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A meta-analysis comparing aspirin alone versus dual antiplatelet therapy for the prevention of venous graft failure following coronary artery bypass surgery
CARREV-01736; No of Pages 5 Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Cardiovascular Revascularization Medicine
A meta-analysis comparing aspirin alone versus dual antiplatelet therapy for the prevention of venous graft failure following coronary artery bypass surgery Kirstin Hesterberg a, Aranyak Rawal a, Sajjad Khan b, Abdul Rashid c, David Jones a, Tariq Siddiqui d, Thekrayat A. Khader a, Manu Nayyar a, Rahman Shah a,e,⁎ a
Department of Medicine, University of Tennessee, Memphis, TN, USA Department of Medicine, Aga Khan University, Pakistan c Jackson Clinic, University of Tennessee, Jackson, TN, USA d Department of Medicine, Texas Tech University Health Sciences Center El Paso, TX, USA e Department of Cardiology, Gulf Coast Regional Medical Center, Panama City, FL, USA b
a r t i c l e
i n f o
Article history: Received 16 May 2019 Received in revised form 4 September 2019 Accepted 21 October 2019 Available online xxxx Keywords: Aspirin Saphenous vein graft Coronary artery bypass grafting P2Y12 inhibitors Antiplatelet therapy
a b s t r a c t Background: Aspirin (ASA) monotherapy is the current standard of care after coronary artery bypass grafting (CABG) to prevent saphenous vein graft (SVG) failure. Several small, randomized clinical trials (RCTs) have suggested that dual antiplatelet therapy (DAPT) may be more effective at preventing SVG failure than ASA alone; however, it is unclear whether some P2Y12 inhibitors are more effective than others for the prevention of SVG failure. Methods: Scientific databases and websites were searched to find RCTs. Both traditional pairwise meta-analysis using random-effect model and network meta-analysis using mixed-treatment comparison models were performed to compare the efficacy of various anti-platelet strategies for the prevention of SVG failure. Results: Nine RCTs, which included a total of 1677 patients, were analyzed. Compared to ASA alone, DAPT decreased the risk of graft failure by 37% (RR: 0.63, 95% CI: 0.47–0.86; p = 0.003). In the moderator analysis, the decreased risk of graft failure with DAPT was not significantly different in the ASA + clopidogrel group than in the ASA + ticagrelor group (P-interaction = 0.17). The results of the network meta-analysis were consistent with those from pairwise analyses. The risk of major bleeding was not statistically significantly different between DAPT and ASA alone (RR: 1.35, 95% CI: 0.62–2.94; p = 0.45). Conclusion: In post-CABG patients, DAPT seems to be more effective at preventing graft failure than ASA alone. This strategy does not seem to significantly increase major bleeding risk. Clopidogrel- and ticagrelor-based DAPT seem to be equally effective for this indication. © 2019 Published by Elsevier Inc.
1. Introduction Coronary artery bypass graft surgery (CABG) is the standard of care for the majority of patients with multivessel coronary artery disease (CAD) and high SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) scores or diabetes [1,2]. However, the long-term prognosis of CABG is limited due to the high failure rate of saphenous vein grafts (SVG) as up to 25% fail as early as within a year post-CABG [3]. Therefore, current guidelines supported by clinical trials recommend aspirin (ASA) therapy as a class I indication following CABG to prevent graft ⁎ Corresponding author at: Gulf Coast Regional Medical Center, 449 W 23rd St., Panama City, FL, USA. E-mail address: [email protected] (R. Shah).
occlusion [4,5]; however, despite the routine use of ASA and other advancements in the management of post-CABG patients, SVG failure remains a leading cause of poor outcomes in these patients [6]. Several small, randomized clinical trials (RCTs) suggest that dual antiplatelet therapy (DAPT), which involves both ASA and a P2Y12 inhibitor, could be more effective than ASA alone for the prevention of SVG failure [7–11]; however, the findings of individual trials have been scrutinized for their small sample sizes and lack of statistical power. Additionally, it is unclear whether some P2Y12 inhibitors are more effective than others for the prevention of SVG failure. Therefore, we performed a standard pairwise meta-analysis with moderator analysis and a Bayesian network meta-analysis, with the largest sample to date due to including recently published trials, to evaluate the efficacy and safety of various antiplatelet agents for the prevention of SVG failure.
https://doi.org/10.1016/j.carrev.2019.10.022 1553-8389/© 2019 Published by Elsevier Inc.
