial. J Am Coll Cardiol 2005;46:575 [Cuando hablo de los resultados con BMS, en donde va el metaanálisis de Daemen]. [10] Hueb W, Lopes NH, Gersh BJ, Soares P, Machado LA, Jatene FB, et al. Five-year followup of the Medicine, Angioplasty, or Surgery Study (MASS II): a randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation 2007;115:1082–9. [11] Booth J, Clayton T, Pepper J, Nugara F, Flather M, Sigwart U, et al. Randomized, controlled trial of coronary artery bypass surgery versus percutaneous coronary intervention in patients with multivessel coronary artery disease: six-year followup from the Stent or Surgery Trial (SoS). Circulation 2008;118:381–8. [12] Rodriguez AE. Are drug-eluting stents superior to bare metal stents when compared to coronary artery bypass surgery? Show me the data. Cardiovasc Revasc Med 2013; 14(2):90–2. [13] Mohr FW, Morice MC, Kappetein AP, Feldman TE, Ståhle E, Colombo A, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381(9867):629–38 [Donde ponemos el metaanálisis]. [14] Rodriguez AE, Maree AO, Mieres J, Berrocal D, Grinfeld L, Fernandez-Pereira C, et al. Late loss of early benefit from drug-eluting stents when compared with bare-metal stents and coronary artery bypass surgery: 3 years follow-up of the ERACI III registry. Eur Heart J 2007;28(17):2118–25.
423
[15] Farooq V, Serruys PW, Zhang Y, Mack M, Ståhle E, Holmes DR, et al. Short and long term clinical impact of stent thrombosis and graft occlusion in the synergy between percutaneous coronary intervention with Taxus and Cardiac Surgery Trial: The SYNTAX Trial at 5 years. J Am Coll Cardiol 2013;62(25):2360–9. [16] Verma S, Farkouh ME, Yanagawa B, Fitchett DH, Ahsan MR, Ruel M, et al. Comparison of coronary artery bypass surgery and percutaneous coronary intervention in patients with diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 2013;1(4):317–28. [17] Kappetein AP, Head SJ, Morice MC, Banning AP, Serruys PW, Mohr FW, et al. Treatment of complex coronary artery disease in patients with diabetes: 5-year results comparing outcomes of bypass surgery and percutaneous coronary intervention in the SYNTAX trial. Eur J Cardiothorac Surg 2013;43(5):1006–13. [18] Dangas GD, Farkouh ME, Sleeper LA, Yang M, Schoos MM, Macaya C, et al. Long term outcome of PCI versus CABG in insulin and non-insulin treated diabetic patients: results from the FREEDOM Trial. J Am Coll Cardiol 2014;64:1189–97. [19] Antoniucci D. SYNTAX mistakes. Rev Argent Cardioangiol 2013;4(03): 151–0154. [20] Stone GW, Midei M, Newman W, Sanz M, Hermiller JB, Williams J, et al. Randomized comparison of everolimus-eluting and paclitaxel-eluting stents: two-year clinical follow-up from the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions (SPIRIT) III trial. Circulation 2009;119:680–6. [21] Brener SJ, Kereiakes DJ, Simonton CA, Rizvi A, Newman W, Mastali K, et al. Everolimus-eluting stents in patients undergoing percutaneous coronary intervention: final 3-year results of the Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With de Novo Native Coronary Artery Lesions trial. Am Heart J 2013;166(6):1035–42. [22] Byrne RA, Kastrati A, Kufner S, Massberg S, Birkmeier KA, Laugwitz KL, et al. Intracoronary stenting and angiographic results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Investigators. Randomized, noninferiority trial of three limus agent-eluting stents with different polymer coatings: the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Trial. Eur Heart J 2009;30(20):2441–9. [23] Stefanini GG, Byrne RA, Serruys PW, de Waha A, Meier B, Massberg S, et al. Biodegradable polymer drug-eluting stents reduce the risk of stent thrombosis at 4 years in patients undergoing percutaneous coronary intervention: a pooled analysis of individual patient data from the ISAR-TEST 3, ISAR-TEST 4, and LEADERS randomized trials. Eur Heart J 2012;33(10):1214–22. [24] Sarno G, Lagerqvist B, Fröbert O, Nilsson J, Olivecrona G, Omerovic E, et al. Lower risk of stent thrombosis and restenosis