Abstract
Introduction: Currently, it is still controversial to treat stroke with ticagrelor alone. The purpose of our study was to systematically review and analyze the efficacy and safety of ticagrelor on cerebrovascular outcomes in patients with vascular risk factors. Methods: The PubMed, Cochrane Library, and Embase databases were systematically searched using the keywords stroke, ticagrelor, clopidogrel, and aspirin to identify randomized controlled trials (RCTs). Primary outcomes included reported stroke, ischemic stroke, and complex events; the secondary outcome was hemorrhagic stroke. The safety outcomes included major bleeding events, major or minor bleeding, and intracranial bleeding. The pooled odds ratio (OR), hazard ratios (HRs), and 95% confidence interval (CI) were calculated. We used I2 statistics to assess statistical heterogeneity. Results: This meta-analysis included 15 RCTs involving 63,865 patients. Compared to the control group, ticagrelor reduced the risk of stroke (OR: 0.90; 95% CI: 0.81–0.99, p = 0.03; I2 = 3%), ischemic stroke (OR: 0.81; 95% CI: 0.74–0.90, p < 0.0001; I2 = 0%). Ticagrelor was not associated with an increased risk of all-cause mortality (OR: 0.94; 95% CI: 0.84–1.06, p = 0.31; I2 = 62%), major bleeding (OR: 1.06; 95% CI: 0.97–1.15, p = 0.20; I2 = 17%), hemorrhagic strokes (OR: 1.22, 95% CI: 0.76–1.96, p = 0.41; I2 = 0%), and intracranial hemorrhage (OR: 1.06; 95% CI: 0.78–1.43, p = 0.71; I2 = 12%). There was an increased risk of major or minor bleeding with ticagrelor compared to the control group (OR: 1.40; 95% CI: 1.19–1.66, p < 0.0001; I2 = 56%). Additional analyses demonstrated that ticagrelor reduced the risk of incident recurrent stroke (HR: 0.83; 95% CI: 0.75–0.93, p = 0.0009; I2 = 0%), recurrent ischemic stroke (HR: 0.79; 95% CI: 0.71–0.89, p < 0.0001; I2 = 0%) among patients with a history of acute ischemic stroke (AIS) or transient ischemic attack (TIA). There were no significant differences in safety outcomes. Conclusion: Ticagrelor is slightly better than clopidogrel and aspirin in preventing stroke, especially ischemic stroke, with significant safety risks. For patients with a history of AIS/TIA, the use of ticagrelor was superior to the use of clopidogrel or aspirin in reducing the risk of subsequent stroke. We believe that ticagrelor is a potential alternative to aspirin or clopidogrel in some cases, especially for patients with CYP2C19 deficiency.
Introduction
As of 2019, stroke was the second leading cause of death (6.6 million) and the third leading cause of disability (143 million) worldwide. Over the past 30 years, the global incidence of stroke has increased by 70%, prevalence has increased by 85%, mortality has increased by 43%, and disability due to stroke has increased by 32% [1]. Currently, some studies have discovered that ticagrelor is more advantageous than traditional antiplatelet drugs in preventing acute ischemic stroke (AIS). Ticagrelor is a reversible direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12, which inhibits P2Y12 faster, stronger, and more stably than clopidogrel [2]. Recent studies suggest that ticagrelor is similar to aspirin in reducing stroke, life-threatening bleeding, myocardial infarction, or mortality [3], especially in patients with acute atherosclerotic stroke or transient ischemic attack (TIA); ticagrelor is even superior to aspirin [4]. The results of a large randomized controlled trial (RCT) (THALES trial) showed that ticagrelor plus aspirin significantly reduced the number of strokes or deaths within 30 days of mild stroke or TIA compared to aspirin alone [5]. Based on the results of the study, the US Food and Drug Administration (FDA) expanded the use of ticagrelor from cardiovascular disease to patients with mild to moderate stroke. The 2021 American Heart Association/American Stroke Association guidelines state that for patients with recent (<24 h) minor to moderate stroke (NIHSS score ≤5), high-risk TIA (ABCD2 score ≥6), or symptomatic intracranial or extracranial ≥30% stenosis of an artery that could explain the event, DAPT with ticagrelor plus aspirin for 30 days can be considered to reduce the risk of recurrent stroke at 30 days [6]. For patients with non-cardioembolic stroke or TIA, aspirin and clopidogrel are the classic secondary prevention drugs. At present, there is no evidence that ticagrelor is superior to aspirin or clopidogrel in antiplatelet therapy alone for stroke. There is also no evidence that ticagrelor in combination with aspirin or clopidogrel is superior to the classical dual antibodies (aspirin and clopidogrel) in the treatment of stroke. The results of the THALES trial study and the 2021 American Heart Association/American Stroke Association guideline recommendations give us a glimpse of the possibilities of ticagrelor in stroke prevention. The purpose of this meta-analysis is to compare the advantages and disadvantages of ticagrelor versus aspirin and clopidogrel for stroke prevention in patients with vascular basis diseases, to further demonstrate the possibility of ticagrelor as a substitute for aspirin or clopidogrel, especially for patients who are not tolerant to aspirin or clopidogrel.