Please cite this article as: K. Hesterberg, A. Rawal, S. Khan, et al., A meta-analysis comparing aspirin alone versus dual antiplatelet therapy for the prevention of venou..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.022
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Table 1 Characteristics of included trials. Trial
DACAB 2017
Total numbers
Age (years) Type of P2Y12 inhibitor ASA DAPT ASA DAPT
Male (%)
Diabetes (%)
HTN (%)
ASA
ASA
ASA
DAPT
DAPT
DAPT
166
168
64
64
Ticagrelor
141 (85)
134 (80)
67 (40)
75 (45)
120 (72)
127 (76)
TEG-CABG 2017 Saw 2016
81
79
67
65
35
35
63
62
Clopidogrel 56 (69) Ticagrelor 31 (89)
53 (67) 30 (86)
26 (32) 10 (29)
25 (32) 11 (31)
66 (81) 28 (80)
61 (77) 26 (74)
ASAP-CABG 2016 CRYSSA 2012 CASCADE 2010 Gao 2010
8
12
NR
NR
Clopidogrel NR
NR
150
59
59
57
56
68
65
Clopidogrel 113 (75) Clopidogrel 50 (88) Clopidogrel 93 (84) Clopidogrel 34 (87) Clopidogrel NR
110 (73) 51 (91) 93 (82) 38 (95) NR
5 (42) 0
7 (88)
150
5 (63) 0 19 (33) 45 (41) 14 (36) NR
14 (25) 45 (40) 13 (33) NR
12 (100) 71 (47) 27 (48) 70 (62) 27 (68) NR
111
113
60
58
Sun 2010
39
40
64
65
Mujanovic 2009
10
10
60
58
68 (45) 30 (53) 63 (57) 25 (64) NR
Median follow-up (months)
Indication for CABG
Method for imaging graft
ASA
DAPT
SA 30% UA 66% NSTEMI 4% NR
SA 33% UA 64% NSTEMI 3% NR
MSCTA or coronary angiography
SA 71% UA 9% NSTEMI 20% NR
SA 63% UA 11% NSTEMI 26% NR
CCTA
All stable CAD ACS 12.5%
All stable CAD ACS 22.8%
MSCTA
a
NR
NR
MSCTA
1.7
NR
NR
CCTA
3a
NR
NR
Coronary angiography
12
a
3a 3
12a 12a 12a 3
MSCT
CCTA
IVUS
ACS - acute coronary syndrome; ASA – aspirin; ASAP- CABG – aspirin and plavix following coronary artery bypass grafting; CABG – coronary artery bypass grafting; CASCADE – clopidogrel after surgery for coronary artery disease; CCTA – cardiac computed tomography angiography; CRYSSA – prevention of coronary artery bypass occlusion after off-pump procedures; DACAB - dual ticagrelor plus aspirin antiplatelet strategy after coronary artery bypass grafting; DAPT - dual antiplatelet therapy; IVUS – intravascular ultrasound; MSCTA – multislice computer tomography angiography; NR – not reported; SA – stable angina; NTEMI – non-ST-segment elevation myocardial infarction; TEG-CABG – thrombelastographic hypercoagulability and antiplatelet therapy after coronary artery bypass surgery; UA – unstable angina. a Planned follow up.
2. Methods This meta-analysis was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic reviews and meta-analyses [12]. A computerized literature review of PubMed and the Cochrane databases was conducted to locate relevant studies. Data was collected by two independent investigators and disagreements were resolved by consensus. The following keywords were used: “aspirin,” “antiplatelet,” “saphenous vein graft,” “coronary artery bypass graft surgery,” and “randomized controlled trial.” Trials were included if the enrolled post-CABG patients with SVG were randomly assigned to treatment with either ASA or DAPT. The additional inclusion criterion was that the trial reported the graft failure rate as this was our primary efficacy endpoint. The safety endpoint was the incidence of major bleeding. Study definitions were used for the outcome data Table S1 (online Supplementary Appendix).
Standard pairwise meta-analyses were performed according to the Comprehensive Meta-Analysis system version 3 (Comprehensive Meta-Analysis; Biostat Inc., Englewood, NJ, USA). Pooled risk ratios were calculated using a random-effects model. Additionally, moderator analysis was performed to evaluate if the rate of SVG failure was modified by a specific type of P2Y12 inhibitor. We evaluated the heterogeneity across trials using the Cochran Q test and the Higgins I2 test [13]. Publication bias was not assessed because the number of included trials was inadequate (b10) to properly assess a funnel plot or to use more advanced regression-based assessments [14]. Finally, a Bayesian network meta-analysis was performed using mixed-treatment comparison models to evaluate the efficacy of various antiplatelet strategies for preventing SVG failure [15]. For the network meta-analysis, we converted the events rate to events per 100,000 patient-days because the follow-up duration varied across trials. All analyses were performed using the WinBUGs Bayesian software package and NetMetaXL (Cornerstone Research Group, Burlington, Ontario, L7N 3H8 Canada) [16].
