JSUR Journal

Introduction

Coronary Artery Bypass Grafting (CABG) has been proven to be an efficacious intervention for individuals suffering from severe coronary artery disease [1]. For patients with CABG, aspirin is advised as a basic secondary preventive drug to preserve the advantages of revascularization and avoid significant adverse cardiovascular events [2].  Nevertheless, individuals who undergo coronary artery bypass grafting (CABG) still face a significant likelihood of experiencing serious ischemic cardiac and cerebrovascular events following the surgery. This risk can surpass 10% within the initial 6 to 12 months post-operation [3]. The diminished postoperative sensitivity to aspirin, along with increased platelet activation and blood clot formation, leads to a state of systemic hypercoagulability and early graft failure. These elements have been recognized as crucial contributors in this specific circumstance [4,5]. Each year, about 400,000 individuals in the United States and Europe receive coronary artery bypass grafting (CABG). The risks and benefits of antiplatelet regimens in these patients have been the focus of numerous trials [6]. It is recommended to use aspirin alone as the usual treatment for patients who are in a stable clinical condition. In the past ten years, multiple trials have examined the possible benefits of dual antiplatelet treatment (DAPT) compared to using only aspirin in terms of effectiveness and safety outcomes [7,8]. A meta-analysis conducted by [9]  indicated that patients who present with ACS (Acute Coronary Syndrome) may experience favorable outcomes from Dual Antiplatelet Therapy (DAPT) following Coronary Artery Bypass Grafting (CABG). This data aligns with previous research on patients with Acute Coronary Syndrome (ACS) who received medical treatment with Dual Antiplatelet Therapy (DAPT), specifically clopidogrel in combination with aspirin [10]. Additional investigations explicitly examined the effectiveness of dual Antiplatelet Therapy (DAPT) compared to aspirin in maintaining the openness of bypass grafts following Coronary Artery Bypass Grafting (CABG). These trials found that DAPT resulted in higher rates of bypass graft patency, as reported by [11,12].

Dual Antiplatelet Therapy (DAPT) using aspirin and a P2Y12 receptor antagonist (such as clopidogrel or ticagrelor) has been shown to enhance the antiplatelet effect. This therapy has been reported to slow down the progression of native coronary stenosis and improve graft patency in patients who have undergone Coronary Artery Bypass Grafting (CABG). Additionally, DAPT can help prevent recurrent strokes in patients with ischemic cerebrovascular disease. Nevertheless, the inquiry into whether the advantages linked to DAPT, particularly the potential enhancement in graft patency, result in superior clinical outcomes has not been thoroughly examined and has yielded inconsistent findings [13-15]. Administering aspirin within 48 hours after Coronary Artery Bypass Grafting (CABG) significantly decreased the risk of death, Myocardial Infarction (MI), and stroke during the patient’s hospital stay (Mangano et al., 2002). These findings led to other trials involving the use of Dual Antiplatelet Treatment (DAPT) with clopidogrel and aspirin. However, the results regarding clinical outcome and graft patency were contradictory. Ticagrelor bypasses the need for the two-step CYP-dependent metabolism that hindered clopidogrel’s effectiveness. The PLATO research demonstrated that ticagrelor is more effective than clopidogrel in lowering cardiovascular events [16].   People who had Coronary Artery Bypass Grafting (CABG) and then started taking the study drug again after the surgery had a lower risk of cardiovascular death and overall mortality when they were treated with ticagrelor [17]. Historically, aspirin has consistently been the preferred medication for preventing graft occlusion and severe cardiac events during coronary artery bypass grafting [2]. The Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events trial [18] showed that clopidogrel alone was more effective than aspirin alone in lowering the occurrence of ischemic stroke after CABG surgery. It is thought that adding a P2Y12 inhibitor will help keep the graft open and lower the risk of bad cardiac events by stopping the platelet-driven progression of graft disease. However, the effectiveness of Dual Antiplatelet Therapy (DAPT) in preserving graft openness and reducing negative cardiac events is not clearly demonstrated [2,19,20]. Hence, this present study compare the effectiveness of Dual Antiplatelet Therapy (DAPT) and Single Antiplatelet Therapy (SAPT) with Aspirin after CABG.