with unrestricted use of 'newgeneration' drug-eluting stents: a report from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Eur Heart J 2012;33 (5):606–1325. [25] Grube E, Chevalier B, Guagliumi G, Smits PC, Stuteville M, Dorange C, et al. The SPIRIT V diabetic study: a randomized clinical evaluation of the XIENCE V everolimus eluting stent vs the TAXUS Liberté paclitaxel-eluting stent in diabeticpatients with de novo coronary artery lesions. Am Heart J 2012;163:867–75. [26] Park GM, Lee SW, Park SW, Kim YH, Yun SC, Cho YR, et al. Comparison of zotarolimus-eluting stent versus sirolimus-eluting stent for de novo coronary artery disease in patients with diabetes mellitus from the ESSENCE-DIABETES II trial. Am J Cardiol 2013;112(10):1565–70. [27] Simsek C, Räber L, Magro M, Boersma E, Onuma Y, Stefanini GG, et al. Long-term outcome of the unrestricted use of everolimus-eluting stents compared to sirolimuseluting stents and paclitaxel-eluting stents indiabetic patients: the Bern–Rotterdam diabetes cohort study. Int J Cardiol 2013;170:36–42. [28] Muramatsu T, Onuma Y, van Geuns RJ, Chevalier B, Patel TM, Seth A, et al. 1-Year clinical outcomes of diabetic patients treated with everolimus-eluting bioresorbable vascular scaffolds. J Am Coll Cardiol Intv 2014;7:482–93. [29] Serruys PW, Onuma Y, Garg S, Vranckx P, De Bruyne B, Morice MC, et al. 5-year clinical outcomes of the ARTS II (Arterial Revascularization Therapies Study II) of the sirolimus-eluting stent in the treatment of patients with multivessel de novo coronary artery lesions. J Am Coll Cardiol 2010;55(11):1093–101. [30] Boothroyd DM, Mieres JJ, Grinfeld L, Fernández-Pereira C, Rodríguez-Granillo AM, Berrocal D, et al. Comparative effectiveness at five years of drug-eluting stents, bare metal stents, and coronary bypass surgery: the ERACI III study. Rev Argent Cardioangiol 2012;3(03):0135–46. [31] Haiek C, Fernandez-Pereira C, Santaera O, Sarmiento R, Larribau M, Pocovi A, et al. Revascularization strategies for patients with multiple vessel disease and unprotected left main with a cobalt-chromium rapamycin eluting stent (ERACI IV Registry). European Congress of Cardiology, Abstract Presentation 303, Barcelona, Spain, August 31, 2014; 2014.
Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
Coronary artery bypass surgery or coronary stenting in diabetic patients: too soon to make a statement?☆ Alfredo E. Rodriguez ⁎ Head Cardiac Unit, Otamendi Hospital, Buenos Aires School of Medicine
a r t i c l e
i n f o
Article history: Received 29 June 2014 Received in revised form 29 September 2014 Accepted 7 October 2014 Keywords: Diabetes Coronary artery bypass surgery Drug eluting stent Multiple vessel disease
a b s t r a c t Diabetic patients have been associated with poor procedural and long term outcome if they were treated either with percutaneous coronary interventions or coronary artery bypass surgery. Recently several randomized clinical trials (RCT) in this subset of patients have been published showing a greater incidence of major adverse cardiovascular events, death/myocardial infarction/stroke, if they were treated with first generation drug eluting stents (DES) which was not observed previously in the bare metal stent era. However, almost simultaneously with this data, several RCT demonstrated better safety profile with new generation DES including biocompatible polymers, biodegradable polymers and lately complete absorbable DES, all of them showed reduction in adverse cardiac events compared to 1st generation DES in patients with diabetes. In this editorial we review the old and new randomized data in diabetic patients and conclude that there are many unresolved issues to make a definitive statement regarding which is the best revascularization preference in diabetic patients and the measured final efficacy of PCI and CABG will not be reached until the arrival of RCT using next generation DES, including complete absorbable scaffolds. © 2014 Elsevier Inc. All rights reserved.