Fig. 1. Saphenous vein graft failure. Individual and pooled risk ratios for saphenous vein graft failure. ASA = aspirin; DAPT = dual antiplatelet therapy. Study names as in Table 1.
Please cite this article as: K. Hesterberg, A. Rawal, S. Khan, et al., A meta-analysis comparing aspirin alone versus dual antiplatelet therapy for the prevention of venou..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.022
K. Hesterberg et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Fig. 2. Network meta-analysis for saphenous vein graft failure. The network meta-analysis comparison of various anti-platelet strategies for the prevention of saphenous vein graft failure. ASA = aspirin; CI = confidence interval; clo = clopidogrel; OR = odds ratio; Tic = ticagrelor.
3. Results Nine RCTs, which together included 1677 patients, met our inclusion criteria [7–11,17–20]. The search flow diagram is shown in Fig. S1 (online-only Data Supplement). Table S2 (online Supplementary Appendix) lists the inclusion and exclusion criteria for each trial. Table 1 describes the characteristics of each individual trial. The trials included patients both with stable angina and acute coronary syndrome. The majority of the trials used computer tomography angiography to detect SVG occlusion at a median follow-up of 12 months (postCABG). In 2 trials, DAPT was comprised of ASA + ticagrelor; ASA + clopidogrel was used in all the other trials. In the direct comparison meta-analysis, DAPT decreased the risk of SVG failure by 37% (risk ratio [RR]: 0.63, 95% confidence interval [CI]: 0.47–0.86; p = 0.003) compared to ASA alone (Fig. 1). There was no significant heterogeneity between the trials (Q = 13.24; p = 0.1, I2 = 39.6). In the moderator analysis, the decreased risk of graft failure with DAPT was not significantly different in the ASA + clopidogrel group than in the ASA + ticagrelor group (P-interaction = 0.17). Similarly, in the mixed-treatment comparison models, both the ASA + ticagrelor (OR: 0.46, 95% CI: 0.38–0.56) and ASA + clopidogrel (OR: 0.55, 95% CI: 0.50–0.60) treatments decreased the risk of SVG failure compared to ASA alone (Fig. 2). In addition, the risk of graft failure trended lower with ASA + ticagrelor compared to ASA + clopidogrel, but the difference did not reach statistical significance (OR, 0.84; 95% CI, 0.68–1.04). Finally, DAPT was associated with a higher risk of major bleeding compared to ASA alone, but the difference was not statistically significant (RR: 1.35, 95% CI: 0.62–2.94; p = 0.45) (Fig. 3). There was no
significant heterogeneity between the trials (Q = 1.67; p = 0.80, I2 = 0.00) for the risk of major bleeding. Similarly, in mixed-treatment comparison models, no significant differences in the risk of major bleeding were found between ASA alone and ASA + clopidogrel (OR, 0.84; 95% CI, 0.44–1.28). However, when compared to ASA + ticagrelor, a trend toward lower risk of bleeding seemed apparent with ASA alone and with ASA + clopidogrel (Fig. 4). 4. Discussion In this comprehensive meta-analysis of 9 trials, which involves the largest number (1677) of patients ever reported on this topic, two types of DAPT were compared to ASA alone for the prevention of SVG failure. We found that DAPT decreased the risk of SVG failure by 37% at a median follow-up of 12 months. Furthermore, the risk of graft failure trended lower with clopidogrel-based DAPT compared to ticagrelorbased DAPT, but the difference did not reach statistical significance. Finally, the risk of major bleeding trended higher with DAPT compared to ASA alone, but again, the difference did not reach statistical significance. In patients with multivessel disease and high SYNTAX scores or diabetes, CABG improves survival compared to percutaneous coronary interventions [1,2]. Therefore, CABG is the standard of care for those patients and a class I indication per guidelines [21]. A continued limitation of CABG is SVG failure, which is associated with poor outcomes at short and long term follow up. Internal thoracic artery grafts have 10year patency rates reported up to 91% [22,23]. However, SVG failure rates are reported as 10–25% at one year, with up to 50% failing at 10 years [3,23–26]. Despite high failure rates, vein grafts are commonly
Fig. 3. Major bleeding. Individual and pooled risk ratios for major bleeding. ASA = aspirin; DAPT = dual antiplatelet therapy. Study names as in Table 1.
