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CABG versus PCI in diabetic patients with multivessel disease after risk stratification by the SYNTAX score: A pooled analysis of the SYNTAX and FREEDOM trials
548
Letters to the Editor
CABG versus PCI in diabetic patients with multivessel disease after risk stratification by the SYNTAX score: A pooled analysis of the SYNTAX and FREEDOM trials☆ Davide Capodanno ⁎, Piera Capranzano, Corrado Tamburino Ferrarotto Hospital, University of Catania, Catania, Italy
a r t i c l e
i n f o
Article history: Received 15 January 2014 Received in revised form 9 March 2014 Accepted 12 March 2014 Available online 20 March 2014 Keywords: CABG PCI Diabetes
The 2010 European guidelines for myocardial revascularization indicate coronary artery bypass grafting (CABG) as a class I recommendation for patients with stable coronary multivessel disease (MVD), regardless of the angiographic burden reflected by the SYNTAX score [1]. In contrast, percutaneous coronary intervention (PCI) is contraindicated (class III) in patients with MVD and intermediate to high (N22) SYNTAX score, while it is considered reasonable (class IIa) in patients with MVD and low (0–22) SYNTAX score. Recently, in the 2013 European guidelines on the management of patients with diabetes mellitus, PCI for MVD has been given a class IIb indication for symptom relief and as an alternative to CABG in patients with low SYNTAX score [2]. This stricter recommendation for MVD and diabetes mainly stems from the findings of the SYNTAX and FREEDOM trials [3,4]. In SYNTAX, a trial of PCI versus CABG in patients with complex coronary artery disease, diabetic patients (N = 452) were part of a pre-specified sub-analysis and accounted for 25% of the entire population [3]. In FREEDOM, patients with diabetes (N = 1900) and MVD were randomized to PCI or CABG [4]. Data on the treatment by SYNTAX score interaction for the composite outcome of all-cause death, non-fatal myocardial infarction, or stroke are available for both trials at 5 years, with mixed results. In the SYNTAX trial, CABG was superior to PCI only in patients with high SYNTAX score, with no differences in the low and intermediate SYNTAX score groups, whereas in the FREEDOM trial, the rates of all-cause death, nonfatal myocardial infarction, or stroke at 5 years were higher with PCI regardless of the SYNTAX score category, although formal statistical significance was achieved only in the intermediate SYNTAX score group, possibly as the reflection of a power issue, particularly evident in patients with high SYNTAX score. A recent meta-analysis by Verma et al. [5] including study-level data from the SYNTAX and FREEDOM trials, focused on the comparison between CABG and PCI in the overall diabetic population, but did not explore the effect of the two revascularization strategies according to baseline angiographic complexity [5]. To clarify whether the SYNTAX score impacts on the comparative effectiveness of CABG and PCI in patients with MVD and diabetes, and increase the power of intra-group comparisons, we conducted a studylevel pooled analysis of the SYNTAX (diabetic cohort) and the FREEDOM ☆ The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Cardiology Department, Ferrarotto Hospital, University of Catania, Via Citelli 6, 95124 Catania, Italy. Tel.: + 39 0957436202; fax: +39 095362429. E-mail address: [email protected] (D. Capodanno).
trials (i.e., the only revascularization trials reporting outcomes of patients with diabetes stratified by the SYNTAX score). The endpoint of interest was the 5-year incidence of all-cause death, non-fatal myocardial infarction, or stroke. Risk ratios (RRs) and confidence intervals (CIs) were derived on the basis of the reported Kaplan–Meier time-to-event estimates (%) and the number of patients at risk for each treatment arm (N). The number of events for each group was estimated as n = N*%. The results of the studies were combined using a randomeffects model, which incorporate between-trial heterogeneity and give wider and more conservative CIs compared with fixed effects models. A 2-tailed alpha of 5% was used for hypothesis testing. Statistical heterogeneity was assessed with Cochran Q via a chi-square test and quantified with the I2 test. Statistical analysis was performed using Review Manager version 5.2. Only first-generation drug-eluting stents were used in the PCI arms of both trials. Hemoglobin A1c ≥7.0% at study entry was noted in 57% of patients in the SYNTAX diabetic cohort and 64% of patients in the FREEDOM trial. Three-vessel disease was similarly prevalent in the two studies (83%), while only the SYNTAX trial allowed the inclusion of patients with left main disease (29%). Only 6% of patients in the diabetes cohort of the SYNTAX trial presented with left main only or left main plus one vessel. A higher mean number of coronary lesions were treated in the FREEDOM trial than in the SYNTAX trial (5.7 ± 2.2 versus 4.6 ± 1.8). However, the mean SYNTAX score was higher in the SYNTAX trial (29.0 ± 11.2 versus 26.2 ± 8.6), likely reflecting the inclusion