Effect of antiplatelet therapy on the incidence, prognosis, and rebleeding of intracerebral hemorrhage

Abstract Objective Antiplatelet medications are increasingly being used for primary and secondary prevention of ischemic attacks owing to the increasing prevalence of ischemic stroke occurrences. Currently, many patients receive antiplatelet therapy (APT) to prevent thromboembolic events. However, long‐term use of APT might also lead to an increased occurrence of intracerebral hemorrhage (ICH) and affect the prognosis of patients with ICH. Furthermore, some research suggest that restarting APT for patients who have previously experienced ICH may result in rebleeding events. The precise relationship between APT and ICH remains unknown. Methods We searched PubMed for the most recent related literature and summarized the findings from various studies. The search terms included “antiplatelet,” “intracerebral hemorrhage,” “cerebral microbleeds,” “hematoma expansion,” “recurrent,” and “reinitiate.” Clinical studies involving human subjects were ultimately included and interpreted in this review, and animal studies were not discussed. Results When individuals are administered APT, the risk of thrombotic events should be weighted against the risk of bleeding. In general, for some patients’ concomitant with risk factors of thrombotic events, the advantages of antiplatelet medication may outweigh the inherent risk of rebleeding. However, the use of antiplatelet medications for other patients with a higher risk of bleeding should be carefully evaluated and closely monitored. In the future, a quantifiable system for assessing thrombotic risk and bleeding risk will be necessary. After evaluation, the appropriate time to restart APT for ICH patients should be determined to prevent underlying ischemic stroke events. According to the present study results and expert experience, most patients now restart APT at around 1 week following the onset of ICH. Nevertheless, the precise time to restart APT should be chosen on a case‐by‐case basis as per the patient's risk of embolic events and recurrent bleeding. More compelling evidence‐based medicine evidence is needed in the future. Conclusion This review thoroughly discusses the relationship between APT and the development of ICH, the impact of APT on the course and prognosis of ICH patients, and the factors influencing the decision to restart APT after ICH. However, different studies' conclusions are inconsistent due to the differences in quality control. To support future clinical decisions, more large‐scale randomized controlled trials are required.


| INTRODUC TI ON
The activation and aggregation of platelet are the root cause of arterial thrombosis. Antiplatelet drugs have been reported to reversibly or irreversibly inhibit platelet aggregation and reduce blood coagulation's ability to prevent thrombosis and vascular embolization events. 1 Some of the commonly used antiplatelet drugs include aspirin (inhibits thromboxane-A2 production), clopidogrel and ticagrelor (inhibit adenosine diphosphate receptor on platelet membrane), and dipyridamole (inhibits adenosine uptake and the enzyme cyclic guanine monophosphate phosphodiesterase). 2 Dual antiplatelet therapy (APT), which involves the use of two antiplatelet drugs with different mechanisms, was previously used for patients with myocardial infarction who did not have antithrombotic contraindications. Later, dual APT began to be recommended for patients who have had drugeluting and bare-metal stents placed. 3,4 The early treatment with aspirin plus extended-release dipyridamole for transient ischemic attack or ischemic stroke within 24 h of symptom onset (EARLY) trial subsequently demonstrated that combination therapy with aspirin and dipyridamole is effective for the secondary prevention of cerebrovascular disease and transient ischemic attack, with no increased risk of bleeding compared with the use of aspirin alone. 5 Following the publication of the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial, combination therapy with aspirin and clopidogrel for 21 days was widely used in patients with acute cerebral infarction and transient ischemic attacks. 6 The Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke (POINT) study reported that aspirin combined with clopidogrel for 90 days reduced the risk of major ischemic events (hazard ratio [HR] 0.75%, 95% confidence interval [CI], 0.59-0.95, p = 0.02) but increased the risk of major hemorrhage (HR 2.32; 95% CI 1.10-4.87, p = 0.02) compared with patients treated with aspirin alone. 7 The CHANCE-2 study found that ticagrelor plus aspirin was more effective than clopidogrel plus aspirin in preventing recurrent stroke in patients with mild ischemic stroke and transient ischemic attack carrying the CYP2C19-inactivated allele. 8 Multiple studies have demonstrated that combining dual antiplatelet drugs for 3 months can reduce recurrent ischemic events without increasing bleeding events in patients with severe intracranial macrovascular stenosis (70%-99%). [9][10][11][12] To prevent recurrent stroke events, The American Heart Association/American Stroke Association (AHA/ ASA) for 2021 recommend that such patients should be treated with dual antiplatelet drugs for 3 months, followed by treatment with a single antiplatelet drug. 13 Many studies have demonstrated that long-term APT could reduce the frequency of ischemic cardiovascular and cerebral events.
However, it might also cause an increased occurrence of intracerebral hemorrhage (ICH). 14,15 With an annual incidence of 10-30 per 100,000 persons, ICH is the second most common type of stroke after cerebral infarction. 16 It has been reported that the mortality rate of patients with ICH is as high as 50% within 1 month of onset, and only less than 40% of patients eventually return to functional independence. 17 Approximately 20%-30% of ICH patients were reported to be on APT. 18 The benefits of APT in reducing the risk of ischemic events and the possibility of hemorrhagic events following APT need to be evaluated individually to develop a safe and effective dosing regimen. It is also unknown how antiplatelet aggregating medications affect the development and prognosis of ICH.
Furthermore, it is important to consider whether APT should be restarted after ICH. To address the abovementioned unclear clinical issues, in this review, we summarize related studies and discuss the influence of APT on the incidence of ICH, the effects of prior APT on the development and prognosis of ICH, and whether to restart APT in patients with a history of ICH ( Figure 1). We searched PubMed for the most recent related literature and summarized the findings from various studies. The search terms included "antiplatelet," "intracerebral hemorrhage," "cerebral microbleeds," "hematoma expansion," "recurrent," and "reinitiate." Clinical studies involving human subjects were ultimately included and interpreted in this review, and animal studies were not discussed.