Methods
Search Strategy
The systematic review protocol, registered in PROSPERO (CRD42022329220), was developed following the Preferred Reporting Items for Systematic Review. This meta-analysis has adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses [7].
Two researchers independently searched for all studies with keywords ticagrelor, aspirin, clopidogrel, and stroke published in the PubMed, Embase, and Cochrane Library databases. The article search was limited by study design of RCTs. The search was performed until March 31, 2022. In addition, the references of the included studies were also retrieved to supplement the relevant research, including gray literature (e.g., clinical trials). When the opinions of the two researchers differed, a third researcher was consulted.
Inclusion and Exclusion Criteria
We identified studies investigating cerebrovascular outcomes in patients treated with ticagrelor and other antiplatelet agents (aspirin or clopidogrel) or placebo. We used the outcome data reported for 90 mg dose of ticagrelor in all our analyses. The inclusion criteria for our study were as follows: (1) randomized controlled design; (2) studies including patients treated with ticagrelor versus other antiplatelet agents or placebo; (3) available data on adverse cerebrovascular outcomes as primary or secondary endpoints; (4) patients with vascular disease; (5) adult patients (>18 years old); (6) study cohort size >50. On the contrary, the exclusion criteria included the following: (1) nonrandomized controlled studies; (2) single-arm studies; (3) studies that did not report or could not extract or calculate results of interest from published results; (4) repeated published studies.
Data Extraction
All retrieved articles were independently reviewed by two authors. In case of disagreements regarding the literature search results, the remaining coauthors were consulted, and disagreement was resolved with mutual consensus. The following information was extracted: name of study, first author and year of publication, mean age, sex distribution, trial name, total number and type of study participants, primary and secondary endpoints, follow-up duration. When the trials were greater than two sets or had multi-factor designs, we only extracted content relevant to this study.
The primary outcomes of interest included stroke, ischemic stroke and composite events of stroke-heart, myocardial infarction, and death, whereas secondary outcomes included hemorrhagic stroke. Our primary safety outcomes comprised major bleeding, major or minor bleeding (according to PLATO, TIMI, or BARC bleeding definitions), and intracranial bleeding.
Risk of Bias Assessment
Two investigators independently searched for studies using different search strategies and screened for studies that met the inclusion criteria. Researchers evaluated the quality of the included RCTs using the Cochrane Library risk of bias assessment tool. The seven items used to assess bias in each trial included random sequence generation, allocation concealment, double blindness of participants and trial performers, blindness of outcome assessment, incomplete outcome data, selective reporting, and other biases. Each quality item was divided and classified into high risk, undefined risk, and low risk. The quality of the included trials was classified as low quality, high quality, or medium quality according to the following criteria: (1) if random sequence generation or allocation concealment was assessed to be of high risk, the trial would be considered of low quality regardless of the risk of other projects; (2) if random sequence generation and allocation concealment were assessed as low risk, and all other items were evaluated to be of low or an undefined risk, the test would be of high quality; and (3) if the tests did not meet the high-risk or low-risk criteria, the quality of the trial was considered moderate [8].