of patients with left main disease. Pooled analyses by SYNTAX score groups demonstrated that there was a significant increase in the composite endpoint at 5 years after PCI with increasing SYNTAX scores (22.6%, 26.4% and 30.9% in the low, intermediate and high SYNTAX score groups, respectively, P = 0.04), while this was not significant for CABG (17.5%, 18.2% and 21%, respectively, P = 0.50). The outcomes of the meta-analysis are shown in Fig. 1. No significant heterogeneity was found between the two trials. In patients with low and intermediate SYNTAX scores, respectively, there was a trend towards significant 22% and 28% relative risk reductions for the composite endpoint with CABG versus PCI (low SYNTAX score: OR 0.78, 95% CI 0.59–1.04, P = 0.09; intermediate SYNTAX score: OR 0.72, 95% CI 0.51–1.00, P = 0.05). In patients with high SYNTAX score, CABG significantly reduced the risk of the composite endpoint by 31% (OR 0.69, 95% CI 0.51–0.92, P = 0.01). The RRs of CABG versus PCI for the three SYNTAX score groups did not differ significantly (P for interaction = 0.81). The conclusions drawn from this meta-analysis are obviously subject to the limitations of the original included studies themselves. In particular, a residual type II error to explain the lack of formal statistical significance for the difference between CABG and PCI observed in the low and intermediate SYNTAX score groups is likely. Nevertheless, we found the signal of a strong numerical reduction in the composite of all-cause death, non-fatal myocardial infarction or stroke with CABG versus PCI regardless of the SYNTAX score category. Also, the test for interaction was negative, suggesting that the established benefit of CABG in diabetic patients with MVD is independent from the angiographic complexity reflected by the SYNTAX score. Of note, a gradient in adverse events after PCI with increasing SYNTAX score tertiles was shown, which was not observed with CABG. In the SYNTAX trial, there was a larger numerical absolute increase in hard events from the lowest to the highest SYNTAX score
Letters to the Editor
549
Fig. 1. Forest plot for all-cause death, non-fatal myocardial infarction or stroke at 5 years.Individual study and pooled RRs for all-cause death, non-fatal myocardial infarction or stroke in trials comparing patients with diabetes and multivessel coronary artery disease who had CABG or PCI after 5 years. The pooled RRs with 95% CI were calculated using randomeffects models both overall and for the subgroups of SYNTAX score. CABG = coronary artery bypass graft surgery. CI = confidence interval. PCI = percutaneous coronary intervention. RR = risk ratio.
tertile with PCI compared with CABG for both all-cause death (+ 10.3% vs 1.3%) and non-fatal myocardial infarction (+ 2.3% vs − 0.3%) at 5 years [6]. This may be explained by the notion that over the long term CABG offers prophylaxis against the development of newly-onset proximal disease, making the angiographic complexity of the bypassed vessel of less importance, while PCI with stents only addresses localized lesions and does not offer prophylactic advantages against new disease. Also, compared with patients in the lowest SYNTAX score tertiles, patients in the highest tertiles are known to present with a higher prevalence of clinical features (i.e., low left ventricular ejection fraction, impaired renal function) that impact on the long-term outcomes of PCI to a higher extent than what is observed with CABG [7,8]. Our findings complement and extend those from Verma et al., who found a 33% relative reduction in the risk of long-term mortality with CABG over PCI in patients with MVD and diabetes [5]. Based on the above, we suggest that CABG should preferentially be considered in such patients regardless of the angiographic complexity, and the SYNTAX score should not be used as the sole criterion to identify patients who are eventually suitable to PCI. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. http://dx.doi.org/10.1016/j.ijcard.2014.03.077 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
References [1] Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J 2010;31:2501–55. [2] Rydén L, Grant PJ, Anker SD, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 2013;34:3035–87. [3] Kappetein AP, Head SJ, Morice MC, 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;43:1006–13. [4] Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367:2375–84. [5] Verma S, Farkouh ME, Yanagawa B, et al. Comparison of coronary artery bypass surgery and percutaneous coronary intervention in patients with diabetes: a metaanalysis of randomised controlled trials. Lancet Diabetes 2013;1:317–28. [6] Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381:629–38. [7] Capodanno D, Capranzano P, Di Salvo ME, et al. Usefulness of SYNTAX score to select patients with left main coronary artery disease to be treated with coronary artery bypass graft. JACC Cardiovasc Interv 2009;2:731–8. [8] Farooq V, van Klaveren D, Steyerberg EW, et al. Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II. Lancet Feb 23 2013;381(9867):639–50.