Please cite this article as: K. Hesterberg, A. Rawal, S. Khan, et al., A meta-analysis comparing aspirin alone versus dual antiplatelet therapy for the prevention of venou..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.022
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K. Hesterberg et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
Fig. 4. Network meta-analysis for major bleeding. The network meta-analysis comparison of various anti-platelet strategies for major bleeding. ASA = aspirin; CI = confidence interval; clo = clopidogrel; OR = odds ratio; Tic = ticagrelor.
used for surgical revascularization. Different surgical techniques such as avoidance of distention, no-touch, and minimizing trauma to vein grafts have been proposed to decrease graft failure [27]. However, there is no clear consensus on the optimal surgical technique. Studies have shown improved SVG patency with aspirin, which is thought to decrease thrombosis related early graft failure [5]. SVG graft failure remains a persistent problem despite ASA therapy. Graft thrombosis is one of the principle mechanisms of SVG failure within the first year (after CABG); therefore, given the mechanism of action of P2Y12 inhibitors, DAPT (ASA + P2Y12 inhibitor) has been suggested as more beneficial in preventing SVG failure compared to ASA alone [28]. Mujanovic et al. showed significant decrease in SVG failure at 3 months, despite low sample size (n = 20) [7]. Subsequent trials have shown mixed results, with some showing no benefit while other studies demonstrate reduced SVG failure rates [8–11,17–20]. To date, both trials comparing DAPT with ASA + ticagrelor to ASA alone have shown reduced SVG failure rates with DAPT [10,11]. Prior meta-analyses have shown lower rates of SVG occlusion with DAPT therapy, similar to this analysis [29,30]; however, since those meta-analyses were conducted, new RCTs, including the DACAB (Dual Ticagrelor plus aspirin antiplatelet strategy after coronary artery bypass grafting), have been reported. The DACAB is the largest RCT in the field; therefore, those previous meta-analyses are arguably outdated. In addition, debate continues about whether specific P2Y12 inhibitors are more effective for preventing SVG failure following CABG. To date, there has not been a head-to-head trial to evaluate this; we have addressed this issue by our moderator analysis and network meta-analysis. Prevailing wisdom suggests that the patency of SVG should be clinically beneficial [28]. However, it is not clear that graft patency after CABG accessed via imaging translates into meaningful clinical outcomes [28,31]. Some observational studies suggest that patients with occluded grafts had poor outcomes compared to those with patent grafts [32]. However, some of those studies have been criticized because their poor outcomes were driven primarily by increases in revascularization rates, presumably due to occlustenotic reflexes [28]. Other studies have not shown a clear relationship between SVG failure and subsequent major adverse events including mortality and MI [28,33]. Therefore, additional studies are needed so that the graft patency rate can be evaluated for improvement in the clinical outcomes [28,31]. This meta-analysis has several limitations. First, we did not have individual participant data; data from various studies were combined. Each study had its own protocol and definitions as well as follow-up duration; specifically, the definition of major bleeding varied across the studies. In addition, not all of the studies reported the major bleeding rate, and so we cannot be sure if the non-significant (statistically) difference in the bleeding rate is due to a lack of power. Furthermore, efficacy trended higher with ticagrelor compared to clopidogrel, but
the difference was not statistically significant, possibly due to a lack of power. Therefore, a randomized trial with enough power is needed to evaluate whether ticagrelor tops clopidogrel for preventing SVG failure. Finally, in the included trials, DAPT duration varied, and the numbers of trials in the various duration groups were small; therefore, interaction statistics to evaluate whether outcomes were modified by DAPT duration could not be determined. Thus, based on our analyses, we cannot recommend (with certainty) an optimal DAPT duration. In the majority of these trials, DAPT duration was 12 months; therefore, based on current evidence, a 12-month duration seems reasonable. Again, this is best addressed through a randomized trial that compares various DAPT durations. Despite these limitations, this is the most comprehensive meta-analysis with the largest sample size ever reported on this subject. In conclusion, in post-CABG patients, DAPT seems to be more effective at preventing graft failure than ASA alone. This strategy does not seem to significantly increase major bleeding risk. Clopidogrel- and ticagrelor-based DAPT seem to be equally effective for this indication. Funding None. Declaration of competing interest The authors have no conflicts of interest to declare. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.carrev.2019.10.022. References [1] Mohr FW, Morice MC, Kappetein AP, Feldman TE, Stahle 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 followup of the randomised, clinical SYNTAX trial. Lancet (London, England) 2013;381: 629–38. [2] Farkouh ME, Domanski M, Dangas GD, Godoy LC, Mack MJ, Siami FS, et al. Long-term survival following multivessel revascularization in patients with diabetes: the FREEDOM Follow-On Study. J Am Coll Cardiol 2019;73:629–38. [3] Hess CN, Lopes RD, Gibson CM, Hager R, Wojdyla DM, Englum BR, et al. Saphenous vein graft failure after coronary artery bypass surgery: insights from PREVENT IV. Circulation 2014;130:1445–51. [4] Kulik A, Ruel M, Jneid H, Ferguson TB, Hiratzka LF, Ikonomidis JS, et al. Secondary prevention after coronary artery bypass graft surgery: a scientific statement from the American Heart Association. Circulation 2015;131:927–64. [5] Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, et al. Saphenous vein graft patency 1 year after coronary artery bypass surgery and effects of
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Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
A meta-analysis comparing aspirin alone versus dual antiplatelet therapy for the prevention of venous graft failure following coronary artery bypass surgery Kirstin Hesterberg a, Aranyak Rawal a, Sajjad Khan b, Abdul Rashid c, David Jones a, Tariq Siddiqui d, Thekrayat A. Khader a, Manu Nayyar a, Rahman Shah a,e,⁎ a
Department of Medicine, University of Tennessee, Memphis, TN, USA Department of Medicine, Aga Khan University, Pakistan c Jackson Clinic, University of Tennessee, Jackson, TN, USA d Department of Medicine, Texas Tech University Health Sciences Center El Paso, TX, USA e Department of Cardiology, Gulf Coast Regional Medical Center, Panama City, FL, USA b
a r t i c l e
i n f o
Article history: Received 16 May 2019 Received in revised form 4 September 2019 Accepted 21 October 2019 Available online xxxx Keywords: Aspirin Saphenous vein graft Coronary artery bypass grafting P2Y12 inhibitors Antiplatelet therapy
a b s t r a c t Background: Aspirin (ASA) monotherapy is the current standard of care after coronary artery bypass grafting (CABG) to prevent saphenous vein graft (SVG) failure. Several small, randomized clinical trials (RCTs) have suggested that dual antiplatelet therapy (DAPT) may be more effective at preventing SVG failure than ASA alone; however, it is unclear whether some P2Y12 inhibitors are more effective than others for the prevention of SVG failure. Methods: Scientific databases and websites were searched to find RCTs. Both traditional pairwise meta-analysis using random-effect model and network meta-analysis using mixed-treatment comparison models were performed to compare the efficacy of various anti-platelet strategies for the prevention of SVG failure. Results: Nine RCTs, which included a total of 1677 patients, were analyzed. Compared to ASA alone, DAPT decreased the risk of graft failure by 37% (RR: 0.63, 95% CI: 0.47–0.86; p = 0.003). In the moderator analysis, the decreased risk of graft failure with DAPT was not significantly different in the ASA + clopidogrel group than in the ASA + ticagrelor group (P-interaction = 0.17). The results of the network meta-analysis were consistent with those from pairwise analyses. The risk of major bleeding was not statistically significantly different between DAPT and ASA alone (RR: 1.35, 95% CI: 0.62–2.94; p = 0.45). Conclusion: In post-CABG patients, DAPT seems to be more effective at preventing graft failure than ASA alone. This strategy does not seem to significantly increase major bleeding risk. Clopidogrel- and ticagrelor-based DAPT seem to be equally effective for this indication. © 2019 Published by Elsevier Inc.
1. Introduction Coronary artery bypass graft surgery (CABG) is the standard of care for the majority of patients with multivessel coronary artery disease (CAD) and high SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) scores or diabetes [1,2]. However, the long-term prognosis of CABG is limited due to the high failure rate of saphenous vein grafts (SVG) as up to 25% fail as early as within a year post-CABG [3]. Therefore, current guidelines supported by clinical trials recommend aspirin (ASA) therapy as a class I indication following CABG to prevent graft ⁎ Corresponding author at: Gulf Coast Regional Medical Center, 449 W 23rd St., Panama City, FL, USA. E-mail address: [email protected] (R. Shah).
occlusion [4,5]; however, despite the routine use of ASA and other advancements in the management of post-CABG patients, SVG failure remains a leading cause of poor outcomes in these patients [6]. Several small, randomized clinical trials (RCTs) suggest that dual antiplatelet therapy (DAPT), which involves both ASA and a P2Y12 inhibitor, could be more effective than ASA alone for the prevention of SVG failure [7–11]; however, the findings of individual trials have been scrutinized for their small sample sizes and lack of statistical power. Additionally, it is unclear whether some P2Y12 inhibitors are more effective than others for the prevention of SVG failure. Therefore, we performed a standard pairwise meta-analysis with moderator analysis and a Bayesian network meta-analysis, with the largest sample to date due to including recently published trials, to evaluate the efficacy and safety of various antiplatelet agents for the prevention of SVG failure.
https://doi.org/10.1016/j.carrev.2019.10.022 1553-8389/© 2019 Published by Elsevier Inc.
