Comparison efficacy and safety of different antiplatelet or anticoagulation drugs in chronic coronary syndromes patients: A Bayesian network meta-analysis

Abstract

Background:

A systematic review and network meta-analysis (NMA) were conducted to explore the efficacy and safety of different antiplatelet or anticoagulation drugs in chronic coronary syndromes patients.

Methods:

Electronic databases (Pubmed, Embase and Cochrane databases) were systematically searched to identify randomized controlled trials evaluating different antiplatelet or anticoagulation drugs (aspirin, aspirin + clopidogrel, aspirin + clopidogrel + cilostazol, clopidogrel/prasugrel + aspirin, aspirin + rivaoxaban 2.5 mg, aspirin + ticagrelor 60 mg, aspirin + ticagrelor 90 mg, clopidogrel or rivroxaban 5 mg) versus placebo for treatment chronic coronary syndromes patients. Outcomes included major adverse cardiovascular events, all cause death, major bleeding and myocardial infarction. A random-effect Bayesian NMA was conducted for outcomes of interest, and results were presented as odds ratios (ORs) and 95% credible intervals. The NMA was performed using R Software with a GeMTC package. A Bayesian NMA was performed and relative ranking of agents was assessed using surface under the cumulative ranking probabilities.

Results:

Ten randomized controlled trials met criteria for inclusion and finally included in this NMA. In head-to-head comparison, no significant difference was observed between all antithrombotic treatment strategies with respect to primary endpoint of major adverse cardiovascular events. In head-to-head comparison, no significant difference was observed between all antithrombotic treatment strategies with respect to all cause death. Clopidogrel/prasugrel + aspirin (OR = 3.8, 95% credible intervals [CrI]: 1.3–12.0, P < .05) and aspirin + rivaroxaban 2.5 mg (OR = 3.1, 95%CrI: 1.1–9.5, P < .05) was associated with an increase of the major bleeding. Compared with aspirin alone, aspirin + clopidogrel (OR = 0.42, 95%CrI: 0.22–0.76, P < .05) and aspirin + ticagrelor 90 mg (OR = 0.42, 95%CrI: 0.17–0.95, P < .05) was associated with a decrease of the myocardial infarction.

Conclusions:

Myocardial infarction was significantly lower when adding clopidogrel or ticagrelor 90 mg to aspirin than those in the aspirin alone group. However, clopidogrel/prasugrel and rivaroxaban 2.5 mg was associated with an increase of the major bleeding than aspirin alone.

1. Introduction

Coronary artery disease (CAD) is a pathological process characterized by the accumulation of atherosclerotic plaques in the coronary arteries.^[1] Platelets play a pivotal role in the development of coronary thrombosis following the rupture of atherosclerotic plaques, and actively inhibiting their function is a fundamental aspect of managing acute coronary syndromes (ACSs).^[2] Consequently, the utilization of antiplatelet and anticoagulant therapy has been advocated as a fundamental approach in the management of CAD.

Thus, antiplatelet drugs are mandatory in the treatment and secondary prevention of coronary artery disease, particularly in the setting of ACS and percutaneous coronary interventions (PCI).^[3] Aspirin, an inhibitor of the cyclooxygenase pathway, serves as the predominant recommendation for monotherapy due to its ability to diminish thromboxane A2 formation and hinder platelet aggregation.^[4,5]

In 2017, the European Society of Cardiology endorsed a combination therapy consisting of aspirin and ticagrelor (60 mg taken twice daily) for chronic coronary syndromes (CCS) patients at risk of ischemia.^[6] A similar approach was reiterated in the 2020 European Society of Cardiology update, suggesting the inclusion of a secondary antithrombotic agent (such as clopidogrel, prasugrel, or low-dose rivaroxaban) alongside aspirin for prolonged and comprehensive secondary prevention, particularly for individuals at high risk of ischemia and with a low risk of bleeding.^[7]

Nonetheless, a definitive agreement regarding the most advantageous antithrombotic plan following PCI for patients with CCS remains elusive, whether it involves substituting aspirin with alternative antiplatelet agents or introducing a P2Y12 inhibitor or low-dose anticoagulant alongside aspirin. In light of this, we conducted a comprehensive network meta-analysis (NMA) aimed at contrasting various antithrombotic medications with aspirin and evaluating their combined impact on major adverse cardiovascular events (MACE), mortality, as well as ischemic and bleeding incidents among CCS patients.

2. Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Network Meta-Analysis Extension statement will be followed during the conduct of this systematic review and NMA.^[8]

2.1. Search strategy

A search was conducted by 2 reviewers (Chang Liu and Lei Ma) for potentially relevant randomized controlled trials (RCTs) about different antiplatelet or anticoagulation drugs in CCS patients on Pubmed, Embase and Cochrane databases up to June, 2023. A structured search was performed using the following search string: “Aspirin” OR “clopidogrel” OR “cilostazol” OR “prasugrel” OR “rivaoxaban” OR “ticagrelor” AND (“coronary syndromes patients” OR “percutaneous coronary intervention”). Search strategies can be seen in Supplement S1, http://links.lww.com/MD/K927. The titles, abstracts, and full publications were screened against pre-defined criteria by 2 independent reviewers. Disagreements were either resolved through discussion leading to a consensus or by seeking the intervention of a third reviewer. For this systematic review and meta-analysis, manual searches will be conducted for reference lists, related citations, and gray literature from websites. No ethics approval was necessary as there was no patient contact involved.

2.2. Inclusion criteria and exclusion criteria

To be included in the meta-analysis, studies had to fulfill the population, intervention, comparator, outcome, study design criteria as follows: population (P)—CCS patients; intervention (I)—the intervention group received different antiplatelet or anticoagulation drugs (aspirin, aspirin + clopidogrel, aspirin + clopidogrel + cilostazol, clopidogrel/prasugrel + aspirin, aspirin + rivaoxaban 2.5 mg, aspirin + ticagrelor 60 mg, aspirin + ticagrelor 90 mg, clopidogrel or rivroxaban 5 mg), or placebo; outcomes (O)—MACE, all cause death, major bleeding and myocardial infarction; study design (S)—RCTs. Retrospective studies, cadaver studies, comments, letters, editorials, protocols, guidelines, surgical registries, and review papers were excluded.

2.3. Literature selection

After collecting all relevant studies, they were imported into Endnote X7 and duplicate literature was removed. Two researchers (Chang Liu and Lei Ma) then independently reviewed the titles and abstracts to exclude studies that did not meet the population, intervention, comparator, outcome, study design criteria. Any remaining irrelevant studies were subsequently removed. In case of any disagreement regarding which literature to include, a senior reviewer was consulted.

2.4. Data extraction

Two independent reviewers (Chang Liu and Lei Ma) extracted the available data from the included studies, which consisted of information such as author, participants, ratio of PCI, total number of the patients, intervention and control group, MACE definition, MACE, all cause death, cardiovascular death, myocardial infarction, stent thrombosis, any revascularization, bleeding definition, major bleeding, fatal bleeding, intracranial bleeding and follow up. The primary outcomes assessed were MACE, all cause death, major bleeding and myocardial infarction. If any data was missing, we contacted the corresponding author of the study to obtain the necessary information.

2.5. Quality assessment

Two reviewers (Chang Liu and Lei Ma) evaluated the risk of bias in RCTs based on the Cochrane Handbook for Systematic Reviews of Interventions version,^[9] which included items such as sequence generation, allocation concealment, blinding of participants and outcome assessors, incomplete outcome data, reporting bias, and other bias. Any discrepancies in the evaluations between the 2 reviewers were resolved by a third reviewer.

2.6. Data analysis and statistical methods

We will use Bayesian methods, specifically JAGS via R with the R package gemtc (https://cran.r-project.org/web/packages/gemtc/gemtc.pdf), for the NMAs of efficacy outcomes. To ensure the reliability of our results, we performed sampling simulations and MCMC calculations using a random effects model. We evaluated the convergent diagnostic results using diagnostic plots such as trajectory plots and density plots. We calculated the means under the random effects model and fixed effects model and examined the homogeneity in the literature using the BlandAltmanLeh package. Good homogeneity is indicated when the distances between all points are within 95% of the LoA. To test consistency between direct and indirect comparisons, we used the node-splitting approach and deemed P values >.05 to be favorable. We investigated further heterogeneity when it was detected, with I² values over 50% indicating heterogeneity, and we considered the total I² pair and I² cons for the overall results. We also performed sensitivity analyses by excluding 1 study at a time and combining the remaining studies for analysis to evaluate the potential impact on the results. We calculated the mean surface under the cumulative ranking (SUCRA) curve for each intervention, with a higher SUCRA indicating a higher rank of the protocol. Moreover, NMA regression was performed by R software with gemtc package. Publication bias was performed by Stata 14.0 (STATA SE 14.0, Stata Corp, College Station, TX, USA).