Research Methodology

This review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. There were several stages to the method. Prior to developing the inclusion and exclusion criteria, the methodology was developed. Then, using the criteria of the abstract, title, and full text, we searched databases for research. Data extraction was followed by a synthesis of the earlier literature. A flowchart showing the stages is shown in Figure 1.

Figure 1: PRISMA Flow Chart

Research Protocol

The protocol was created in accordance with the Cochrane Handbook for Systematic Review and it established the primary research questions that directed the selection of papers to search for, the data sources to use in the search, the inclusion and exclusion criteria, and the outcomes. The study questions served as the foundation for this evaluation, and they were used as a guide to finding high-quality papers and resources across several databases.

Inclusion and Exclusion Criteria

In view of the present study, only studies that addressed the research topic Monotherapy (Aspirin) Versus Dual Antiplatelet Therapy (Prasugrel vs Ticagrelor) Following Coronary Artery Bypass Grafting were taken into consideration. The inclusion papers were randomized control design studies, studies published in the last 10 years (2014-2024) and only the studies written in English were taken into consideration in order to provide the most valid literature review possible. Systematic literature review papers, studies, and conference papers are excluded criteria.

Research Question

The research question was developed using PECOS (Participant, Exposure, Comparator, Outcome and Study Design) framework (Table 1). This framework is used to inform the search string and the entire search strategy.

Using the above framework, this review aim to answer one research questions we trying to answer from this research was : “Is Single Antiplatelet Therapy (SAPT) better in comparison to dual antiplatelet therapy after CABG in preventing graft occlusion aswell as other secondary prevention”.

Data Source and Search strategy

Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), we use PubMed, Science Direct and EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) for relevant published randomized controlled trials (RCTs) to get the studies that were used for this systematic review from year 2014 to 2024 following the inclusion and exclusion criteria earlier mentioned. The following precise keywords were used in the literature search: (“single Antiplatelet Therapy” OR “Aspirin Monotherapy”) AND (“Dual Antiplatelet Therapy” OR Prasugrel OR Ticagrelor) AND (“Coronary Artery Bypass Grafting” OR “heart bypass surgery”)). Table 2

Table 2: Number of hit generated from database

Quality Assessment or Risk of Bias

Considering the nature of this research, quality assessment of the eligible studies was performed using Cochrane risk of bias assessment via review manager (RevMan 5.4). Each of the study was appraised based on the CASP checklist for qualitative studies (Table 3). The appraisal was basically “Low, Moderate and High” each study was asses. The checklist criteria of assessment were 7 questions. The risk of bias is termed low if the study has 70% and above assessment score, moderate if it have within 50% to 70% score and high if it has below 50%.

Table 3: Quality Assessment Questions

Study Selection

The exclusion criteria for the selected studies were reported as case reports, review articles, case series and articles in that is not written in English language were excluded. Full text studies on the research topic were included. Randomized controlled trials were the study types that were taken into consideration. Each article’s title and abstract were examined for inclusion and exclusion criteria.

Data Extraction and Quality Assessment

A pre-defined sheet was used to collect the following information from the included studies: research design, author’s first name, year of publication, country, study design, all-cause mortality, cardiovascular mortality, Major Adverse Cardiac And Cerebrovascular Events(MACCE), myocardial infarction, stroke, or major bleeding and graft occlusion. the prisma flowchart was then used to display the final list of studies that will be included. after the data were extracted, the risk bias range was divided into three categories: low, high, and uncertain.

Data Extraction and Analysis

The data were transferred to Excel, where RevMan was used to analyze the features of the chosen studies and check for the presence of heterogeneity using the inconsistency index. The numerical data extracted from the included studies were analyzed using number, event, and total. To analyse the primary and secondary outcomes, we adopted a random effect meta-analysis with a odd ratio OR that measured the effect size. The results was visualized using a forest plot, the plot shows the overall OR for each studies. The heterogeneity across each studies was measured using (I2). A 95% Confidence level and 5% level of significance was chosen for decision making. The null hypothesis of no significant difference between the two groups would be rejected if the estimated p – value is less than the significance level. The publication bias was assessed using funnel plot. The criteria was that, if all studies were within the funnel, and the funnel is symmetric, there is no evidence of publication bias across the included studies.