Statistical Analysis
We performed a meta-analysis and calculated the odds ratio (OR), hazard ratio (HR), and 95% confidence interval (CI). The pooled ORs and HRs were used to estimate the efficacy of ticagrelor for stroke prevention using the Mantel-Haenszel method. We used I2 statistics to assess statistical heterogeneity. An I2 value of 0–25% indicates no significant heterogeneity; 26–50%, low heterogeneity; 51–75%, moderate heterogeneity; and >75%, high heterogeneity [9]. Data were pooled using the fixed-effects model when the I2 value was <50%; data were pooled using the random-effects model when the I2 value was >50%. The test level was set at α = 0.05; p values of 0.05 were considered to indicate that the difference was statistically significant. We used the Review Manager 5.2 software (The Cochrane Collaboration, Oxford, UK) to perform the meta-analysis and forest plot analysis. To ensure the robustness of the results, we performed sensitivity analysis using Stata 13.0 software (Stata Corp., College Station, TX).
Results
Study Search
A total of 1,028 results were retrieved according to the retrieval strategy. Duplicate results were removed, and the remaining 924 study titles and abstracts were screened, of which 38 potentially eligible studies were retained. After the full-text version was retrieved, 23 of the 38 studies mentioned above were excluded due to lack of reporting on stroke outcomes, repeated reporting, or nonrandomized study design. We ultimately included 15 RCTs of ticagrelor versus other antiplatelet agents (Fig. 1).
Characteristics and Risk of Bias
This meta-analysis included 15 RCTs involving 63,865 patients [3, 10‒23]. Seven RCTs [10‒15, 20] included patients with acute coronary syndrome, 3 RCTs [19, 22, 23] included patients after coronary artery bypass grafting, 4 RCTs [3, 16, 18, 21] included patients with stroke or TIA, and 1 RCT [17] included patients with peripheral arterial disease. In 11 RCTS [10‒20] patients in the control group received clopidogrel; and in 4 RCTS [3, 21‒23]. Table 1 shows the specific characteristics and data of the included studies. The included studies had a low overall risk of bias, and no risk of bias or performance bias was found in the included studies, except for a few RCTs with open-label design that were moderately biased in terms of allocation concealment and performance bias (Fig. 2).
Specific characteristics and data of the included studies
. | Author . | Country . | Study population . | Study design . | Follow-up, months . | Treatment – ticagrelor, control . | Dual antiplatelet or antiplatelet alone . | Patients – ticagrelor versus control . | Outcomes of interest . |
---|---|---|---|---|---|---|---|---|---|
TALOS-AMI | Kim et al. [11] | Korean | ACS | Open-label, randomized trial | 12 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 1,348 versus 1,349 | 1, 4, 5, 6 |
TICAKOREA | Park et al. [12] | Korean | ACS | Open-label, randomized trial | 12 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 400 versus 400 | 1, 2, 3, 4, 5, 6 |
Wang and Wang [20] | China | ACS | Double-blind, randomized trial | 12 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 100 versus 100 | 1, 4, 5, 6 | |
PLATO | Wallentin et al.[10] | Multiple | ACS | Double-blind, randomized trial | 12 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 9,333 versus 9,291 | 1, 2, 3, 4, 5, 6, 7 |