3. Results

3.1. Search results

We identified 855 relevant studies from various databases (Pubmed, Embase and Cochrane databases) based on our search strategies. No additional records were identified through other sources such as reference lists. Using Endnote Software (Version X7, Thompson Reuters, CA), we removed 266 duplicate studies. After screening the titles and abstracts, we excluded 579 studies by reading the full text (Fig. 1). Finally, 10 studies were included in our meta-analysis.^[10–19]

Figure 1.

Flow diagram of the literature selection process.

3.2. Study characteristics

The general characteristic of the included RCTs were listed in Table 1. All of them evaluated the efficacy and safety of different antiplatelet or anticoagulation drugs for CCS patients that underwent PCI.

Table 1.

General characteristic of the included studies.

Author	Participants	PCI	Total	Intervention group	Control group	MACE definition	MACE
Bonaca 2014	Myocardial infarction 1–3 yr earlier	83.20%	21162	A + T90 (n = 7050)	A + placebo (n = 7067)	Cardiac death, MI, or stroke	493/7050 vs 578/7067
Collet 2014	CAD with PCI > 12 mo	100%	1259	A + C (91%)/P (9%) (n = 635)	A/P (8%) (n = 624)	Death, MI, stent thrombosis, stroke, or urgent revascularisation	24/635 vs 27/624
Connolly 2018	CCS or with PAD	60%	24824	A + R2.5 (n = 8313)	A(n = 8261)	Cardiac death, MI, or stroke	347/8313 vs 460/8216
Helft 2016	CAD with PCI > 12 mo	100%	1385	A + C(n = 695)	A(n = 690)	All-cause mortality, MI, stroke or major bleeding	40/695 vs 52/690
Koo 2021	CAD with PCI > 12 mo	100%	5438	C(n = 2710)	A(n = 2728)	All-cause mortality, MI, stroke, readmission due to ACS and major bleeding	152/2710 vs 207/2728
Lee 2014	CAD with PCI > 12 mo	100%	5045	A + C (n = 2531)	A (n = 2514)	Cardiac death, MI, or stroke	61/2531 vs 57/2514
Mauri 2014	CAD with PCI > 12 mo	100%	9991	A + C/P(N = 5020)	A + placebo (n = 4941)	Death, MI or stroke	211/5020 vs 285/4941
Park 2023	CAD with PCI > 12 mo	100%	985	A + C (n = 320)	A + C + C (n = 317)	Death, MI or stroke	28/320 vs 35/317
Park 2019	CAD with PCI > 12 mo	100%	2791	A + C (n = 1357)	A (n = 1344)	MI, stroke, or death from cardiac cause	28/1357 vs 15/1344
Steg 2019	CCS with diabetes without MR	79.80%	19220	A + T90/60 (n = 9616)	A + placebo(n = 9601)	Cardiac death, MI, or stroke	736/9619 vs 818/9601

A, Aspirin, B, Aspirin + clopidogrel, C, Aspirin + clopidogrel + cilostazol, D, Clopidogrel/prasugrel + aspirin; E, Aspirin + rivaoxaban 2.5 mg; F, Aspirin + ticagrelor 60 mg; G, Aspirin + ticagrelor 90 mg; H, clopidogrel, I, Rivroxaban 5 mg.

ACS = acute coronary syndrome, CCS = chronic coronary syndromes, MACE = major adverse cardiovascular events, PCI = percutaneous coronary interventions.

All 10 included literatures were published between 2014 and 2023. Sample of the included studies ranged from 985 to 21162. The duration of follow-up ranged from 12 to 44 months. MACE definition was provided by the included studies.

3.3. Risk of bias

Risk of bias summary and risk of bias graph can be seen in Figures 2 and 3 respectively. For random sequence generation, 1 of the ten studies were classified as high risk of bias, rest studies were rated as low risk of bias. Ten studies were rated as low risk of bias for allocation concealment. Five studies were listed as low risk of bias for blinding of participant and personnel and 5 studies were rated as high risk of bias. Only 1 study was rated as high risk of bias for blinding of outcome assessment. Only 1 studies were listed as high risk of bias for selective reporting. All included studies were listed as low risk of bias for other bias.