Percutaneous coronary intervention (PCI) in diabetic patients has been associated with poorer outcomes compared to coronary artery by-pass graft (CABG) since the beginning of this therapeutic option for the treatment of coronary artery disease (CAD). This fact was not modified by the introduction of 1st generation drug eluting stents (DES) [1,2]. Furthermore, the largest trial ever performed in this cohort of patients, FREEDOM Trial (comparison of two treatments for multivessel coronary artery disease in individuals with diabetes), showed a significant lower incidence of the primary endpoint—the composite of death, myocardial infarction (MI) and cerebrovascular accident (CVA)—at 4-year follow-up if patients were treated with CABG [3,4]. In an accompanying editorial in the journal where the trial was published, the author stated that all diabetic patients had to be treated with CABG and all patients were to be aware of the benefits of the surgical procedure, signing an informed consent after a coronary angiography [5]. We recognize that diabetic patients with coronary artery disease were and are a therapeutic challenge to PCI. However, in spite of negative long term results from large randomized clinical trials (RCT), we consider that we still do not have enough data to close the door on PCI; furthermore, there are certain clinical situations where PCI with stent implantation should be a revascularization option. Briefly, we will expound the data in which we base our assumptions and contextualize when and on whom PCI could be performed: ☆ No conflict of interest to report. ⁎ Corresponding author. Sanatorio Otamendi y Miroli, Cardiac Unit, Azcuenaga 870 PB, Argentina, C1024AAA Buenos Aires, Argentina. Tel./fax: +541149648721. E-mail address: [email protected] (A. E. Rodriguez). http://dx.doi.org/10.1016/j.carrev.2014.10.003 1553-8389/© 2014 Elsevier Inc. All rights reserved.
1. Results on diabetics in the youngest tertile are similar between PCI and CABG A meta-analysis from 10 RCT [6] showed that, over a median followup of 5.9 years, the effect of CABG vs. PCI on mortality varied according to age with an adjusted CABG:PCI hazard ratios of 1.23 (0.95–1.59) in the youngest tertile, 0.89 (0.73–1.10) in the middle tertile, and 0.79 (0.67–0.94) in the oldest tertile, with a CABG:PCI HR b 1 (favor to CABG) for patients aged 59 and older. In such analysis, younger diabetic patients had similar 5.9-year survival independently to revascularization treatment, 19% with CABG and PCI: HR. 0.89 (0.55–1.46) p = 0.65 unadjusted and 0.93 (0.55–1.55) p = 0.77 adjusted. 2. Meta-analysis of RCT comparing bare metal stents (BMS) vs. CABG—such as ARTS, ERACI II, MASS II and SoS—showed similar findings at 5 years, even in diabetic patients In this meta-analysis performed by Daemen et al [7], for the composite end point of death, MI and CVA, no heterogeneity in treatment was found between patients with diabetes and those without diabetes (p for interaction = 0.65). In diabetics, the cumulative incidence of death was not significantly higher in the PCI group, 12.4% compared to 7.9% in the CABG group (p = 0.09), and the cumulative incidence of death, MI or CVA, the primary end point, was similar after PCI with BMS vs. CABG (21.4% vs. 20.9%, respectively; p = 0.9). The only significant difference was a threefold incidence of repeat revascularization in the PCI group; HR increase for repeat revascularization was 0.18 (95% CI, 0.11 to 0.29) in the PCI group [7–11]. Additionally, if we compare
422
A.E. Rodriguez / Cardiovascular Revascularization Medicine 15 (2014) 421–423