TREAT | Berwanger et al. [13] | Multiple | ACS | Open-label, randomized trial | 12 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 1,913 versus 1,886 | 1, 2, 3, 4, 5, 6, 7 |
He et al. [14] | China | ACS | Double-blind, randomized trial | 6 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 133 versus 133 | 1, 2, 4, 5 | |
PHILO | Goto et al. [15] | East Asian | ACS | Double-blind, randomized trial | 12 | Ticagrelor, clopidogrel | All patients: placebo | 401 versus 400 | 1, 4, 5, 6 |
EUCLID | Hiatt et al. [17] | Multiple | PAD | Double-blind, randomized trial | 30 | Ticagrelor, clopidogrel | Antiplatelet alone | 6,930 versus 6,955 | 2, 4, 5, 6, 7 |
Tang et al. [19] | China | CABG | Double-blind, randomized trial | 12 | Ticagrelor, clopidogrel | All patients: placebo | 70 versus 77 | 1, 5 | |
PRINCE | Wang et al. [18] | China | Stroke/TIA | Open-label, randomized trial | 12 | Ticagrelor, clopidogrel | All patients: placebo | 336 versus 339 | 1, 2, 3, 4, 5, 6, 7 |
CHANCE-2 | Wang et al. [16] | China | Stroke/TIA | Double-blind, randomized trial | 3 | Ticagrelor, clopidogrel | All patients: placebo | 3,205 versus 3,207 | 1, 2, 6, 7 |
DACAB | Zhao et al. [23] | China | CABG | Double-blind, randomized trial | 12 | Ticagrelor, aspirin | Antiplatelet alone | 166 versus 166 | 1, 4 |
TiCAB | Schunkert et al. [22] | Europe | CABG | Double-blind, randomized trial | 12 | Ticagrelor, aspirin | All patients: placebo | 931 versus 928 | 1, 3, 4, 5, 6 |
Zeinhom et al. [21] | Egypt | Stroke | Open-label, randomized trial | 3 | Ticagrelor, aspirin | Antiplatelet alone | 85 versus 84 | 2, 3, 4, 5, 6 | |
SOCRATES | Johnston et al. [3] | Multiple | Stroke/TIA | Double-blind, randomized trial | 3 | Ticagrelor, aspirin | Antiplatelet alone | 6,589 versus 6,610 | 1, 2, 4, 5, 6, 7 |
. | Author . | Country . | Study population . | Study design . | Follow-up, months . | Treatment – ticagrelor, control . | Dual antiplatelet or antiplatelet alone . | Patients – ticagrelor versus control . | Outcomes of interest . |
---|---|---|---|---|---|---|---|---|---|
TALOS-AMI | Kim et al. [11] | Korean | ACS | Open-label, randomized trial | 12 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 1,348 versus 1,349 | 1, 4, 5, 6 |
TICAKOREA | Park et al. [12] | Korean | ACS | Open-label, randomized trial | 12 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 400 versus 400 | 1, 2, 3, 4, 5, 6 |
Wang and Wang [20] | China | ACS | Double-blind, randomized trial | 12 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 100 versus 100 | 1, 4, 5, 6 | |
PLATO | Wallentin et al.[10] | Multiple | ACS | Double-blind, randomized trial | 12 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 9,333 versus 9,291 | 1, 2, 3, 4, 5, 6, 7 |
TREAT | Berwanger et al. [13] | Multiple | ACS | Open-label, randomized trial | 12 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 1,913 versus 1,886 | 1, 2, 3, 4, 5, 6, 7 |
He et al. [14] | China | ACS | Double-blind, randomized trial | 6 | Ticagrelor, clopidogrel | All patientsAspirin 100 mg daily | 133 versus 133 | 1, 2, 4, 5 | |
PHILO | Goto et al. [15] | East Asian | ACS | Double-blind, randomized trial | 12 | Ticagrelor, clopidogrel | All patients: placebo | 401 versus 400 | 1, 4, 5, 6 |
