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Meta-analysis of everolimus-eluting stents versus first-generation drug-eluting stents in patients with left main coronary artery undergoing percutaneous coronary intervention
1718
Letters to the Editor
Meta-analysis of everolimus-eluting stents versus first-generation drug-eluting stents in patients with left main coronary artery undergoing percutaneous coronary intervention Davide Capodanno ⁎, Piera Capranzano, Alessio La Manna, Corrado Tamburino Cardiology Department, Ferrarotto Hospital, University of Catania, Via Citelli 6, 95124, Catania, Italy
a r t i c l e
i n f o
Article history: Received 12 January 2013 Accepted 28 March 2013 Available online 30 April 2013 Keywords: Everolimus-eluting stents Left main coronary artery Percutaneous coronary intervention
In a pooled analysis of randomized clinical trials, percutaneous coronary intervention (PCI) of the left main coronary artery (LMCA) with first-generation drug-eluting stents (DES) was shown to achieve similar 1-year rates of death and myocardial infarction (MI), higher rates of repeat revascularization, and lower rates of stroke compared with coronary artery bypass grafting (CABG) [1]. Second-generation everolimus-eluting stents (EES) compare favorably with first generation DES [2,3]. However, whether EES are more effective than firstgeneration DES in the context of LMCA PCI is unknown. We therefore performed a meta-analysis to examine the relative effectiveness of EES compared with first-generation DES in patients with LMCA disease. We searched MEDLINE, EMBASE and Cochrane databases from January 2002 to December 2012 using Internet-based engines, with no language restrictions. The terms used for research included “left main”, “percutaneous coronary intervention”, and “everolimus-eluting stent(s)”. Additional sources included www.clinicaltrials.gov, www.clinicaltrialresults.org, www.tctmd.com, www.cardiosource.com, Google Scholar and abstracts/presentations from major cardiovascular meetings. Furthermore, we searched the reference lists of relevant studies and reviews, editorials and letters. We restricted our analysis to studies that met all the following inclusion criteria: 1) study population of LMCA disease; 2) comparison of EES vs. first-generation sirolimus-eluting [SES] and/or paclitaxel-eluting stents [PES]; and 3) efficacy outcomes were reported. The most updated or inclusive data for a given study were chosen for abstraction. The following outcomes were extracted: death (all-cause or cardiac), non-fatal MI, repeat revascularization (target vessel revascularization or target lesion revascularization), and stent thrombosis (ST, definite or probable/definite combined). Because of the varying lengths of follow-up and varying baseline risk among studies, the measure of association derived was a relative risk rather than absolute risk or event rate. Hazard ratios (HRs) or odds ratios (ORs) with confidence intervals (CIs) were either directly abstracted or derived on the basis of the reported event rates. When both hazard ratios (HR) and OR were reported as endpoints across studies, they were combined, assuming that the follow-up was fairly complete (and thus the HR would be similar to the expected OR). Similarly, Kaplan–Meier rates and percentages were combined when 1 of the 2 was not available for an endpoint. For observational studies reporting unadjusted, adjusted, or propensity-matched data, the highest-quality estimate was picked for the overall meta-analysis (using the following rank order: propensity matched N adjusted N unadjusted). The results of all studies were combined using a random-effects model to minimize ⁎ Corresponding author. Tel.: +39 0957436202; fax: +39 095362429. E-mail address: [email protected] (D. Capodanno).