Figure 2.

Risk of summary of the included studies.

Figure 3.

Risk of bias graph of the included studies.

3.4. Major adverse cardiovascular events

A total of 9 studies, including 9 treatments (Aspirin, rivaroxaban 5 mg, clopidogrel, aspirin + ticagrelor 90 mg, aspirin + ticagrelor 60 mg, aspirin + rivaroxaban 2.5 mg, clopidogrel/prasugrel + aspirin, aspirin + clopidogrel + cilostazol and aspirin + clopidogrel) contributed to the clinical outcome of MACE. As displayed in Figure 4A, the network structure diagrams detailed the direct comparisons between different treatment in the case fatality.

Figure 4.

(A) Network structure diagrams of MACE; (B) forest plot of the MACE as compared with aspirin; (C) surface under the cumulative ranking (SUCRA) curve probabilities of different treatments for MACE. A, Aspirin, AC, Aspirin + clopidogrel, ACC, Aspirin + clopidogrel + cilostazol, ACP Clopidogrel/prasugrel + aspirin; AR2.5, Aspirin + rivaoxaban 2.5 mg; AT60, Aspirin + ticagrelor 60 mg; AT90, Aspirin + ticagrelor 90 mg; C, clopidogrel, R5 Rivroxaban 5 mg. MACE = major adverse cardiovascular events.

In head-to-head comparison, no significant difference was observed between all antithrombotic treatment strategies with respect to primary endpoint of MACE (Fig. 4B and Table 2). NMA showed no heterogeneity with global I² = 0% (Supplement S2 A, http://links.lww.com/MD/K928).

Table 2.

General characteristic of the included studies.

Author	All cause death	Cardiovascular death	Myocardial infarction	Stent thrombosis	Any revascularisation	Bleeding definition	Major bleeding	Fatal bleeding	Intracranial bleeding	Follow up
Bonaca 2014	326/7050 vs 326/7067	182/7050 vs 210/7067	275/7050 vs 338/7067			TIMI	127/6988 vs 54/6996		29/6988 vs 23/6996	36 mo
Collet 2014	7/635 vs 9/624		9/635 vs 9/624	0/635 vs 3/624	8/635 vs 3/624	TIMI	0/635 vs 0/624	0/635 vs 0/624		17 mo
Connolly 2018	262/8313 vs 339/8261	10/695 vs 14/690	11/695 vs 16/690	6/695 vs 1/690	35/695 vs 35/690	TIMI	4/695 vs 4/690	1/695 vs 0/690	1/695 vs 2/690	44 mo
Helft 2016	16/695 vs 24/690	174/7045 vs 210/7067	285/7045 vs 338/7067				115/6958 vs 54/6996	11/6958 vs 12/6996	28/6958 vs 23/6996
Koo 2021	51/2710 vs 36/2728	19/2710 vs 14/2728	18/2710 vs 28/2728	56/2710 vs 69/2728		BARC type ≥ 3	33/2710 vs 53/2728		4/2710 vs 17/2728	24 mo
Lee 2014	46/2531 vs 32/2514	28/2531 vs 19/2514	19/2531 vs 27/2514	7/2513 vs 11/2514	81/2531 vs 65/2514	TIMI	34/2531 vs 24/2514	1/2513 vs 4/2514	5/2531 vs 3/2514	24 mo
Mauri 2014	98/5020 vs 74/4941	45/5020 vs 47/4941	99/5020 vs 198/4941	19/5020 vs 65/4941		BARA type ≥ 3	129/4713 vs 4/4650	7/4713 vs 44/4650	13/4713 vs 9/4650	18 mo
Park 2023	11/320 vs 17/317	4/320 vs 11/317	2/320 vs 17/317	1/320 vs 1/317	14/320 vs 15/317	TIMI	7/320 vs 17/317		1/320 vs 0/317	12 mo
Park 2019	20/1357 vs 13/1344	13/1357 vs 8/1344	10/1357 vs 7/1344	5/1357 vs 4/1344	36/1357 vs 26/1344	TIMI	3/1357 vs 1/1344	0/1357 vs 0/1344		24 mo
Steg 2019	579/9619 vs 592/9601	364/9619 vs 357/9601	274/9619 vs 328/9601		828/9619 vs 879/9601	TIMI	206/9562 vs 100/9531	17/9562 vs 46/9531	70/9562 vs 46/9531	39.9 mo

A, Aspirin, B, Aspirin + clopidogrel, C, Aspirin + clopidogrel + cilostazol, D, Clopidogrel/prasugrel + aspirin; E, Aspirin + rivaoxaban 2.5 mg; F, Aspirin + ticagrelor 60 mg; G, Aspirin + ticagrelor 90 mg; H, clopidogrel, I, Rivroxaban 5 mg.