results from this meta-analysis with those obtained in RCT between 1st generation DES vs. CABG, such as SYNTAX and FREEDOM, an indirect comparison suggested that 1st generation DES had a greater number of death/MI rate than BMS in spite of a significant reduction of repeat revascularization procedures. Moreover, this lack of benefit with 1st generation DES was seen in diabetic and non-diabetic population, in fact, the observed incidence in the composite of death, MI and CVA in FREEDOM was 20% higher than previously seen in diabetic patients randomized in BMS/CABG trials [3,7,12,13]. These findings imply that if we used a wrong stent device to treat diabetic patients in the above mentioned trials it would be, perhaps, the main limitation to search potential benefits of PCI in these trials. 3. Threefold increased incidence of CVA with CABG CABG was associated with higher incidence of CVA at 5-year followup in all randomized trials, RR 1.72 (1.18–2.53). This finding was particularly observed in diabetics [16,17]. In the FREEDOM trial, diabetics had a significant greater incidence of CVA:RR 2.16 (1.27–3.69). Furthermore, in FREEDOM, the 5-year increased CVA rate following CABG compared to PCI was independent of diabetic status 7.5% vs. 3.7% for CABG and PCI in insulin treated diabetics (ITDM) and 4.3% vs. 1.7% for CABG and PCI in non-insulin treated diabetic patients (non-ITDM) [18]. Similarly, at 5 years, the SYNTAX trial nonITDM patients had a 5.2% non-fatal stroke rate which was higher than the 1.6% incidence seen in the DES arm (p = 0.09), although it is not significant due to the small sample size [17]. Therefore, due to the reduced sample size of ITDM patients in both FREEDOM and SYNTAX, it would be impossible to determine significant differences between the outcomes of PCI and CABG in those patients; in FREEDOM composite of death/MI/CVA, PCI vs. CABG HR was 1.21 [0.87–1.69] [18]. 4. FREEDOM showed significant differences in favor to CABG only in USA and Canada sites This is a crucial point: not all centers performed either PCI or CABG in the same fashion. This is also true in other RCT such as SYNTAX where there were also large differences among sites [19]. In FREEDOM, primary end point was reached in favor of CABG only in USA and Canada sites, death/MI/CVA was 16% and 28% with DES and CABG respectively, from a population of 770 patients. Conversely, non-USA and Canada sites, from a population of 1130 patients, primary end point was 25% with DES and 21% with CABG, not statistically significant, with p = 0.05 for interaction between North American and outside North American sites [3]. In the past, certain RCT showed lower incidence of death with PCI at one year compared to CABG, and this difference was less significant but remained in favor of PCI at 5-year follow-up [8]. In fact, two studies from South America—ERACI II and MASS II— showed similar mortality with both revascularization strategies in diabetic patients treated either with BMS or CABG [RR 1 (0.27–3.72) and 0.95 (0.41–2.22) in ERACI II and MASS II, respectively] [8,10,15]. In contrast, other trials conducted in Great Britain and Europe showed significant survival advantage with CABG at 6 years: RR 0.13 (0.02–1.04) [11], and the advantage in the latter was driven for an incidence of inhospital mortality with CABG less than 1%. Thus, old—ERACI, MASS and SoS—and new RCT—FREEDOM and SYNTAX—are consistent to show geographic disparities in the results between PCI and CABG. 5. 1st generation DES were largely replaced with latest ones In the past few years several RCT either comparing 2nd or 3rd generation DES versus the 1st ones were conducted.