Results

Study selection and Screening process

After the keywords were entered into the aforementioned database, a total of 2,152 publications were retrieved from it. The 2,152 papers were first entered into the reference manager Endnote for review. We read through the titles and abstracts of the studies during the screening stage, eliminating any duplicates and studies that did not pertain to the aim of our study. Studies that were concentrated on a different intervention were also disregarded. 500 publications remained after the identification and screening phases; these 30 papers underwent full-text screening before being assessed for methodology and data analysis, both of which required to be done in accordance with the current study’s scope.

There were 18 studies left after the eligibility procedure.

Quality Assessment Result

In total, 18 studies were included, out of which 18 studies is at low risk bias under the random sequence generation. 17 studies were of low-risk for the allocation concealment and 1 study is unclear for the allocation of concealment. 15 studies are of lowrisk for blinding of participants, 2 studies is at high risk and a study is unclear. 15 studies blinding of outcome assessment were at lowrisk and 3 studies are unclear. 13 studies are of incomplete outcome data are of low-risk, 4 study are unclear and a study is at high risk. 14 studies were of low risk of selective reporting and 4 studies are unclear of selecting reporting. Lastly, other bias associated with 17 studies are of low risk while a study associated with other bias is unclear as shown in Figure 2. The percentage of the grading is shown in Figure 3.

Figure 2: The quality assessment summary of the included studie

Figure 3: Percentage of the quality assessment level of the included studies

Distribution of studies with respect to year of publication

Figure 4 display the publication year of the included studies, 4 articles of the included studies was published in the year 2017 and 2019 respectively, 3 articles published in year 2014, 2 articles published each in year 2016, 2018 and 2024 respectively while a study was published in year 2021.

Figure 4: Publication year

Meta Analysis

Data evaluation and analysis

RevMan 5.4 was used to conduct the meta-analysis. We adopted a more cautious approach and used a random-effects model because it was unknown whether there was a “true” effect size underlying all studies. The standard mean difference as well as its associated 95% Confidence Intervals (CLs) was used to estimate the effect size. The degree of heterogeneity was evaluated using the I2 test.

Data Extraction and Analysis

The data was extracted to excel and Review Manager was used to analyze the selected studies characteristics and the intervention measure also test for the heterogeneity’s presence using the inconsistency index. Also was included in the forest plot is the chi statistic and the inconsistency index I2 statistics to access if the studies were heterogeneous. An indication of I2 that was less than fifty percent indicated low heterogeneity. A value between fifty and seventy-five was a sign of mild heterogeneity and above seventy-five showed a high level of heterogeneity. Therefore, the researcher had high confidence on whether to generalize the studies to a larger sample depending on the results.Table 4, present the pooled analyses comparing DAPT with SAPT with 121004 and 97121 patients, respectively, in 18 studies. DAPT, compared with SAPT, was associated with significantly lower rates of Cardiovascular mortality (OR 0.71, 95% CI 0.54, 0.93, p=0.01), MACCE (OR 0.68, 95% CI 0.61, 0.76, p=0.0001) and Myocardial infarction (OR 0.78, 95% CI 0.64, 0.94, p=0.009). While there is no association with lower rates of graft occlusion (OR 0.86, 95% CI 0.68, 1.10, p=0.23), stroke (OR 0.82, 95% CI 0.63, 1.45, p=0.82), but high rates of All cause of death (OR 1.06, 95% CI 0.61, 1.84, p=0.84) and major bleeding (OR 1.21, 95% CI 0.81, 1.81, p=0.0001). In summary there were no significant difference in the outcomes of graft occlusion, all cause of death, stroke and major bleeding with p values greater than 5% significance level while there is significant differences in the outcome of cardiovascular mortality,  MACCE and myocardial infarction with p values lesser than 5% significance level.

Table 4: Pooled Analysis results for DAPT against SAP.

P values <0.05 are asterik. DAPT, dual antiplatelet therapy; MACCE, major adverse cardiovascular and cerebrovascular events; SAPT, single antiplatelet therapy

Figure 5: Forest plot showing the Graft occlusion of DAPT and SAPT

The statistics estimated is not statistically significant with overall odd ratio of 0.86, [95% CI: 0.68, 1.10] when p- value (0.23) is greater than the level of significant (0.05) which implies that there is no significant difference between DAPT and SAPT for across all studies. But a significant lower event rates was found. The heterogeneity, I^ = 46% across the studies is moderate with a insignificant value (p = 0.09) indicating that the heterogeneity is not statistically significant, which makes the graft occlusion of DAPT and SAPT to be consistent across the different studies with insignificant variability.