The SUCRA shows that clopidogrel/prasugrel + aspirin ranked first (SUCRA, 92.1%), aspirin + rivaroxaban 2.5 mg ranked second (SUCRA, 75.4%), rivaroxaban 5 mg ranked third (SUCRA, 59.7%) and placebo ranked the last (SUCRA, 0.1%, Fig. 4C).

3.5. All cause death

A total of 9 studies, including 9 treatments (Aspirin, rivaroxaban 5 mg, clopidogrel, aspirin + ticagrelor 90 mg, aspirin + ticagrelor 60 mg, aspirin + rivaroxaban 2.5 mg, clopidogrel/prasugrel + aspirin, aspirin + clopidogrel + cilostazol and aspirin + clopidogrel) contributed to the clinical outcome of all cause death. As displayed in Figure 5A, the network structure diagrams detailed the direct comparisons between different treatment in the case fatality.

Figure 5.

(A) Network structure diagrams of all cause death; (B) forest plot of the all cause death as compared with aspirin; (C) surface under the cumulative ranking (SUCRA) curve probabilities of different treatments for all cause death. A, Aspirin, AC, Aspirin + clopidogrel, ACC, Aspirin + clopidogrel + cilostazol, ACP Clopidogrel/prasugrel + aspirin; AR2.5, Aspirin + rivaoxaban 2.5 mg; AT60, Aspirin + ticagrelor 60 mg; AT90, Aspirin + ticagrelor 90 mg; C, clopidogrel, R5 Rivroxaban 5 mg.

In head-to-head comparison, no significant difference was observed between all antithrombotic treatment strategies with respect to all cause death (Fig. 5B and Table 2). NMA showed no heterogeneity with global I² = 0% (Supplement S2 B, http://links.lww.com/MD/K928).

The SUCRA shows that clopidogrel/prasugrel + aspirin ranked first (SUCRA, 69.2%), clopidogrel ranked second (SUCRA, 68.0%), aspirin + rivaroxaban 2.5 mg ranked third (SUCRA, 67.1%) and aspirin + clopidogrel ranked the last (SUCRA, 28.3%, Fig. 5C).

3.6. Major bleeding

A total of 9 studies, including 9 treatments (Aspirin, rivaroxaban 5 mg, clopidogrel, aspirin + ticagrelor 90 mg, aspirin + ticagrelor 60 mg, aspirin + rivaroxaban 2.5 mg, clopidogrel/prasugrel + aspirin, aspirin + clopidogrel + cilostazol and aspirin + clopidogrel) contributed to the clinical outcome of major bleeding. As displayed in Figure 6A, the network structure diagrams detailed the direct comparisons between different treatment in the case fatality.

Figure 6.

(A) Network structure diagrams of major bleeding; (B) forest plot of the major bleeding as compared with aspirin; (C) surface under the cumulative ranking (SUCRA) curve probabilities of different treatments for major bleeding. A, Aspirin, AC, Aspirin + clopidogrel, ACC, Aspirin + clopidogrel + cilostazol, ACP Clopidogrel/prasugrel + aspirin; AR2.5, Aspirin + rivaoxaban 2.5 mg; AT60, Aspirin + ticagrelor 60 mg; AT90, Aspirin + ticagrelor 90 mg; C, clopidogrel, R5 Rivroxaban 5 mg.

In head-to-head comparison, clopidogrel/prasugrel + aspirin (odds ratio [OR = 3.8, 95% credible intervals [CrI]: 1.3–12.0, P < .05) and aspirin + rivaroxaban 2.5 mg (OR = 3.1, 95%CrI: 1.1–9.5, P < .05) was associated with an increase of the major bleeding (Fig. 6B and Table 2). NMA showed no heterogeneity with global I² = 0% (Supplement S2 C, http://links.lww.com/MD/K928).