EUCLID | Hiatt et al. [17] | Multiple | PAD | Double-blind, randomized trial | 30 | Ticagrelor, clopidogrel | Antiplatelet alone | 6,930 versus 6,955 | 2, 4, 5, 6, 7 |
Tang et al. [19] | China | CABG | Double-blind, randomized trial | 12 | Ticagrelor, clopidogrel | All patients: placebo | 70 versus 77 | 1, 5 | |
PRINCE | Wang et al. [18] | China | Stroke/TIA | Open-label, randomized trial | 12 | Ticagrelor, clopidogrel | All patients: placebo | 336 versus 339 | 1, 2, 3, 4, 5, 6, 7 |
CHANCE-2 | Wang et al. [16] | China | Stroke/TIA | Double-blind, randomized trial | 3 | Ticagrelor, clopidogrel | All patients: placebo | 3,205 versus 3,207 | 1, 2, 6, 7 |
DACAB | Zhao et al. [23] | China | CABG | Double-blind, randomized trial | 12 | Ticagrelor, aspirin | Antiplatelet alone | 166 versus 166 | 1, 4 |
TiCAB | Schunkert et al. [22] | Europe | CABG | Double-blind, randomized trial | 12 | Ticagrelor, aspirin | All patients: placebo | 931 versus 928 | 1, 3, 4, 5, 6 |
Zeinhom et al. [21] | Egypt | Stroke | Open-label, randomized trial | 3 | Ticagrelor, aspirin | Antiplatelet alone | 85 versus 84 | 2, 3, 4, 5, 6 | |
SOCRATES | Johnston et al. [3] | Multiple | Stroke/TIA | Double-blind, randomized trial | 3 | Ticagrelor, aspirin | Antiplatelet alone | 6,589 versus 6,610 | 1, 2, 4, 5, 6, 7 |
(1) stroke, (2) ischemic stroke, (3) hemorrhagic stroke, (4) major bleeding, (5) major or minor bleeding, (6) composite of stroke, myocardial infarction, or cardiovascular death, (7) intracerebral hemorrhage.
ACS, acute coronary syndrome; PAD, peripheral artery disease; CABG, coronary artery bypass grafting; TIA, transient ischemic attack.
Primary Outcomes
Compared to aspirin or clopidogrel, ticagrelor reduced risk of stroke (13 RCTs; OR: 0.90; 95% CI: 0.81–0.99, p = 0.03; I2 = 3%; Fig. 3a) and decreased risk of ischemic stroke (9 RCTs; OR: 0.81; 95% CI: 0.74–0.90; p < 0.0001; I2 = 0%; Fig. 3b). Ticagrelor did not increase the risk of all-cause mortality compared with aspirin or clopidogrel (12 RCTs; OR: 0.94; 95% CI: 0.84–1.06, p = 0.31; I2 = 62%; Fig. 3c).
Comparison between ticagrelor and control group on stroke prevention. a Risk of stroke. b Risk of ischemic stroke. c Risk of all-cause mortality. d Risk of hemorrhagic stroke.
Comparison between ticagrelor and control group on stroke prevention. a Risk of stroke. b Risk of ischemic stroke. c Risk of all-cause mortality. d Risk of hemorrhagic stroke.
Secondary Outcomes
Patients treated with ticagrelor did not increase the risk of hemorrhagic strokes (6 RCTs; OR: 1.22, 95% CI: 0.76–1.96, p = 0.41; I2 = 0%; Fig. 3d).
Safety Outcomes
There was no significant difference in the risk of major bleeding (13 RCTs; OR: 1.06, 95% CI: 0.97–1.15, p = 0.20; I2 = 17%; Fig. 4a) between ticagrelor and control group. There was no significant difference in the risk of intracranial hemorrhage (7 RCTs; OR: 1.06; 95% CI: 0.78–1.43, p = 0.71; I2 = 12%; Fig. 4b) between ticagrelor and control group. There was an increased risk of major or minor bleeding with ticagrelor compared to control group (13 RCTs; OR: 1.40, 95% CI: 1.19–1.66, p < 0.0001; I2 = 56%; Fig. 4c).
Comparison between ticagrelor and control group in safety outcomes. a Risk of major bleeding. b Risk of intracranial hemorrhage. c Risk of major or minor bleeding.