All of them consistently showed a significant reduction in the incidence of cardiac late events including cardiac death and/or MI death/ MI and very late stent thrombosis with the latest generations DES [20–24]. Randomized studies with the everolimus eluted stents (EES) with durable polymer, compared to paclitaxel eluted stents (PES/Taxus, Boston Scientific Corp.) showed a significant reduction in death/MI (p b 0.02), stent thrombosis and target lesion revascularization (TLR) (p b 0.001 for both) in the non-diabetic population. In the randomized SPIRIT V diabetic study, late lumen loss and 1-year cardiac death or MI was significantly reduced with EES, although, incidence of ischemic driven target lesion revascularization (ID-TLR) rate on ITDM was higher with EES than with paclitaxel eluted stents (PES), and differences in therapeutic responses with these two drugs in hyperglycemic status can be linked to these findings [25]. However, the more recent ESSENCE-DIABETES study found an extremely low IDTLR rate with EES [26] which is in agreement from last Bern-Rotterdam registry [27] in diabetic patients. In addition, with the introduction of absorbable polymer or complete bioabsorbable stents (BVS), we are observing promising results in the diabetic patient cohort. Pooled results [24] from individual patient-level data from 3 RCT— ISAR-TEST 3, ISAR-TEST 4 and LEADERS—comparing biodegradable polymer DES with durable polymer SES, reported at 4 years a significant reduction of stent thrombosis, definite or probable, in diabetic patients treated with biodegradable polymer DES (hazard ratio = 0.52, 95% CI = 0.28–0.96, p = 0.04), and the difference was driven by significantly lower stent thrombosis rates with biodegradable polymer DES between 1 and 4 years (0.4% vs. 2.8%; hazard ratio = 0.15, 95% CI = 0.03–0.70, p = 0.02). Furthermore, a pooled analysis from one year-follow up of diabetic patients from several trials using a 2nd generation permanent polymer EES: SPIRIT FIRST, SPIRIT II, SPIRIT III, SPIRIT IV compared with a 3rd generation complete absorbable DES (BVS): ABSORB Cohort B and ABSORB EXTEND trial, showed that on patients with diabetes treated with BSV, the incidence of target lesion failure (TLF), cardiac death, MI, and IDTLR was—for the first time in the stent era—lower when compared with non-diabetic population. The cumulative incidence of adverse events at one year did not differ between diabetic and non-diabetic patients treated with BVS (3.7% vs. 5.1%, p = 0.64), whereas incidence of stent thrombosis between diabetics and non-diabetics was also equal (0.7%) [28]. Of course, these promising data are preliminary, longer follow-up will be necessary and potential bias with presence of co-founding factors in this retrospective analysis cannot be excluded. Nevertheless, role of restoration of vasomotor function, one of the advantages of BSV, might be of particular interest to diabetics in which endothelial dysfunction is a rule. The very low incidence of very late stent thrombosis rate with all these new devices with either biocompatible, bioabsorbable polymers or complete absorbable stents (1.0%/0.4%/0.7% respectively) are far from the unacceptable high stent thrombosis numbers reported with 1st generation DES in patients with multiple vessel disease at 5-year follow-up, 9% in ARTS 2, 6.2% in ERACI III and 15.4% in SYNTAX [14,15,29–31]32. On the same wave length, recent data from ERACI IV registry with patients with multiple vessel disease and left main, treated with 2nd generation DES, showed, at mid-term follow-up, a remarkable low incidence of death/MI/CVA, 1.8%, either in comparison with CABG, p b 0.001, or first generation DES, p = 0.004, and these advantages were also seen in diabetics, p = 0.04 vs. CABG and p = 0.02 vs. 1st generation DES. 33 In summary, 1st generation DES used in FREEDOM and SYNTAX have been largely replaced by the safer and newer generations of DES, therefore, measured final efficacy of PCI and CABG will not be reached until the arrival of RCT using next generation DES, including BSV scaffolds.
A.E. Rodriguez / Cardiovascular Revascularization Medicine 15 (2014) 421–423