heterogeneity between groups, and confirmed by a fixed-effects model to avoid overweighting of smaller studies and account for differential loss to follow-up in treatment arms, if any. 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. The influence of single studies was examined by excluding individual studies, and testing for systematic bias was performed using funnel plots and Begg's test. Statistical analysis was performed using Comprehensive Meta-Analysis v2.0 (Biostat, Englewood NJ). We identified 14 potentially relevant studies. Eleven studies were excluded after title and abstract screening. The remaining 3 studies were retrieved in full for detailed evaluation and were found to meet the inclusion criteria [4–6]. We identified one more relevant study by searching unpublished trials on tctmd.com [7]. Four studies were therefore included in this systematic review [4–7] (Table 1). All studies were observational, reporting data from 2231 patients. Two studies compared EES versus PES [4,6], one study compared EES versus SES [6], and one study compared EES versus a combination of PES and SES [5]. Two studies provided adjusted outcomes by propensity score matching [4,6] and two studies by multivariate analysis [5,7]. Separate estimates of death and MI were not reported in the ESTROFA-LM study [6]. The outcomes of the meta-analysis are listed in Table 2. There were no statistically significant differences in death (HR 1.04, 95% CI 0.69–1.58, P = 0.25), non fatal MI (HR 0.58, 95% CI 0.22–1.53, P =0.27) and repeat revascularization (HR 0.78, 95% CI 0.41–1.49, P =0.45) with EES versus first-generation DES. On the other hand, a trend was noted towards a reduction of ST with EES (HR 0.51, 95% CI 0.22–1.15, P = 0.11). No systematic bias was reported across the studies, but there was a significant heterogeneity in the endpoint of repeat revascularization (I2 = 73%, P = 0.01), with no differences in analyses restricted to studies comparing EES versus PES (HR 0.66, 95% CI 0.12–3.59, P = 0.64) or SES (HR 1.14, 95% CI 0.64–2.05, P = 0.66). However, none of the studies was found to unduly influence the significance of each estimate. The conclusions drawn from this meta-analysis are obviously subject to the limitations of the original included studies themselves. We found the signal of a numerical yet not significant relative reduction in ST with second-generation EES, consistent with recent meta-analyses of EES versus first-generation DES in PCI trials [2,3]. In our study, however, this benefit was not found to translate into a significant difference in death, non fatal MI and repeat revascularization compared with firstgeneration DES. The only randomized trial of EES in LMCA disease reported so far showed similar clinical and angiographic outcomes at 1-year follow up versus zotarolimus-eluting stents [8]. The ongoing EXCEL trial (NCT01205776) is randomizing patients with LMCA disease to EES or CABG. The use of EES, along with a strong recommendation for intravascular ultrasound guidance, the exclusion of repeat revascularization from the primary endpoint, and restriction to patients with SYNTAX score b33, is expected to ameliorate the outcomes of PCI compared with the SYNTAX trial [9]. However, based on the present meta-analysis of adjusted observational data, the expectation that EES will play a major role in driving this improvement could be overoptimistic. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
Letters to the Editor
1719
Table 1 Clinical, angiographic and procedural characteristics of included studies. Author
Ref.
Year
Group
N
Age (mean years)
Male (%)
Diabetes (%)
ACS
Distal LMCA disease (%)
MVD (%)
SYNTAX score (mean n)
IVUS (%)
2 stents for distal LMCA (%)
Angiographic follow up (%)
ESTROFA-LM (unmatched cohorts) ESTROFA-LM (matched cohorts) Bern–Rotterdam
6
2013
6
2013
7
2012
77 79 78 77 75
42 31 38 33 17
70 69 69 70 46
5
2012
Valenti et al (unmatched cohorts) Valenti et al (matched cohorts)
4
2012 2012
63 62 71 71 71 71
71 76 77 80 77 75
35 33 24 30 24 26
45 47 53 67 53 65
53 53 47 45 NR NR 72 67 91 86 91 85
74 67 66 65 NR NR 57 71 75 70 NR NR
NR NR NR NR NR NR 21 24 NR NR NR NR
35 26 33 36 NR NR 90 90 57 49 NR NR
10 17 6 7 NR NR 26 34 31 40 31 30
NR NR NR NR NR NR 61 76 98
4
355 415 200 200 233 410 334 327 166 224 166 166
68 69 67 67 67
PRECOMBAT 2
EES Control EES Control EES Control EES Control EES Control EES Control
NR NR
ACS = acute coronary syndromes; IVUS = intravascular ultrasound, LMCA = left main coronary artery; MVD = multivessel disease; PES = paclitaxel eluting stents; SES =sirolimus-eluting stents.
Table 2 Clinical outcomes.
Death Non fatal MI Repeat revascularization ST
Studies, n
N
Random effects
P
Fixed effects
P
I2, %
Heterogeneity, P
Systematic bias, P
3 3 4 4
1461 1461 2231 2231
1.04 (0.69–1.58) 0.58 (0.22–1.53) 0.78 (0.41–1.49) 0.51 (0.22–1.15)
0.25 0.27 0.45 0.11
1.04 (0.69–1.58) 0.60 (0.27–1.32) 0.85 (0.61–1.17) 0.51 (0.22–1.15)
0.25 0.21 0.31 0.11
0 32 73 0
0.48 0.23 0.01 0.40
0.12 0.60 1.00 0.50
MI = myocardial infarction; ST = stent thrombosis.