The SUCRA shows that aspirin ranked first (SUCRA, 90.6%), aspirin + ticagrelor 90 mg ranked second (SUCRA, 78.0%), aspirin + ticagrelor 60 mg ranked third (SUCRA, 73.8%) and clopidogrel/prasugrel + aspirin ranked the last (SUCRA, 20.8%, Fig. 6C).

3.7. Myocardial infarction

A total of 9 studies, including 9 treatments (Aspirin, rivaroxaban 5 mg, clopidogrel, aspirin + ticagrelor 90 mg, aspirin + ticagrelor 60 mg, aspirin + rivaroxaban 2.5 mg, clopidogrel/prasugrel + aspirin, aspirin + clopidogrel + cilostazol and aspirin + clopidogrel) contributed to the clinical outcome of myocardial infarction. As displayed in Figure 7A, the network structure diagrams detailed the direct comparisons between different treatment in the case fatality.

Figure 7.

(A) Network structure diagrams of myocardial infarction; (B) forest plot of the myocardial infarction as compared with aspirin; (C) surface under the cumulative ranking (SUCRA) curve probabilities of different treatments for myocardial infarction. A, Aspirin, AC, Aspirin + clopidogrel, ACC, Aspirin + clopidogrel + cilostazol, ACP Clopidogrel/prasugrel + aspirin; AR2.5, Aspirin + rivaoxaban 2.5 mg; AT60, Aspirin + ticagrelor 60 mg; AT90, Aspirin + ticagrelor 90 mg; C, clopidogrel, R5 Rivroxaban 5 mg.

In head-to-head comparison, compared with aspirin alone, aspirin + clopidogrel (OR = 0.42, 95%CrI: 0.22–0.76, P < .05) and aspirin + ticagrelor 90 mg (OR = 0.42, 95%CrI: 0.17–0.95, P < .05) was associated with a decrease of the myocardial infarction (Fig. 7B and Table 2). NMA showed no heterogeneity with global I² = 0% (Supplement S2 D, http://links.lww.com/MD/K928).

The SUCRA shows that clopidogrel/prasugrel + aspirin ranked first (SUCRA, 69.2%), clopidogrel ranked second (SUCRA, 68.0%), aspirin + rivaroxaban 2.5 mg ranked third (SUCRA, 67.1%) and aspirin + clopidogrel ranked the last (SUCRA, 28.3%, Fig. 7C).

3.8. Publication bias, meta-regression and contribution plot

There was no significant publication bias found for MACE (Fig. 8A), all cause death (Fig. 8B), major bleeding (Fig. 8C) and myocardial infarction (Fig. 8D). Network meta-regression determines if effect size (i.e., treatment outcome) differs according to a given covariate (i.e., a potential effect modifier). None of these modifiers have effects on the final outcomes (Table 3). Supplement S3, http://links.lww.com/MD/K929 shows the contribution of each direct comparison to the network summary effects.

Figure 8.

The funnel plot used for publication bias for MACE (A), all cause death (B), major bleeding (C) and myocardial infarction (D). A, Aspirin, B, Aspirin + clopidogrel, C, Aspirin + clopidogrel + cilostazol, D, Clopidogrel/prasugrel + aspirin; E, Aspirin + rivaoxaban 2.5 mg; F, Aspirin + ticagrelor 60 mg; G, Aspirin + ticagrelor 90 mg; H, clopidogrel, I, Rivroxaban 5 mg. MACE = major adverse cardiovascular events.

Table 3.

Network meta-regression of the outcomes.

	Covariates	b	95% credible interval of b
MACE	Publication yr	0.6052	0.0732; 1.2378
	Sample size	0.3173	0.0134; 1.1153
	Risk of bias	0.2851	0.0643; 1.0232
All cause death	Publication yr	0.1699	0.0868;1.1265
	Sample size	0.9432	0.0513;1.9826
	Risk of bias	0.5263	0.0321;1.6322
Major bleeding	Publication yr	0.6369	0.0142;1.5329
	Sample size	0.6777	0.0132;1.2672
	Risk of bias	0.6296	0.0105;1.0542
Myocardial infarction	Publication yr	0.7602	0.1942; 1.1742
	Sample size	0.7731	0.0990;1.2523
	Risk of bias	0.6234	0.3693;1.1429

MACE = major adverse cardiovascular events.