In conclusion, after the analysis from new and old RCT between PCI with stents vs. CABG, at 5-year follow-up, diabetic patients were at higher risk of death, MI and stroke when they were treated with 1st generation DES. Nevertheless and taking into account some of the observations mentioned above, like the higher risk of stroke with CABG, large geographic disparities in the results with PCI and CABG, similar survival in diabetic young patients treated with either CABG or PCI and finally the significant improvement in safety with newer generation DES, it appears to be too soon to make a definite statement regarding revascularization preference for diabetic patients. References [1] Bari Investigators. The final 10-years follow-up results from the BARI randomized trial. J Am Coll Cardiol 2007;49:1600–6 [2]. [2] Hlatky MA, Boothroyd DB, Bravata DM, Boersma E, Booth J, Brooks MM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet 2009;373(9670):1190. [3] Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367 (25):2375–84. [4] Farkouh ME, Dangas G, Leon MB, Smith C, Nesto R, Buse JB, et al. Design of the future revascularization evaluation in patients with diabetes mellitus: optimal management of multivessel disease (FREEDOM) trial. Am Heart J 2008;155:215–23. [5] Hlatky MA. Compelling evidence for coronary-bypass surgery in patients with diabetes. N Engl J Med 2012;367(25):2437–8. [6] Flather M, Rhee JW, Boothroyd DB, Boersma E, Brooks MM, Carrié D, et al. The effect of age on outcomes of coronary artery bypass surgery compared with balloon angioplasty or bare-metal stent implantation among patients with multivessel coronary disease. A collaborative analysis of individual patient data from 10 randomized trials. J Am Coll Cardiol 2012;60(21):2150–7 [En el punto de edad, punto primero]. [7] Daemen J, Boersma E, Flather M, Booth J, Stables R, Rodriguez 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. [8] Rodriguez AE, Baldi J, Fernández Pereira C, Navia J, Rodriguez Alemparte M, Delacasa A, et al. Five-year follow-up of the Argentine randomized trial of coronary angioplasty with stenting versus coronary bypass surgery in patients with multiple vessel disease (ERACI II). J Am Coll Cardiol 2005;46(4):582–6. [9] Serruys PW, Ong AT, van Herwerden LA, Sousa JE, Jatene A, Bonnier JJ, et al. Five-year outcomes after coronary stenting versus bypass surgery for the treatment of multivessel disease: the final analysis of the Arterial Revascularization Therapies Study (ARTS) randomized trial. J Am Coll Cardiol 2005;46:575 [Cuando hablo de los resultados con BMS, en donde va el metaanálisis de Daemen]. [10] Hueb W, Lopes NH, Gersh BJ, Soares P, Machado LA, Jatene FB, et al. Five-year followup of the Medicine, Angioplasty, or Surgery Study (MASS II): a randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation 2007;115:1082–9. [11] Booth J, Clayton T, Pepper J, Nugara F, Flather M, Sigwart U, et al. Randomized, controlled trial of coronary artery bypass surgery versus percutaneous coronary intervention in patients with multivessel coronary artery disease: six-year followup from the Stent or Surgery Trial (SoS). Circulation 2008;118:381–8. [12] Rodriguez AE. Are drug-eluting stents superior to bare metal stents when compared to coronary artery bypass surgery? Show me the data. Cardiovasc Revasc Med 2013; 14(2):90–2. [13] Mohr FW, Morice MC, Kappetein AP, Feldman TE, Ståhle E, Colombo A, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381(9867):629–38 [Donde ponemos el metaanálisis]. [14] Rodriguez AE, Maree AO, Mieres J, Berrocal D, Grinfeld L, Fernandez-Pereira C, et al. Late loss of early benefit from drug-eluting stents when compared with bare-metal stents and coronary artery bypass surgery: 3 years follow-up of the ERACI III registry. Eur Heart J 2007;28(17):2118–25.
423