References [1] Capodanno D, Stone GW, Morice MC, Bass TA, Tamburino C. Percutaneous coronary intervention versus coronary artery bypass graft surgery in left main coronary artery disease: a meta-analysis of randomized clinical data. J Am Coll Cardiol 2011;58:1426–32. [2] Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012;379:1393–402. [3] de Waha A, Cassese S, Park DW, Burzotta F, et al. Everolimus-eluting versus sirolimuseluting stents: an updated meta-analysis of randomized trials. Clin Res Cardiol 2012;101:461–7. [4] Valenti R, Migliorini A, Parodi G, et al. Clinical and angiographic outcomes of patients treated with everolimus-eluting stents or first-generation Paclitaxel-eluting stents for unprotected left main disease. J Am Coll Cardiol 2012;60:1217–22. [5] Kim YH, Park DW, Ahn JM, et al. Everolimus-eluting stent implantation for unprotected left main coronary artery stenosis. The PRECOMBAT-2 (Premier of Randomized
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.03.135
[6]
[7]
[8]
[9]
Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease) study. JACC Cardiovasc Interv 2012;5:708–17. De la Torre Hernandez JM, Alfonso F, Recalde AS, et al. Comparison of paclitaxeleluting stents (Taxus) and everolimus-eluting stents (Xience) in left main coronary artery disease with 3 years follow-up (from the ESTROFA-LM Registry). Am J Cardiol 2013 Mar 1;111:676–83. Moschovitis A, Stefanini GG, Magro M, et al. The impact of left main disease on longterm clinical outcomes among patients treated with the unrestricted use of everolimus-, sirolimus-, and paclitaxel-eluting stents. a substudy of the Bern– Rotterdam Registry. Presented at Transcatheter Cardiovascular Therapeutics in Miami (FL); October 2012. Mehilli J. Zotarolimus- vs. everolimus-eluting stents for treatment of unprotected left main coronary artery lesions. Presented at Transcatheter Cardiovascular Therapeutics in Miami (FL); October 2012. Capodanno D, Tamburino C. Unraveling the EXCEL: promises and challenges of the next trial of left main percutaneous coronary intervention. Int J Cardiol 2012;156:1–3.
Letters to the Editor
Meta-analysis of everolimus-eluting stents versus first-generation drug-eluting stents in patients with left main coronary artery undergoing percutaneous coronary intervention Davide Capodanno ⁎, Piera Capranzano, Alessio La Manna, Corrado Tamburino Cardiology Department, Ferrarotto Hospital, University of Catania, Via Citelli 6, 95124, Catania, Italy
a r t i c l e
i n f o
Article history: Received 12 January 2013 Accepted 28 March 2013 Available online 30 April 2013 Keywords: Everolimus-eluting stents Left main coronary artery Percutaneous coronary intervention
In a pooled analysis of randomized clinical trials, percutaneous coronary intervention (PCI) of the left main coronary artery (LMCA) with first-generation drug-eluting stents (DES) was shown to achieve similar 1-year rates of death and myocardial infarction (MI), higher rates of repeat revascularization, and lower rates of stroke compared with coronary artery bypass grafting (CABG) [1]. Second-generation everolimus-eluting stents (EES) compare favorably with first generation DES [2,3]. However, whether EES are more effective than firstgeneration DES in the context of LMCA PCI is unknown. We therefore performed a meta-analysis to examine the relative effectiveness of EES compared with first-generation DES in patients with LMCA disease. We searched MEDLINE, EMBASE and Cochrane databases from January 2002 to December 2012 using Internet-based engines, with no language restrictions. The terms used for research included “left main”, “percutaneous coronary intervention”, and “everolimus-eluting stent(s)”. Additional sources included www.clinicaltrials.gov, www.clinicaltrialresults.org, www.tctmd.com, www.cardiosource.com, Google Scholar and abstracts/presentations from major cardiovascular meetings. Furthermore, we searched the reference lists of relevant studies and reviews, editorials and letters. We restricted our analysis to studies that met all the following inclusion criteria: 1) study population of LMCA disease; 2) comparison of EES vs. first-generation sirolimus-eluting [SES] and/or paclitaxel-eluting stents [PES]; and 3) efficacy outcomes were reported. The most updated or inclusive data for a given study were chosen for abstraction. The following outcomes were extracted: death (all-cause or cardiac), non-fatal MI, repeat revascularization (target vessel revascularization or target lesion revascularization), and stent thrombosis (ST, definite or probable/definite combined). Because of the varying lengths of follow-up and varying baseline risk among studies, the measure of association derived was a relative risk rather than absolute risk or event rate. Hazard ratios (HRs) or odds ratios (ORs) with confidence intervals (CIs) were either directly abstracted or derived on the basis of the reported event rates. When both hazard ratios (HR) and OR were reported as endpoints across studies, they were combined, assuming that the follow-up was fairly complete (and thus the HR would be similar to the expected OR). Similarly, Kaplan–Meier rates and percentages were combined when 1 of the 2 was not available for an endpoint. For observational studies reporting unadjusted, adjusted, or propensity-matched data, the highest-quality estimate was picked for the overall meta-analysis (using the following rank order: propensity matched N adjusted N unadjusted). The results of all studies were combined using a random-effects model to minimize ⁎ Corresponding author. Tel.: +39 0957436202; fax: +39 095362429. E-mail address: [email protected] (D. Capodanno).