| Influence of prior APT on the incidence of ICH
Antiplatelet drugs are frequently used to prevent acute cardiocerebrovascular attacks in individuals at a high risk of ischemic stroke.
However, it remains unclear whether these drugs might increase the incidence of ICH events. 19 According to some studies, APT may increase the incidence of ICH. For instance, He 21 Hald et al. compared changes in the use of antiplatelet drugs and anticoagulants between 2005 and 2018 and found that the age-and sex-matched incidence of ICH decreased from 33 per 10,000 person-years in 2005 to 24 per 10,000 person-years in 2018 (p < 0.001 for the trend) as the frequency of antiplatelet medication use reduced (24.7% in 2005 vs. 21.4% in 2018). 22 While some researchers reported that APT did not affect ICH. 23,24 García-Rodríguez et al. found that APT decreased the risk of subarachnoid hemorrhage (OR 0.82, 95% CI 0.67-1.00) but did not increase that of ICH (OR 1.06, 95% CI 0. 93-1.21). In addition, patients who have taken aspirin for longer than 3 years may be protected from subarachnoid hemorrhage (OR 0.63, 95% CI 0. 45-0.90) compared to those who have not taken aspirin. 23 Furthermore, results from a large-scale observational study in the United States (Atherosclerosis Risk in Communities, ARIC) involving 15,719 patients with a follow-up period of more than 20 years revealed that antiplatelet drug users had a lower risk of ICH than nonusers at the most recent follow-up before ICH (HR 0.53, 95% CI 0.30-0.92), indicating that APT might even reduce the risk of ICH. 24 The correlation between the risk of ICH and the antithrombotic benefit of APT has to be further validated ( demonstrated that patients with low thrombotic event risk (e.g., healthy individuals aged <50 years) might not be suggested to start APT for primary antithrombotic prevention. 25,26 The Physicians' Health Study, a randomized, double-blind, placebo-controlled trial, found that aspirin only reduced the incidence of myocardial infarction in healthy individuals aged >50 years. 25 Another study found that prophylactic aspirin use did not reduce the rate of nonfatal strokes or myocardial infarction in healthy individuals and that the incidence of disabling strokes was higher in the aspirin treatment group. 26 The factors that may increase the risk of ICH in patients receiving APT treatment should be evaluated in advance. It is well known that patients with hypertension have an increased risk of hemorrhagic stroke. 27 Furthermore, Puddey's review noted that a negative relationship between cholesterol levels and brain bleeding risk has been observed in multiple studies. 28   Overall, no evidence of a dose-dependent relationship between APT and the incidence of ICH was noted. Dual APT may thereby reduce the probability of subsequent ischemic cardiovascular and cerebrovascular events, although this beneficial effect may be counterbalanced by a higher risk of significant bleeding.

| Association between APT and the incidence of ICH in patients with cerebral microbleeds (CMBs)
Small, normal, or almost normal chronic blood product lesions in the brain tissue are known as CMBs, and they are typically detected using blood-sensitive magnetic resonance sequences (e.g., T2*-weighted GRE sequences or susceptibility-weighted imaging sequences). 33 The incidence of CMBs was as high as 11.1%-23.5% in a survey of elderly individuals (age > 60 years) living in a community. 34,35 Similar to spontaneous ICH, the location of CMBs has been reported to indicate different disease causes, such as those located in the cerebral lobe, which may be associated with cerebral amyloid angiopathy, and those located in the deep basal ganglia, which may be associated with hypertension and arteriosclerosis. 35 CMBs are also found in healthy elderly individuals. 33 Currently, hypertension is thought to be the best predictor of CMBs, with OR values of 2.3 and 3.9 in healthy adults and stroke patients, respectively. 36 Other risk factors for ICH, such as age 37 and low serum cholesterol levels, 35 have also been linked to the occurrence and extent of CMBs. Several studies have discovered that individuals with CMBs may experience more ICH events and recurrent hemorrhages than those without CMBs. 38 According to a recent study, APT may also increase the risk of CMBs. Previous studies have reported that antithrombotic drug use is a risk factor for CMBs. 45