Comparison between ticagrelor and control group in safety outcomes. a Risk of major bleeding. b Risk of intracranial hemorrhage. c Risk of major or minor bleeding.
Comparison with Aspirin
Ticagrelor is better than aspirin in preventing stroke (4 RCTs; OR: 0.88, 95% CI: 0.76–1.00, p = 0.05; I2 = 0%; Fig. 5a), but it is not statistically significant. There was no significant difference in the risk of major bleeding between ticagrelor and aspirin (4 RCTs; OR: 0.92, 95% CI: 0.61–1.38, p = 0.68; I2 = 0%; Fig. 5b).
Comparison between ticagrelor and aspirin on stroke prevention. a Risk of stroke. b Risk of major bleeding.
Comparison between ticagrelor and aspirin on stroke prevention. a Risk of stroke. b Risk of major bleeding.
Comparison with Clopidogrel
Compared to clopidogrel, ticagrelor reduced the risk of stroke (11 RCTs; OR: 0.87, 95% CI: 0.77–0.98, p = 0.02; I2 = 13%; Fig. 6a) and ischemic stroke (7 RCTs; OR: 0.82, 95% CI: 0.73–0.93, p = 0.003; I2 = 0%; Fig. 6b). Compared to clopidogrel, ticagrelor did not reduce the risk of intracranial hemorrhage (6 RCTs; OR: 1.17; 95% CI: 0.84–1.63, p = 0.36; I2 = 0%; Fig. 6c). There was no significant difference in risk of major bleeding between ticagrelor and clopidogrel (9 RCTs; OR: 1.06, 95% CI: 0.98–1.16, p = 0.16; I2 = 32%; Fig. 6d).
Comparison between ticagrelor and clopidogrel on stroke prevention. a Risk of stroke. b Risk of ischemic stroke. c Risk of intracranial hemorrhage. d Risk of major bleeding.
Comparison between ticagrelor and clopidogrel on stroke prevention. a Risk of stroke. b Risk of ischemic stroke. c Risk of intracranial hemorrhage. d Risk of major bleeding.
Additional Analysis Based on Previous Stroke History
We conducted a retrospective study based on four stroke-based history-based studies and a PLATO sub-study. Among patients with a history of AIS or TIA, ticagrelor reduced the risk of stroke (4 RCTs; HR: 0.83, 95% CI: 0.75–0.93, p = 0.0009; I2 = 0%; Fig. 7a), ischemic stroke (4 RCTs; HR: 0.79, 95% CI: 0.71–0.89, p < 0.0001; I2 = 0%; Fig. 7b) and composite stroke, myocardial infarction or cardiovascular death (5 RCTs; HR: 0.83, 95% CI: 0.75–0.92, p = 0.0003; I2 = 0%; Fig. 7c) compared to controls. There was no significant difference between the ticagrelor group and the control group in reducing the risk of hemorrhagic stroke (3 RCTs; OR: 0.62, 95% CI: 0.20–1.90, p = 0.40; I2 = 0%; Fig. 7d), intracranial hemorrhage (4 RCTs; OR: 0.73, 95% CI: 0.42–1.27, p = 0.27; I2 = 0%; Fig. 7e), and major bleeding (4 RCTs; OR: 0.91, 95% CI: 0.69–1.20, p = 0.50; I2 = 0%; Fig. 7f).
Evaluation of ticagrelor and the control group among the patients with prior history of AIS or TIA. a Risk of stroke. b Risk of ischemic stroke. c Risk of all-cause mortality. d Risk of hemorrhagic stroke. e Risk of intracranial hemorrhage. f Risk of major bleeding.
Evaluation of ticagrelor and the control group among the patients with prior history of AIS or TIA. a Risk of stroke. b Risk of ischemic stroke. c Risk of all-cause mortality. d Risk of hemorrhagic stroke. e Risk of intracranial hemorrhage. f Risk of major bleeding.