heterogeneity between groups, and confirmed by a fixed-effects model to avoid overweighting of smaller studies and account for differential loss to follow-up in treatment arms, if any. 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. The influence of single studies was examined by excluding individual studies, and testing for systematic bias was performed using funnel plots and Begg's test. Statistical analysis was performed using Comprehensive Meta-Analysis v2.0 (Biostat, Englewood NJ). We identified 14 potentially relevant studies. Eleven studies were excluded after title and abstract screening. The remaining 3 studies were retrieved in full for detailed evaluation and were found to meet the inclusion criteria [4–6]. We identified one more relevant study by searching unpublished trials on tctmd.com [7]. Four studies were therefore included in this systematic review [4–7] (Table 1). All studies were observational, reporting data from 2231 patients. Two studies compared EES versus PES [4,6], one study compared EES versus SES [6], and one study compared EES versus a combination of PES and SES [5]. Two studies provided adjusted outcomes by propensity score matching [4,6] and two studies by multivariate analysis [5,7]. Separate estimates of death and MI were not reported in the ESTROFA-LM study [6]. The outcomes of the meta-analysis are listed in Table 2. There were no statistically significant differences in death (HR 1.04, 95% CI 0.69–1.58, P = 0.25), non fatal MI (HR 0.58, 95% CI 0.22–1.53, P =0.27) and repeat revascularization (HR 0.78, 95% CI 0.41–1.49, P =0.45) with EES versus first-generation DES. On the other hand, a trend was noted towards a reduction of ST with EES (HR 0.51, 95% CI 0.22–1.15, P = 0.11). No systematic bias was reported across the studies, but there was a significant heterogeneity in the endpoint of repeat revascularization (I2 = 73%, P = 0.01), with no differences in analyses restricted to studies comparing EES versus PES (HR 0.66, 95% CI 0.12–3.59, P = 0.64) or SES (HR 1.14, 95% CI 0.64–2.05, P = 0.66). However, none of the studies was found to unduly influence the significance of each estimate. The conclusions drawn from this meta-analysis are obviously subject to the limitations of the original included studies themselves. We found the signal of a numerical yet not significant relative reduction in ST with second-generation EES, consistent with recent meta-analyses of EES versus first-generation DES in PCI trials [2,3]. In our study, however, this benefit was not found to translate into a significant difference in death, non fatal MI and repeat revascularization compared with firstgeneration DES. The only randomized trial of EES in LMCA disease reported so far showed similar clinical and angiographic outcomes at 1-year follow up versus zotarolimus-eluting stents [8]. The ongoing EXCEL trial (NCT01205776) is randomizing patients with LMCA disease to EES or CABG. The use of EES, along with a strong recommendation for intravascular ultrasound guidance, the exclusion of repeat revascularization from the primary endpoint, and restriction to patients with SYNTAX score b33, is expected to ameliorate the outcomes of PCI compared with the SYNTAX trial [9]. However, based on the present meta-analysis of adjusted observational data, the expectation that EES will play a major role in driving this improvement could be overoptimistic. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
Letters to the Editor
1719
Table 1 Clinical, angiographic and procedural characteristics of included studies. Author
Ref.
