Meta-analysis of efficacy and safety of dual antiplatelet therapy versus aspirin monotherapy after coronary artery bypass grafting

About seven million patients suffer with acute myocardial infarction (AMI) worldwide with 20% experiencing a second cardiovascular (CV) event in the first year.1,2 However despite such a significant disease burden, preventive strategies against major adverse cardiovascular events (MACEs) remain suboptimal.3 The EUROASPIRE surveys across Europe suggest that among patients with a high CV risk or patients with established coronary artery disease, there is lack of healthy life style or adequate use of drug therapies to improve CV outcomes.1,3 Aspirin (ASA) monotherapy is considered as the standard of care to prevent graft occlusion and MACEs following coronary artery bypass grafting (CABG).4 While dual antiplatelet therapy (DAPT) is recommended in acute coronary syndrome (ACS) after revascularization,5 the potential impact of DAPT on saphenous vein graft (SVG) patency and MACE after CABG remains uncertain. Recent randomized controlled trials (RCTs) have suggested superior efficacy of DAPT over ASA in maintaining graft patency at one year.4,6 To update the evidence, we conducted a meta-analysis comparing DAPT vs ASA in patients following CABG at one-year follow-up. Five RCTs4,6–9 (837 patients) were identified by searching MEDLINE, EMBASE, and CENTRAL from inception of the databases to April 2018 (Table 1). The data was abstracted on baseline characteristics of the participants and key outcomes. The risk of bias was assessed on the Cochrane bias risk assessment tool. The literature search, screening of the articles, and data abstraction were performed by ST and ML independently. The primary outcome was MACEs (composite of myocardial infarction (MI), stroke and all-cause mortality). Secondary outcomes were components of MACE and CV mortality, SVG occlusion, and major bleeding. Clinical characteristics of the study participants. ACS: acute coronary syndrome; ASAP-CABG: ASpirin and Plavix Following Coronary Artery Bypass Grafting; CRoB scale: Cochrane Risk of Bias scale; CRYSSA: prevention of Coronary arteRY bypaSS occlusion After off-pump procedures; CASCADE: The Clopidogrel After Surgery for Coronary Artery Disease; CABG: coronary artery bypass graft; CURE: Clopidogrel in Unstable Angina to Prevent Recurrent Events; DACAB: Compare the Efficacy of Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery; DM: diabetes mellitus; Hb: hemoglobin; HTN: hypertension; ICH: intracranial hemorrhage; PLATO: Platelet Inhibition and Patient Outcomes; TIMI: Thrombolysis in Myocardial Infarction. Scale constitutes of seven domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete data reporting (attrition bias), selective reporting (reporting bias), and other bias. Each domain carries one star and ≥5 stars represents good quality. Clinically significant bleeding leading to disability or ≥3 g/dl but <5 g/dl drop in hemoglobin or requiring 2–3 units of blood transfusion. Substantially disabling bleeding, intraocular bleeding leading to the loss of vision, or bleeding necessitating the transfusion of at least two units of blood. Clinical characteristics of the study participants. ACS: acute coronary syndrome; ASAP-CABG: ASpirin and Plavix Following Coronary Artery Bypass Grafting; CRoB scale: Cochrane Risk of Bias scale; CRYSSA: prevention of Coronary arteRY bypaSS occlusion After off-pump procedures; CASCADE: The Clopidogrel After Surgery for Coronary Artery Disease; CABG: coronary artery bypass graft; CURE: Clopidogrel in Unstable Angina to Prevent Recurrent Events; DACAB: Compare the Efficacy of Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery; DM: diabetes mellitus; Hb: hemoglobin; HTN: hypertension; ICH: intracranial hemorrhage; PLATO: Platelet Inhibition and Patient Outcomes; TIMI: Thrombolysis in Myocardial Infarction. Scale constitutes of seven domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete data reporting (attrition bias), selective reporting (reporting bias), and other bias. Each domain carries one star and ≥5 stars represents good quality. Clinically significant bleeding leading to disability or ≥3 g/dl but <5 g/dl drop in hemoglobin