Please cite this article as: K. Hesterberg, A. Rawal, S. Khan, et al., A meta-analysis comparing aspirin alone versus dual antiplatelet therapy for the prevention of venou..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.022
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Table 1 Characteristics of included trials. Trial
DACAB 2017
Total numbers
Age (years) Type of P2Y12 inhibitor ASA DAPT ASA DAPT
Male (%)
Diabetes (%)
HTN (%)
ASA
ASA
ASA
DAPT
DAPT
DAPT
166
168
64
64
Ticagrelor
141 (85)
134 (80)
67 (40)
75 (45)
120 (72)
127 (76)
TEG-CABG 2017 Saw 2016
81
79
67
65
35
35
63
62
Clopidogrel 56 (69) Ticagrelor 31 (89)
53 (67) 30 (86)
26 (32) 10 (29)
25 (32) 11 (31)
66 (81) 28 (80)
61 (77) 26 (74)
ASAP-CABG 2016 CRYSSA 2012 CASCADE 2010 Gao 2010
8
12
NR
NR
Clopidogrel NR
NR
150
59
59
57
56
68
65
Clopidogrel 113 (75) Clopidogrel 50 (88) Clopidogrel 93 (84) Clopidogrel 34 (87) Clopidogrel NR
110 (73) 51 (91) 93 (82) 38 (95) NR
5 (42) 0
7 (88)
150
5 (63) 0 19 (33) 45 (41) 14 (36) NR
14 (25) 45 (40) 13 (33) NR
12 (100) 71 (47) 27 (48) 70 (62) 27 (68) NR
111
113
60
58
Sun 2010
39
40
64
65
Mujanovic 2009
10
10
60
58
68 (45) 30 (53) 63 (57) 25 (64) NR
Median follow-up (months)
Indication for CABG
Method for imaging graft
ASA
DAPT
SA 30% UA 66% NSTEMI 4% NR
SA 33% UA 64% NSTEMI 3% NR
MSCTA or coronary angiography
SA 71% UA 9% NSTEMI 20% NR
SA 63% UA 11% NSTEMI 26% NR
CCTA
All stable CAD ACS 12.5%
All stable CAD ACS 22.8%
MSCTA
a
NR
NR
MSCTA
1.7
NR
NR
CCTA
3a
NR
NR
Coronary angiography
12
a
3a 3
12a 12a 12a 3
MSCT
CCTA
IVUS
ACS - acute coronary syndrome; ASA – aspirin; ASAP- CABG – aspirin and plavix following coronary artery bypass grafting; CABG – coronary artery bypass grafting; CASCADE – clopidogrel after surgery for coronary artery disease; CCTA – cardiac computed tomography angiography; CRYSSA – prevention of coronary artery bypass occlusion after off-pump procedures; DACAB - dual ticagrelor plus aspirin antiplatelet strategy after coronary artery bypass grafting; DAPT - dual antiplatelet therapy; IVUS – intravascular ultrasound; MSCTA – multislice computer tomography angiography; NR – not reported; SA – stable angina; NTEMI – non-ST-segment elevation myocardial infarction; TEG-CABG – thrombelastographic hypercoagulability and antiplatelet therapy after coronary artery bypass surgery; UA – unstable angina. a Planned follow up.
2. Methods This meta-analysis was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic reviews and meta-analyses [12]. A computerized literature review of PubMed and the Cochrane databases was conducted to locate relevant studies. Data was collected by two independent investigators and disagreements were resolved by consensus. The following keywords were used: “aspirin,” “antiplatelet,” “saphenous vein graft,” “coronary artery bypass graft surgery,” and “randomized controlled trial.” Trials were included if the enrolled post-CABG patients with SVG were randomly assigned to treatment with either ASA or DAPT. The additional inclusion criterion was that the trial reported the graft failure rate as this was our primary efficacy endpoint. The safety endpoint was the incidence of major bleeding. Study definitions were used for the outcome data Table S1 (online Supplementary Appendix).
Standard pairwise meta-analyses were performed according to the Comprehensive Meta-Analysis system version 3 (Comprehensive Meta-Analysis; Biostat Inc., Englewood, NJ, USA). Pooled risk ratios were calculated using a random-effects model. Additionally, moderator analysis was performed to evaluate if the rate of SVG failure was modified by a specific type of P2Y12 inhibitor. We evaluated the heterogeneity across trials using the Cochran Q test and the Higgins I2 test [13]. Publication bias was not assessed because the number of included trials was inadequate (b10) to properly assess a funnel plot or to use more advanced regression-based assessments [14]. Finally, a Bayesian network meta-analysis was performed using mixed-treatment comparison models to evaluate the efficacy of various antiplatelet strategies for preventing SVG failure [15]. For the network meta-analysis, we converted the events rate to events per 100,000 patient-days because the follow-up duration varied across trials. All analyses were performed using the WinBUGs Bayesian software package and NetMetaXL (Cornerstone Research Group, Burlington, Ontario, L7N 3H8 Canada) [16].
Fig. 1. Saphenous vein graft failure. Individual and pooled risk ratios for saphenous vein graft failure. ASA = aspirin; DAPT = dual antiplatelet therapy. Study names as in Table 1.