Figure 5: Forest plot showing the Graft occlusion of DAPT and SAPT.

Figure 6: Forest plot showing the all cause of death of DAPT and SAPT.

The statistics estimated is statistically not significant with overall odd ratio of 1.06, [95% CI: 0.61, 1.84] when p- value (0.84) is greater than the level of significant (0.05) which implies that the overall effect has no significant impact. But a significant high event rates was found. The heterogeneity, I^ = 90% across the studies is high with a significant value (p < 0.00001) which makes the all cause of death of the DAPT and SAPT to be inconsistent across the different studies.

Figure 6: Forest plot showing the all cause of death of DAPT and SAPT.

Figure 7: Forest plot showing the Cardiovascular mortality of DAPT and SAPT

The statistics estimated is statistically significant with overall odd ratio of 0.71, [95% CI: 0.54, 0.93] when p- value (0.01) is less than the level of significant (0.05) which implies that the overall effect has a significant impact  and a significant low event rates was found. The heterogeneity, I^ = 0% across the studies is very low with a insignificant value (p 0.59) which makes the Cardiovascular mortality of the DAPT and SAPT to be consistent across the different studies.

Figure 7: Forest plot showing the Cardiovascular mortality of DAPT and SAPT

Figure 8: Forest plot showing the MACCE of DAPT and SAPT

The statistics estimated is statistically significant with overall odd ratio of 0.68, [95% CI: 0.61, 0.76] when p- value (0.00001) is less than the level of significant (0.05) which implies that the overall effect has a significant impact and a significant low event rates was found. The heterogeneity, I^ = 0% across the studies is very low with a insignificant value (p 0.46) which makes the MACCE of the DAPT and SAPT to be consistent across the different studies.

Figure 8: Forest plot showing the MACCE of DAPT and SAPT

Figure 9: Forest plot showing the MI of DAPT and SAPT.

The statistics estimated is statistically significant with overall odd ratio of 0.78, [95% CI: 0.64, 0.94] when p- value (0.009) is less than the level of significant (0.05) which implies that the overall effect has a significant impact and a significant low event rates was found. The heterogeneity, I^ = 26% across the studies is low with a insignificant value (p 0.18) which makes the MI of the DAPT and SAPT to be consistent across the different studies.

Figure 9: Forest plot showing the MI of DAPT and SAPT.

Figure 10: Forest plot showing the stroke of DAPT and SAPT.

The statistics estimated is statistically not significant with overall odd ratio of 0.95, [95% CI: 0.63, 1.45] when p- value (0.82) is less than the level of significant (0.05) which implies that the overall effect has a significant impact and a significant low event rates was found. The heterogeneity, I^ = 78% across the studies is high with a significant value (p <000001) which makes the stroke of the DAPT and SAPT to be inconsistent across the different studies

Figure 10: Forest plot showing the stroke of DAPT and SAPT.

Figure 11: Forest plot showing the bleeding of DAPT and SAPT.

The statistics estimated is statistically not significant with overall odd ratio of 1.21, [95% CI: 0.81, 1.81] when p- value (0.35) is greater than the level of significant (0.05) which implies that the overall effect has a significant impact and a significant low event rates was found. The heterogeneity, I^ = 65% across the studies is moderate with a significant value (p 0.003) which makes the bleeding of the DAPT and SAPT to be inconsistent across the different studies bleeding.

Figure 11: Forest plot showing the bleeding of DAPT and SAPT.

Funnel Plot

For all research, funnel plots are commonly used to identify publication bias; visual inspection of a funnel plot was done on all comparisons for the papers included in the meta-analysis of graft occlusion forest plot in Figure 12,13 below. The two funnel plot for the DAPT associated with autistic people revealed a symmetrical funnel with outliers, although this implies true heterogeneity rather than publication bias.Base on this, we can conclude none of the studies could be considered to be overly influential.

Figure 12: Graft occlusion funnel plot