Year
Group
N
Age (mean years)
Male (%)
Diabetes (%)
ACS
Distal LMCA disease (%)
MVD (%)
SYNTAX score (mean n)
IVUS (%)
2 stents for distal LMCA (%)
Angiographic follow up (%)
ESTROFA-LM (unmatched cohorts) ESTROFA-LM (matched cohorts) Bern–Rotterdam
6
2013
6
2013
7
2012
77 79 78 77 75
42 31 38 33 17
70 69 69 70 46
5
2012
Valenti et al (unmatched cohorts) Valenti et al (matched cohorts)
4
2012 2012
63 62 71 71 71 71
71 76 77 80 77 75
35 33 24 30 24 26
45 47 53 67 53 65
53 53 47 45 NR NR 72 67 91 86 91 85
74 67 66 65 NR NR 57 71 75 70 NR NR
NR NR NR NR NR NR 21 24 NR NR NR NR
35 26 33 36 NR NR 90 90 57 49 NR NR
10 17 6 7 NR NR 26 34 31 40 31 30
NR NR NR NR NR NR 61 76 98
4
355 415 200 200 233 410 334 327 166 224 166 166
68 69 67 67 67
PRECOMBAT 2
EES Control EES Control EES Control EES Control EES Control EES Control
NR NR
ACS = acute coronary syndromes; IVUS = intravascular ultrasound, LMCA = left main coronary artery; MVD = multivessel disease; PES = paclitaxel eluting stents; SES =sirolimus-eluting stents.
Table 2 Clinical outcomes.
Death Non fatal MI Repeat revascularization ST
Studies, n
N
Random effects
P
Fixed effects
P
I2, %
Heterogeneity, P
Systematic bias, P
3 3 4 4
1461 1461 2231 2231
1.04 (0.69–1.58) 0.58 (0.22–1.53) 0.78 (0.41–1.49) 0.51 (0.22–1.15)
0.25 0.27 0.45 0.11
1.04 (0.69–1.58) 0.60 (0.27–1.32) 0.85 (0.61–1.17) 0.51 (0.22–1.15)
0.25 0.21 0.31 0.11
0 32 73 0
0.48 0.23 0.01 0.40
0.12 0.60 1.00 0.50
MI = myocardial infarction; ST = stent thrombosis.
References [1] Capodanno D, Stone GW, Morice MC, Bass TA, Tamburino C. Percutaneous coronary intervention versus coronary artery bypass graft surgery in left main coronary artery disease: a meta-analysis of randomized clinical data. J Am Coll Cardiol 2011;58:1426–32. [2] Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012;379:1393–402. [3] de Waha A, Cassese S, Park DW, Burzotta F, et al. Everolimus-eluting versus sirolimuseluting stents: an updated meta-analysis of randomized trials. Clin Res Cardiol 2012;101:461–7. [4] Valenti R, Migliorini A, Parodi G, et al. Clinical and angiographic outcomes of patients treated with everolimus-eluting stents or first-generation Paclitaxel-eluting stents for unprotected left main disease. J Am Coll Cardiol 2012;60:1217–22. [5] Kim YH, Park DW, Ahn JM, et al. Everolimus-eluting stent implantation for unprotected left main coronary artery stenosis. The PRECOMBAT-2 (Premier of Randomized
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.03.135
[6]
[7]
[8]
[9]
Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease) study. JACC Cardiovasc Interv 2012;5:708–17. De la Torre Hernandez JM, Alfonso F, Recalde AS, et al. Comparison of paclitaxeleluting stents (Taxus) and everolimus-eluting stents (Xience) in left main coronary artery disease with 3 years follow-up (from the ESTROFA-LM Registry). Am J Cardiol 2013 Mar 1;111:676–83. Moschovitis A, Stefanini GG, Magro M, et al. The impact of left main disease on longterm clinical outcomes among patients treated with the unrestricted use of everolimus-, sirolimus-, and paclitaxel-eluting stents. a substudy of the Bern– Rotterdam Registry. Presented at Transcatheter Cardiovascular Therapeutics in Miami (FL); October 2012. Mehilli J. Zotarolimus- vs. everolimus-eluting stents for treatment of unprotected left main coronary artery lesions. Presented at Transcatheter Cardiovascular Therapeutics in Miami (FL); October 2012. Capodanno D, Tamburino C. Unraveling the EXCEL: promises and challenges of the next trial of left main percutaneous coronary intervention. Int J Cardiol 2012;156:1–3.