Letters to the Editor
CABG versus PCI in diabetic patients with multivessel disease after risk stratification by the SYNTAX score: A pooled analysis of the SYNTAX and FREEDOM trials☆ Davide Capodanno ⁎, Piera Capranzano, Corrado Tamburino Ferrarotto Hospital, University of Catania, Catania, Italy
a r t i c l e
i n f o
Article history: Received 15 January 2014 Received in revised form 9 March 2014 Accepted 12 March 2014 Available online 20 March 2014 Keywords: CABG PCI Diabetes
The 2010 European guidelines for myocardial revascularization indicate coronary artery bypass grafting (CABG) as a class I recommendation for patients with stable coronary multivessel disease (MVD), regardless of the angiographic burden reflected by the SYNTAX score [1]. In contrast, percutaneous coronary intervention (PCI) is contraindicated (class III) in patients with MVD and intermediate to high (N22) SYNTAX score, while it is considered reasonable (class IIa) in patients with MVD and low (0–22) SYNTAX score. Recently, in the 2013 European guidelines on the management of patients with diabetes mellitus, PCI for MVD has been given a class IIb indication for symptom relief and as an alternative to CABG in patients with low SYNTAX score [2]. This stricter recommendation for MVD and diabetes mainly stems from the findings of the SYNTAX and FREEDOM trials [3,4]. In SYNTAX, a trial of PCI versus CABG in patients with complex coronary artery disease, diabetic patients (N = 452) were part of a pre-specified sub-analysis and accounted for 25% of the entire population [3]. In FREEDOM, patients with diabetes (N = 1900) and MVD were randomized to PCI or CABG [4]. Data on the treatment by SYNTAX score interaction for the composite outcome of all-cause death, non-fatal myocardial infarction, or stroke are available for both trials at 5 years, with mixed results. In the SYNTAX trial, CABG was superior to PCI only in patients with high SYNTAX score, with no differences in the low and intermediate SYNTAX score groups, whereas in the FREEDOM trial, the rates of all-cause death, nonfatal myocardial infarction, or stroke at 5 years were higher with PCI regardless of the SYNTAX score category, although formal statistical significance was achieved only in the intermediate SYNTAX score group, possibly as the reflection of a power issue, particularly evident in patients with high SYNTAX score. A recent meta-analysis by Verma et al. [5] including study-level data from the SYNTAX and FREEDOM trials, focused on the comparison between CABG and PCI in the overall diabetic population, but did not explore the effect of the two revascularization strategies according to baseline angiographic complexity [5]. To clarify whether the SYNTAX score impacts on the comparative effectiveness of CABG and PCI in patients with MVD and diabetes, and increase the power of intra-group comparisons, we conducted a studylevel pooled analysis of the SYNTAX (diabetic cohort) and the FREEDOM ☆ The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Cardiology Department, Ferrarotto Hospital, University of Catania, Via Citelli 6, 95124 Catania, Italy. Tel.: + 39 0957436202; fax: +39 095362429. E-mail address: [email protected] (D. Capodanno).
trials (i.e., the only revascularization trials reporting outcomes of patients with diabetes stratified by the SYNTAX score). The endpoint of interest was the 5-year incidence of all-cause death, non-fatal myocardial infarction, or stroke. Risk ratios (RRs) and confidence intervals (CIs) were derived on the basis of the reported Kaplan–Meier time-to-event estimates (%) and the number of patients at risk for each treatment arm (N). The number of events for each group was estimated as n = N*%. The results of the studies were combined using a randomeffects model, which incorporate between-trial heterogeneity and give wider and more conservative CIs compared with fixed effects models. A 2-tailed alpha of 5% was used for hypothesis testing. Statistical heterogeneity was assessed with Cochran Q via a chi-square test and quantified with the I2 test. Statistical analysis was performed using Review Manager version 5.2. Only first-generation drug-eluting stents were used in the PCI arms of both trials. Hemoglobin A1c ≥7.0% at study entry was noted in 57% of patients in the SYNTAX diabetic cohort and 64% of patients in the FREEDOM trial. Three-vessel disease was similarly prevalent in the two studies (83%), while only the SYNTAX trial allowed the inclusion of patients with left main disease (29%). Only 6% of patients in the diabetes cohort of the SYNTAX trial presented with left main only or left main plus one vessel. A higher mean number of coronary lesions were treated in the FREEDOM trial than in the SYNTAX trial (5.7 ± 2.2 versus 4.6 ± 1.8). However, the mean SYNTAX score was higher in the SYNTAX trial (29.0 ± 11.2 versus 26.2 ± 8.6), likely reflecting the inclusion of patients with left main disease. Pooled analyses by SYNTAX score groups demonstrated that there was a