4. Discussion

4.1. Main finding

Our analysis included 10 RCTs to systematically evaluate the efficacy and safety of different antiplatelet or anticoagulation drugs in CCS patients using a Bayesian NMA. The results demonstrated that the myocardial infarction was significantly lower when adding clopidogrel or ticagrelor 90 mg to aspirin than those in the aspirin alone group. However, clopidogrel/prasugrel and rivaroxaban 2.5 mg was associated with an increase of the major bleeding than aspirin alone. There was no significant difference between these treatments in terms of the MACE and all cause death.

4.2. Compared with previous meta-analyses

Only 3 meta-analyses have been conducted to investigate the efficacy and safety of different for antiplatelet or anticoagulation strategies for CCS patients. A previous meta-analysis by Lin et al^[20] reported that adding prasugrel or ticagrelor led to a reduced incidence of myocardial infarction and prasugrel was also found to reduce the risk of MACE and stent thrombosis in CCS patients with low risk of bleeding. However, the meta-analyses showed substantial statistical heterogeneity, especially the meta-analysis of myocardial infarction. Furthermore, no meta-regression analysis was performed by date of publication. Zhu et al^[21] performed an NMA to identify the long-term antithrombotic strategies in CCS patients. They concluded that rivaroxaban plus aspirin appears to be the preferred long-term antithrombotic regimen for patients with CCS and high-risk factors. Differences between the current meta-analysis and previous meta-analyses should be noted. In the current NMA, we performed publication bias analyses and meta-regression to increase the robustness of this meta-analysis. Marques et al^[22] included 5 studies and revealed that clopidogrel monotherapy might provide the best risk-benefit balance in treating CCS. Studies in the meta-analysis are limited and case studies were too small to draw conclusions.

Our main finding was that myocardial infarction was significantly lower when adding clopidogrel or ticagrelor 90 mg to aspirin than those in the aspirin alone group. The present conclusions are consistent with those of a previous meta-analysis addressing similar topics. Malik et al^[23] found that monotherapy with a P2Y12 inhibitor appears to be the superior strategy for optimization of bleeding and thrombotic risk. Although clopidogrel and ticagrelor are both antiplatelets that are P2Y12 adenosine diphosphate receptor blockers, they are structurally different. Unlike clopidogrel, ticagrelor operates as a reversible antagonist of the P2Y12 receptor and does not depend on hepatic conversion to active metabolites to achieve its effectiveness. Consequently, the antiplatelet influence of ticagrelor exhibits greater predictability compared to clopidogrel. When administered alongside aspirin, ticagrelor showcases enhanced patient outcomes for ACS, with no concurrent elevation in major bleeding events. Moreover, the combined regimen of ticagrelor and aspirin leads to a decreased overall incidence of all-cause mortality.

Our results found that aspirin + ticagrelor 90 mg or aspirin + ticagrelor 60 mg will not increase the major bleeding than aspirin alone. Wallentin et al^[24] revealed that among individuals experiencing ACS, either with or without ST-segment elevation, the utilization of ticagrelor, in comparison to clopidogrel, notably diminished the occurrence of vascular-related mortality, myocardial infarction, or stroke. Importantly, this reduction in adverse events was achieved without an associated rise in the overall rate of significant bleeding events. In the HOST-EXAM study, clopidogrel monotherapy was associated with a reduced risk of future adverse clinical events, primarily involving stroke, readmission due to ACS, and major bleeding events. It is noteworthy that no occurrences of myocardial infarction (MI) were reported throughout the 24-month follow-up period in patients with CCS after PCI.^[14]

There are several limitations to this study that require discussion. Firstly, all of the studies we analyzed were found to have some degree of bias, which influence the final results. Secondly, while the dose of these antiplatelet or anticoagulation drugs were different across the studies, which may have affected the accuracy of the results. Thirdly, we only searched 3 databases, so it is possible that we missed other relevant studies. Fourthly, the studies we included were published over a 10-year period, and changes in clinical protocols and outcome definitions may have impacted the reliability of our findings. Fifthly, our results represent an average outcome among patients with different characteristics and clinical presentations.

5. Conclusions

Our study indicates that adding clopidogrel or ticagrelor 90 mg to aspirin was associated with a decrease of the myocardial infarction. Clopidogrel/prasugrel and rivaroxaban 2.5 mg was associated with an increase of the major bleeding than aspirin alone. However, additional high-quality RCTs are required to further confirm our final conclusions.

Author contributions

Project administration: Lei Ma.

Resources: Chang Liu, Lei Ma.

Software: Chang Liu.