Publication Bias
Funnel plot shows no apparent publication bias (Fig. 8).
Funnel plot for assessment of publication bias among trials reporting stroke.
Subgroup Analysis
To explore the sources of heterogeneity and to assess the impact of some grouping factors on the outcomes, we will perform subgroup analyses of outcomes with relatively high heterogeneity. For composite events, we analyzed the clinical outcomes of the follow-up period of less than 1 year (3 RCTs; OR: 0.84, 95% CI: 0.76–0.93, p = 0.001, I2 = 0) and a follow-up period of more than 1 year (9 RCTs; OR: 1.00, 95% CI: 0.85–1.18, p = 0.98, I2 = 68%). The differences between the two subgroups of treatment duration were not statistically significant (p = 0.07; Fig. 9).
Subgroup analysis comparing the risk of all-cause mortality in ticagrelor and control group.
Subgroup analysis comparing the risk of all-cause mortality in ticagrelor and control group.
Discussion
Our systematic review and meta-analysis found that ticagrelor has certain advantages over aspirin or clopidogrel in reducing stroke and ischemic stroke. There was no significant difference in composite events, hemorrhagic stroke, and major bleeding. In addition, we also found that ticagrelor significantly increased the risk of major or minor bleeds.
We divided the control group into the aspirin group and clopidogrel group for comparison with the ticagrelor group. Ticagrelor is more effective than clopidogrel in preventing stroke, especially ischemic stroke. We found that ticagrelor does not have advantage over aspirin in preventing stroke because 95% CI is 0.76–1.00. Ticagrelor did not significantly increase the risk of major bleeding and intracranial hemorrhage when compared with clopidogrel alone. Ticagrelor did not significantly increase the risk of major bleeding when compared with aspirin alone. As not enough RCT study results were included in terms of major or minor bleeding, we did not compare clopidogrel or aspirin alone with ticagrelor.
In an analysis of patients with a history of stroke, ticagrelor was found to have a better effect than other antiplatelet drugs in reducing the risk of stroke, ischemic stroke and the composite of stroke, myocardial infarction, or cardiovascular death. There was no increased risk of hemorrhagic stroke, intracranial hemorrhage, or major hemorrhage.
Antiplatelet therapy is the cornerstone of stroke prevention [24]. Aspirin and clopidogrel are currently the most used drugs for secondary prevention of non-cardioembolic stroke. Aspirin and clopidogrel remain the drugs of choice in the 2021 Guideline for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack [6]. But sometimes, clopidogrel does not seem to work for everyone because mutations with associated genes make clopidogrel ineffective as an antiplatelet agent. Clopidogrel is a prodrug that requires conversion to its active metabolite by hepatic cytochrome p450 (CYP) [25]. Clopidogrel is less effective for secondary stroke prevention in carriers of the loss-of-function allele CYP2C19, which is present in 25% of white patients and 60% of Asian patients [26]. Therefore, the use of clopidogrel in patients with loss-of-function alleles of CYP2C19 deserves our attention. Ticagrelor is a reversible oral antagonist that directly blocks platelet P2Y12 receptors, does not require metabolic activation for its antiplatelet effects, and produces platelet aggregation inhibition similar to or greater than clopidogrel [10]. Compared to clopidogrel, ticagrelor reduced major adverse cardiovascular events in patients with acute coronary syndrome or deletion of the CYP2C19 loss-of-function genotype undergoing percutaneous coronary intervention [27]. Trail PRINCE demonstrates that for patients with loss-of-function alleles of CYP2C19, ticagrelor significantly inhibits platelet aggregation than clopidogrel, and compared to clopidogrel, ticagrelor generates more benefits for patients with stroke or TIA [18]. In a recent trial (CHANCE-2) involving mainly Han Chinese patients with acute minor ischemic stroke or high-risk TIA treated within 24 h after symptom onset who were carriers of the loss-of-function alleles of CYP2C19, the use of ticagrelor and aspirin was superior to the use of clopidogrel and aspirin to reduce the risk of subsequent stroke [16]. Selecting antiplatelet drugs based on CYP2C19 the results of the genetic test of CYP2C19 is a feasible approach [28]. Genotype-guided antiplatelet therapy with ticagrelor as an alternative to clopidogrel in patients with loss-of-function mutations is cost-effective in secondary stroke prevention [29, 30]. It is a new approach to guide clinical medication for stroke prevention based on the detection of the CYP2C19 gene in the future. Our meta-analysis shows ticagrelor is better than clopidogrel in preventing stroke. Ticagrelor instead of clopidogrel to prevent stroke is a feasible treatment option, which not only does not require genetic testing to guide the medication but its therapeutic effect is also worthy of recognition.