Please cite this article as: K. Hesterberg, A. Rawal, S. Khan, et al., A meta-analysis comparing aspirin alone versus dual antiplatelet therapy for the prevention of venou..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.022
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Fig. 2. Network meta-analysis for saphenous vein graft failure. The network meta-analysis comparison of various anti-platelet strategies for the prevention of saphenous vein graft failure. ASA = aspirin; CI = confidence interval; clo = clopidogrel; OR = odds ratio; Tic = ticagrelor.
3. Results Nine RCTs, which together included 1677 patients, met our inclusion criteria [7–11,17–20]. The search flow diagram is shown in Fig. S1 (online-only Data Supplement). Table S2 (online Supplementary Appendix) lists the inclusion and exclusion criteria for each trial. Table 1 describes the characteristics of each individual trial. The trials included patients both with stable angina and acute coronary syndrome. The majority of the trials used computer tomography angiography to detect SVG occlusion at a median follow-up of 12 months (postCABG). In 2 trials, DAPT was comprised of ASA + ticagrelor; ASA + clopidogrel was used in all the other trials. In the direct comparison meta-analysis, DAPT decreased the risk of SVG failure by 37% (risk ratio [RR]: 0.63, 95% confidence interval [CI]: 0.47–0.86; p = 0.003) compared to ASA alone (Fig. 1). There was no significant heterogeneity between the trials (Q = 13.24; p = 0.1, I2 = 39.6). In the moderator analysis, the decreased risk of graft failure with DAPT was not significantly different in the ASA + clopidogrel group than in the ASA + ticagrelor group (P-interaction = 0.17). Similarly, in the mixed-treatment comparison models, both the ASA + ticagrelor (OR: 0.46, 95% CI: 0.38–0.56) and ASA + clopidogrel (OR: 0.55, 95% CI: 0.50–0.60) treatments decreased the risk of SVG failure compared to ASA alone (Fig. 2). In addition, the risk of graft failure trended lower with ASA + ticagrelor compared to ASA + clopidogrel, but the difference did not reach statistical significance (OR, 0.84; 95% CI, 0.68–1.04). Finally, DAPT was associated with a higher risk of major bleeding compared to ASA alone, but the difference was not statistically significant (RR: 1.35, 95% CI: 0.62–2.94; p = 0.45) (Fig. 3). There was no
significant heterogeneity between the trials (Q = 1.67; p = 0.80, I2 = 0.00) for the risk of major bleeding. Similarly, in mixed-treatment comparison models, no significant differences in the risk of major bleeding were found between ASA alone and ASA + clopidogrel (OR, 0.84; 95% CI, 0.44–1.28). However, when compared to ASA + ticagrelor, a trend toward lower risk of bleeding seemed apparent with ASA alone and with ASA + clopidogrel (Fig. 4). 4. Discussion In this comprehensive meta-analysis of 9 trials, which involves the largest number (1677) of patients ever reported on this topic, two types of DAPT were compared to ASA alone for the prevention of SVG failure. We found that DAPT decreased the risk of SVG failure by 37% at a median follow-up of 12 months. Furthermore, the risk of graft failure trended lower with clopidogrel-based DAPT compared to ticagrelorbased DAPT, but the difference did not reach statistical significance. Finally, the risk of major bleeding trended higher with DAPT compared to ASA alone, but again, the difference did not reach statistical significance. In patients with multivessel disease and high SYNTAX scores or diabetes, CABG improves survival compared to percutaneous coronary interventions [1,2]. Therefore, CABG is the standard of care for those patients and a class I indication per guidelines [21]. A continued limitation of CABG is SVG failure, which is associated with poor outcomes at short and long term follow up. Internal thoracic artery grafts have 10year patency rates reported up to 91% [22,23]. However, SVG failure rates are reported as 10–25% at one year, with up to 50% failing at 10 years [3,23–26]. Despite high failure rates, vein grafts are commonly
Fig. 3. Major bleeding. Individual and pooled risk ratios for major bleeding. ASA = aspirin; DAPT = dual antiplatelet therapy. Study names as in Table 1.
Please cite this article as: K. Hesterberg, A. Rawal, S. Khan, et al., A meta-analysis comparing aspirin alone versus dual antiplatelet therapy for the prevention of venou..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.022
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Fig. 4. Network meta-analysis for major bleeding. The network meta-analysis comparison of various anti-platelet strategies for major bleeding. ASA = aspirin; CI = confidence interval; clo = clopidogrel; OR = odds ratio; Tic = ticagrelor.