or requiring 2–3 units of blood transfusion. Substantially disabling bleeding, intraocular bleeding leading to the loss of vision, or bleeding necessitating the transfusion of at least two units of blood. The meta-analysis was performed using DerSimonian and Laird random effects models. Estimates were reported as risk differences (RDs) with 95% confidence intervals (CIs). Statistical significance was set at 0.05. Heterogeneity was quantified via the I2 test and values >75% were consistent with a high degree of heterogeneity. Publication bias was assessed using Egger’s test. Comprehensive meta-analysis software version 3.0 (Biostat, Englewood, New Jersey, USA) was used for all analyses. DAPT was associated with significant absolute risk reduction in MACEs (RD, −0.033, 95% CI, −0.061, −0.005, p = 0.02, I2 = 0) and stroke (RD, −0.019, 95% CI, −0.037, −0.001, p = 0.04, I2 = 0) compared with ASA. There were no significant differences between both groups in terms of MI or all-cause mortality (Figure 1). DAPT had no significant effects on SVG occlusion (RD, −0.041, 95% CI, −0.133, 0.050, p = 0.37, I2 = 0), CV mortality (RD, −0.009, 95% CI, −0.027, 0.009, p = 0.33, I2 = 0), or major bleeding (RD, 0.005, 95% CI, −0.008, 0.018, p = 0.75, I2 = 0). Egger’s test did not detect publication bias (p (two-tailed) = 0.68). Forest plot comparing dual antiplatelet therapy (DAPT) versus aspirin monotherapy for major adverse cardiovascular events (MACEs). ASAP-CABG: ASpirin and Plavix Following Coronary Artery Bypass Grafting; CI: confidence interval; CRYSSA: prevention of Coronary arteRY bypaSS occlusion After off-pump procedures; CASCADE: The Clopidogrel After Surgery for Coronary Artery Disease; DACAB: Compare the Efficacy of Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery; MI: myocardial infarction. Current meta-analysis suggests that there was one fewer patient experiencing MACEs for every 30 patients and one fewer case of stroke for every 52 patients treated with DAPT for one year following CABG. These benefits were achieved without increasing the risk of major bleeding. Stroke remains a major disadvantage of CABG and the optimal antithrombotic therapy to prevent risk of stroke after CABG remains uncertain. In the Compare the Efficacy of Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery (DACAB) study, fewer cases of stroke were noticed with DAPT vs ASA (0% vs 2.4%).4 The current study suggests that DAPT might be superior to ASA in preventing stroke in these cohorts. There is limited data to suggest a beneficial role of DAPT to improve SVG patency. In the DACAB study, patients treated with DAPT had more patent venous grafts (88.7%) vs ASA (76.5%).4 Our report showed numerically fewer events of SVG occlusion with DAPT vs ASA (12.7% vs 20.4%); however, this finding did not reach statistical significance. So far, an existential proof of relationship between graft failure and CV outcomes remains unclear.4 Further RCTs are needed to explore this association. The limitations of this meta-analysis are lack of access to patient-level data, heterogeneity in the study population, low event rates with relatively small sample size, composition of DAPT, CABG technique, and variable definitions of major bleeding. That said, these results should be considered more reliable than previous meta-analyses since the majority of the outcomes were powered, had low risk of bias and low statistical heterogeneity, and were reported after a uniform follow-up duration.10 Moreover, in the case of low event rates and relatively short follow-up duration, a potential larger statistical benefit at longer follow-up duration cannot be completely excluded. In conclusion, this study suggests that DAPT did not improve SVG patency; however, DAPT can be a more effective strategy than ASA for preventing MACEs and stroke in patients after CABG without increasing the risk of major bleeding. Future RCTs should be conducted to validate this impression. SUK contributed to the conception and design of the work. ST, HR, ML, MSK, and HS contributed to the data acquisition, analysis, and interpretation of data for the work. SUK drafted the manuscript. HR, EK, and SS critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.