[15] Farooq V, Serruys PW, Zhang Y, Mack M, Ståhle E, Holmes DR, et al. Short and long term clinical impact of stent thrombosis and graft occlusion in the synergy between percutaneous coronary intervention with Taxus and Cardiac Surgery Trial: The SYNTAX Trial at 5 years. J Am Coll Cardiol 2013;62(25):2360–9. [16] Verma S, Farkouh ME, Yanagawa B, Fitchett DH, Ahsan MR, Ruel M, et al. Comparison of coronary artery bypass surgery and percutaneous coronary intervention in patients with diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 2013;1(4):317–28. [17] Kappetein AP, Head SJ, Morice MC, Banning AP, Serruys PW, Mohr FW, et al. Treatment of complex coronary artery disease in patients with diabetes: 5-year results comparing outcomes of bypass surgery and percutaneous coronary intervention in the SYNTAX trial. Eur J Cardiothorac Surg 2013;43(5):1006–13. [18] Dangas GD, Farkouh ME, Sleeper LA, Yang M, Schoos MM, Macaya C, et al. Long term outcome of PCI versus CABG in insulin and non-insulin treated diabetic patients: results from the FREEDOM Trial. J Am Coll Cardiol 2014;64:1189–97. [19] Antoniucci D. SYNTAX mistakes. Rev Argent Cardioangiol 2013;4(03): 151–0154. [20] Stone GW, Midei M, Newman W, Sanz M, Hermiller JB, Williams J, et al. Randomized comparison of everolimus-eluting and paclitaxel-eluting stents: two-year clinical follow-up from the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions (SPIRIT) III trial. Circulation 2009;119:680–6. [21] Brener SJ, Kereiakes DJ, Simonton CA, Rizvi A, Newman W, Mastali K, et al. Everolimus-eluting stents in patients undergoing percutaneous coronary intervention: final 3-year results of the Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With de Novo Native Coronary Artery Lesions trial. Am Heart J 2013;166(6):1035–42. [22] Byrne RA, Kastrati A, Kufner S, Massberg S, Birkmeier KA, Laugwitz KL, et al. Intracoronary stenting and angiographic results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Investigators. Randomized, noninferiority trial of three limus agent-eluting stents with different polymer coatings: the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Trial. Eur Heart J 2009;30(20):2441–9. [23] Stefanini GG, Byrne RA, Serruys PW, de Waha A, Meier B, Massberg S, et al. Biodegradable polymer drug-eluting stents reduce the risk of stent thrombosis at 4 years in patients undergoing percutaneous coronary intervention: a pooled analysis of individual patient data from the ISAR-TEST 3, ISAR-TEST 4, and LEADERS randomized trials. Eur Heart J 2012;33(10):1214–22. [24] Sarno G, Lagerqvist B, Fröbert O, Nilsson J, Olivecrona G, Omerovic E, et al. Lower risk of stent thrombosis and restenosis with unrestricted use of 'newgeneration' drug-eluting stents: a report from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Eur Heart J 2012;33 (5):606–1325. [25] Grube E, Chevalier B, Guagliumi G, Smits PC, Stuteville M, Dorange C, et al. The SPIRIT V diabetic study: a randomized clinical evaluation of the XIENCE V everolimus eluting stent vs the TAXUS Liberté paclitaxel-eluting stent in diabeticpatients with de novo coronary artery lesions. Am Heart J 2012;163:867–75. [26] Park GM, Lee SW, Park SW, Kim YH, Yun SC, Cho YR, et al. Comparison of zotarolimus-eluting stent versus sirolimus-eluting stent for de novo coronary artery disease in patients with diabetes mellitus from the ESSENCE-DIABETES II trial. Am J Cardiol 2013;112(10):1565–70. [27] Simsek C, Räber L, Magro M, Boersma E, Onuma Y, Stefanini GG, et al. Long-term outcome of the unrestricted use of everolimus-eluting stents compared to sirolimuseluting stents and paclitaxel-eluting stents indiabetic patients: the Bern–Rotterdam diabetes cohort study. Int J Cardiol 2013;170:36–42. [28] Muramatsu T, Onuma Y, van Geuns RJ, Chevalier B, Patel TM, Seth A, et al. 1-Year clinical outcomes of diabetic patients treated with everolimus-eluting bioresorbable vascular scaffolds. J Am Coll Cardiol Intv 2014;7:482–93. [29] Serruys PW, Onuma Y, Garg S, Vranckx P, De Bruyne B, Morice MC, et al. 5-year clinical outcomes of the ARTS II (Arterial Revascularization Therapies Study II) of the sirolimus-eluting stent in the treatment of patients with multivessel de novo coronary artery lesions. J Am Coll Cardiol 2010;55(11):1093–101. [30] Boothroyd DM, Mieres JJ, Grinfeld L, Fernández-Pereira C, Rodríguez-Granillo AM, Berrocal D, et al. Comparative effectiveness at five years of drug-eluting stents, bare metal stents, and coronary bypass surgery: the ERACI III study. Rev Argent Cardioangiol 2012;3(03):0135–46. [31] Haiek C, Fernandez-Pereira C, Santaera O, Sarmiento R, Larribau M, Pocovi A, et al. Revascularization strategies for patients with multiple vessel disease and unprotected left main with a cobalt-chromium rapamycin eluting stent (ERACI IV Registry). European Congress of Cardiology, Abstract Presentation 303, Barcelona, Spain, August 31, 2014; 2014.