Aspirin is a classical antiplatelet drug for stroke prevention and its effectiveness and safety have been proven in many clinical trials. Our meta-analysis found that the effectiveness of ticagrelor compared to aspirin in preventing stroke was similar and did not differ significantly in terms of the risk of causing major bleeding. For minor bleeding, we did not analyze the results for comparison as not enough RCT studies were included. The inclusion of RCTs in our meta-analysis mentioned that there were more cases of minor bleeding with ticagrelor than with aspirin, and this was a major factor in the discontinuation of ticagrelor [3]. Therefore, aspirin is a better choice for stroke prevention based on a combination of effectiveness and safety. But we believe that ticagrelor is a viable alternative if there are adverse conditions associated with aspirin use such as allergies.
Our study also has some limitations. First of all, most of the patients we included had ACS-based disease. There are relatively few studies on stroke as the underlying disease and for the purpose of secondary stroke prevention. Second, most of the included trials compared ticagrelor with clopidogrel, and fewer studies compared aspirin with ticagrelor. Third, the follow-up time of the included studies is inconsistent; most of them have a 1-year follow-up, and a few include a 33-month, 3-month, or even 1-month follow-up. Differences in follow-up time would lead to certain differences in follow-up results, which would lead to bias in the results of our combined study. Fourth, all the studies we included used mainly three different bleeding criteria: BARC, TIMI, and PLOTA. Inconsistency in bleeding criteria can lead to heterogeneity of meta-analysis results. Fifth, additional analysis based on previous stroke history was insufficient in terms of the number of studies included and treatment methods to assess the effects of treatment in the acute phase. Sixth, current guidelines recommend dual antiplatelet therapy for the first 90 days after ischemic stroke or TIA, yet only 3 of the studies we included were followed for 90 days after the acute event.
Conclusions
Our systematic review and meta-analysis suggest that ticagrelor is slightly better than clopidogrel and aspirin in preventing stroke, especially ischemic stroke. Although there was no significant increase in the incidence of major bleeding, the risk of a minor or major bleeding safety event deserves our attention. For patients with a history of AIS/TIA, the use of ticagrelor was superior to the use of clopidogrel or aspirin to reduce the risk of subsequent stroke. We believe that ticagrelor is a potential alternative to aspirin or clopidogrel. Especially for patients with CYP2C19 deficiency, ticagrelor is a more appropriate option. In the future, more well-designed clinical trials are needed to further evaluate the efficacy and safety of ticagrelor in stroke prevention.
Statement of Ethics
An ethics statement is not applicable because this study is based exclusively on published literature.
Conflict of Interest Statement
Xibo Ma, Danfeng Li, Shihua Liu, Yan Chen, and Ping Zhong have no conflicts of interest or disclosures to declare.
Funding Sources
The authors have no sources of funding to declare.
Author Contributions
Xibo Ma, Danfeng Li, Shihua Liu, and Yan Chen were involved in search strategy, article review, data collection, and data analysis and were independently involved in quality assessment of included articles. Xibo Ma and Danfeng Li were involved in manuscript writing. Ping Zhong contributed to reviewing and editing the manuscript.
Data Availability Statement
All data generated or analyzed during this study were included in this article. Further inquiries can be directed to the corresponding author.