used for surgical revascularization. Different surgical techniques such as avoidance of distention, no-touch, and minimizing trauma to vein grafts have been proposed to decrease graft failure [27]. However, there is no clear consensus on the optimal surgical technique. Studies have shown improved SVG patency with aspirin, which is thought to decrease thrombosis related early graft failure [5]. SVG graft failure remains a persistent problem despite ASA therapy. Graft thrombosis is one of the principle mechanisms of SVG failure within the first year (after CABG); therefore, given the mechanism of action of P2Y12 inhibitors, DAPT (ASA + P2Y12 inhibitor) has been suggested as more beneficial in preventing SVG failure compared to ASA alone [28]. Mujanovic et al. showed significant decrease in SVG failure at 3 months, despite low sample size (n = 20) [7]. Subsequent trials have shown mixed results, with some showing no benefit while other studies demonstrate reduced SVG failure rates [8–11,17–20]. To date, both trials comparing DAPT with ASA + ticagrelor to ASA alone have shown reduced SVG failure rates with DAPT [10,11]. Prior meta-analyses have shown lower rates of SVG occlusion with DAPT therapy, similar to this analysis [29,30]; however, since those meta-analyses were conducted, new RCTs, including the DACAB (Dual Ticagrelor plus aspirin antiplatelet strategy after coronary artery bypass grafting), have been reported. The DACAB is the largest RCT in the field; therefore, those previous meta-analyses are arguably outdated. In addition, debate continues about whether specific P2Y12 inhibitors are more effective for preventing SVG failure following CABG. To date, there has not been a head-to-head trial to evaluate this; we have addressed this issue by our moderator analysis and network meta-analysis. Prevailing wisdom suggests that the patency of SVG should be clinically beneficial [28]. However, it is not clear that graft patency after CABG accessed via imaging translates into meaningful clinical outcomes [28,31]. Some observational studies suggest that patients with occluded grafts had poor outcomes compared to those with patent grafts [32]. However, some of those studies have been criticized because their poor outcomes were driven primarily by increases in revascularization rates, presumably due to occlustenotic reflexes [28]. Other studies have not shown a clear relationship between SVG failure and subsequent major adverse events including mortality and MI [28,33]. Therefore, additional studies are needed so that the graft patency rate can be evaluated for improvement in the clinical outcomes [28,31]. This meta-analysis has several limitations. First, we did not have individual participant data; data from various studies were combined. Each study had its own protocol and definitions as well as follow-up duration; specifically, the definition of major bleeding varied across the studies. In addition, not all of the studies reported the major bleeding rate, and so we cannot be sure if the non-significant (statistically) difference in the bleeding rate is due to a lack of power. Furthermore, efficacy trended higher with ticagrelor compared to clopidogrel, but
the difference was not statistically significant, possibly due to a lack of power. Therefore, a randomized trial with enough power is needed to evaluate whether ticagrelor tops clopidogrel for preventing SVG failure. Finally, in the included trials, DAPT duration varied, and the numbers of trials in the various duration groups were small; therefore, interaction statistics to evaluate whether outcomes were modified by DAPT duration could not be determined. Thus, based on our analyses, we cannot recommend (with certainty) an optimal DAPT duration. In the majority of these trials, DAPT duration was 12 months; therefore, based on current evidence, a 12-month duration seems reasonable. Again, this is best addressed through a randomized trial that compares various DAPT durations. Despite these limitations, this is the most comprehensive meta-analysis with the largest sample size ever reported on this subject. In conclusion, in post-CABG patients, DAPT seems to be more effective at preventing graft failure than ASA alone. This strategy does not seem to significantly increase major bleeding risk. Clopidogrel- and ticagrelor-based DAPT seem to be equally effective for this indication. Funding None. Declaration of competing interest The authors have no conflicts of interest to declare. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.carrev.2019.10.022. References [1] Mohr FW, Morice MC, Kappetein AP, Feldman TE, Stahle 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 followup of the randomised, clinical SYNTAX trial. Lancet (London, England) 2013;381: 629–38. [2] Farkouh ME, Domanski M, Dangas GD, Godoy LC, Mack MJ, Siami FS, et al. Long-term survival following multivessel revascularization in patients with diabetes: the FREEDOM Follow-On Study. J Am Coll Cardiol 2019;73:629–38. [3] Hess CN, Lopes RD, Gibson CM, Hager R, Wojdyla DM, Englum BR, et al. Saphenous vein graft failure after coronary artery bypass surgery: insights from PREVENT IV. Circulation 2014;130:1445–51. [4] Kulik A, Ruel M, Jneid H, Ferguson TB, Hiratzka LF, Ikonomidis JS, et al. Secondary prevention after coronary artery bypass graft surgery: a scientific statement from the American Heart Association. Circulation 2015;131:927–64. [5] Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, et al. Saphenous vein graft patency 1 year after coronary artery bypass surgery and effects of
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Please cite this article as: K. Hesterberg, A. Rawal, S. Khan, et al., A meta-analysis comparing aspirin alone versus dual antiplatelet therapy for the prevention of venou..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.022