| Relationship between prior APT and ICH mortality
Previous studies have revealed that ICH patients with hematoma volumes greater than 30 mL, intraventricular hemorrhage (IVH) or hematoma enlargement was associated with higher mortality and disability rates. [46][47][48][49] However, the impact of prior APT on mortality and prognosis in ICH patients remains unclear. According to Thompson that study compared with those who did not receive APT, which may also be a cause of high mortality and poor prognosis. Therefore, the risk of ICH should be carefully considered when vitamin K antagonist is administered in combination with antiplatelet medications. If the combination is required, it is preferable to limit its use to a short period. 57

| Relationship between prior APT and the incidence of hematoma enlargement (HE) in ICH patients
HE is defined as an increase in hematoma volume of >33% or > 12.5 mL from the initial hematoma volume on a steady-state computed tomography (CT) scan. 58  Tranexamic acid is an antifibrinolytic medication that has been shown to reduce the incidence of HE in patients with spontaneous ICH but not to improve functional outcomes. 66    commencing APT after ICH was not related to functional outcomes at 3 months (defined as mRS score 0-2).

| Prognostic effects of platelet transfusion in ICH patients with prior APT
In summary, most of the current findings suggest that regardless of whether APT was administered before ICH, restarting APT after ICH can reduce the incidence of ischemic events without increasing the rate of recurrent ICH. Meanwhile, APT after ICH may not result in higher mortality and a worse functional prognosis ( Table 4).

The Antiplatelet Secondary Prevention International Randomised
Trial After INtracerebral haemorrhaGe (ASPIRING) is an ongoing multicenter, prospective, randomized, blind outcome clinical trial.
ICH patients will be included to evaluate the effect of antiplatelet monotherapy on severe vascular events. A total of 120 patients are planned to be enrolled in this study who will be randomly classified into two groups-starting antiplatelet monotherapy and avoiding antiplatelet monotherapy-in 30 hospitals in China, Australia, and New Zealand (ASPIRING, NCT04522102). This study is expected to provide a high level of evidence for APT initiation in ICH patients.

| What should be taken into consideration when restarting APT post ICH?
Some researchers hypothesized that ICH patients with various bleeding sites would react to antiplatelet medications differently.
Thus, the location of hemorrhage is an important factor to con- In summary, in patients with pre-existing hypertension, antiplatelet medication use may increase the risk of recurrent ICH; however, this is also the main population that benefits from antiplatelet drugs for the prevention of ischemic events. When restarting APT, additional variables such as bleeding site and concomitant with AF or LVAD should also be taken into consideration. 102,103

| CON CLUS ION
The effect of antiplatelet drugs on the occurrence and development of ICH is still not completely known. Moreover, there is no accepted practice or standard procedure for determining whether and when to restart APT after ICH. A detailed literature search was performed, and relevant findings were summarized in this paper. The risk of ICH related to APT, the impact of prior APT on the characteristics and prognosis of ICH patients, and the safety of restarting APT after ICH were the key topics covered in this review.
When individuals are administered APT, the risk of thrombotic events should be weighted against the risk of bleeding. In general, for some patients' concomitant with risk factors of thrombotic events, such as hyperlipidemia, hypercoagulability, chronic AF, and severe atherosclerosis, the advantages of antiplatelet medication may outweigh the inherent risk of rebleeding. However, the use of antiplatelet medications for other patients with a higher risk of bleeding, such as elderly individuals and those with multiple CMB and uncontrolled hypertension, should be carefully evaluated and closely monitored. In the future, a quantifiable system for assessing thrombotic risk and bleeding risk will be necessary.
After evaluation, the appropriate time to restart APT for ICH patients should be determined to prevent underlying ischemic stroke events. According to the present study results and expert experience, most patients now restart APT at around 1 week following the onset of ICH. Nevertheless, the precise time to restart APT should be chosen on a case-by-case basis as per the patient's risk of embolic events and recurrent bleeding. More compelling evidence-based medicine evidence is needed in the future.
To summarize, additional high-quality randomized controlled trials are required in the future to elucidate the relationship between APT and the risk and prognosis of ICH. More specific programs for making judgments about diagnosis and therapy should also be investigated.

AUTH O R CO NTR I B UTI O N S
Review program formulation: Yunjie Li, Gaigai Li, Chao Pan; literature screening: Xia Liu; literature reading and data collection: Yunjie Li, Shiling Chen, Jingyi Wang; paper writing: Yunjie Li; language polishing, paper review and editing: Gaigai Li, Zhouping Tang.

ACK N OWLED G M ENTS
We thank Ge Zhang and Jingfei Yang for technical assistance.

FU N D I N G I N FO R M ATI O N
This work was supported by grant 82,201,474 and 82,071,330 from National Natural Science Foundation of China.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

D ECL A R ATI O N
All authors read and approved the final version of the paper and agreed to submit the manuscript to CNS Neuroscience & Therapeutics.