significant increase in the composite endpoint at 5 years after PCI with increasing SYNTAX scores (22.6%, 26.4% and 30.9% in the low, intermediate and high SYNTAX score groups, respectively, P = 0.04), while this was not significant for CABG (17.5%, 18.2% and 21%, respectively, P = 0.50). The outcomes of the meta-analysis are shown in Fig. 1. No significant heterogeneity was found between the two trials. In patients with low and intermediate SYNTAX scores, respectively, there was a trend towards significant 22% and 28% relative risk reductions for the composite endpoint with CABG versus PCI (low SYNTAX score: OR 0.78, 95% CI 0.59–1.04, P = 0.09; intermediate SYNTAX score: OR 0.72, 95% CI 0.51–1.00, P = 0.05). In patients with high SYNTAX score, CABG significantly reduced the risk of the composite endpoint by 31% (OR 0.69, 95% CI 0.51–0.92, P = 0.01). The RRs of CABG versus PCI for the three SYNTAX score groups did not differ significantly (P for interaction = 0.81). The conclusions drawn from this meta-analysis are obviously subject to the limitations of the original included studies themselves. In particular, a residual type II error to explain the lack of formal statistical significance for the difference between CABG and PCI observed in the low and intermediate SYNTAX score groups is likely. Nevertheless, we found the signal of a strong numerical reduction in the composite of all-cause death, non-fatal myocardial infarction or stroke with CABG versus PCI regardless of the SYNTAX score category. Also, the test for interaction was negative, suggesting that the established benefit of CABG in diabetic patients with MVD is independent from the angiographic complexity reflected by the SYNTAX score. Of note, a gradient in adverse events after PCI with increasing SYNTAX score tertiles was shown, which was not observed with CABG. In the SYNTAX trial, there was a larger numerical absolute increase in hard events from the lowest to the highest SYNTAX score
Letters to the Editor
549
Fig. 1. Forest plot for all-cause death, non-fatal myocardial infarction or stroke at 5 years.Individual study and pooled RRs for all-cause death, non-fatal myocardial infarction or stroke in trials comparing patients with diabetes and multivessel coronary artery disease who had CABG or PCI after 5 years. The pooled RRs with 95% CI were calculated using randomeffects models both overall and for the subgroups of SYNTAX score. CABG = coronary artery bypass graft surgery. CI = confidence interval. PCI = percutaneous coronary intervention. RR = risk ratio.
tertile with PCI compared with CABG for both all-cause death (+ 10.3% vs 1.3%) and non-fatal myocardial infarction (+ 2.3% vs − 0.3%) at 5 years [6]. This may be explained by the notion that over the long term CABG offers prophylaxis against the development of newly-onset proximal disease, making the angiographic complexity of the bypassed vessel of less importance, while PCI with stents only addresses localized lesions and does not offer prophylactic advantages against new disease. Also, compared with patients in the lowest SYNTAX score tertiles, patients in the highest tertiles are known to present with a higher prevalence of clinical features (i.e., low left ventricular ejection fraction, impaired renal function) that impact on the long-term outcomes of PCI to a higher extent than what is observed with CABG [7,8]. Our findings complement and extend those from Verma et al., who found a 33% relative reduction in the risk of long-term mortality with CABG over PCI in patients with MVD and diabetes [5]. Based on the above, we suggest that CABG should preferentially be considered in such patients regardless of the angiographic complexity, and the SYNTAX score should not be used as the sole criterion to identify patients who are eventually suitable to PCI. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. http://dx.doi.org/10.1016/j.ijcard.2014.03.077 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
References [1] Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J 2010;31:2501–55. [2] Rydén L, Grant PJ, Anker SD, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 2013;34:3035–87. [3] Kappetein AP, Head SJ, Morice MC, 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;43:1006–13. [4] Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367:2375–84. [5] Verma S, Farkouh ME, Yanagawa B, et al. Comparison of coronary artery bypass surgery and percutaneous coronary intervention in patients with diabetes: a metaanalysis of randomised controlled trials. Lancet Diabetes 2013;1:317–28. [6] Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381:629–38. [7] Capodanno D, Capranzano P, Di Salvo ME, et al. Usefulness of SYNTAX score to select patients with left main coronary artery disease to be treated with coronary artery bypass graft. JACC Cardiovasc Interv 2009;2:731–8. [8] Farooq V, van Klaveren D, Steyerberg EW, et al. Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II. Lancet Feb 23 2013;381(9867):639–50.