Aspirin + ticagrelor, a dual-antibody therapy suitable for Chinese people!

Recently, the top international authoritative journal NEJM published the full text of theresearch results of CHANCE-2 (Clopidogrel With Aspirin in High-risk Patients With Acute Non-disabling Cerebrovascular Events II) initiated by Professor Wang Yongjun of Beijing Tiantan Hospital affiliated to Capital Medical University .

Recently, the top international authoritative journal NEJM published the full text of theresearch results of CHANCE-2 (Clopidogrel With Aspirin in High-risk Patients With Acute Non-disabling Cerebrovascular Events II) initiated by Professor Wang Yongjun of Beijing Tiantan Hospital affiliated to Capital Medical University .

NEJM

NEJM

The results showed that at 90 days, the stroke recurrence rate of the ticagrelor combined aspirin treatment group was 6.

The results showed that at 90 days, the stroke recurrence rate of the ticagrelor combined aspirin treatment group was 6.

 Cumulative incidence of stroke

 Cumulative incidence of stroke

The results of this study confirm that ticagrelor-based antiplatelet therapy in patients with minor ischemic stroke or TIA with CYP2C19 loss-of-function gene is more effective than standard treatment strategies following existing guidelines

The results of this study confirm that ticagrelor-based antiplatelet therapy in patients with minor ischemic stroke or TIA with CYP2C19 loss-of-function gene is more effective than standard treatment strategies following existing guidelines

Aspirin + ticagrelor, why is the treatment better? Aspirin + ticagrelor, why is the treatment better?

Stroke is the leading cause of death and disability in China, and60% of Asians carry 1 or 2 CYP inactivating alleles

Stroke is the leading cause of death and disability in China, and60% of Asians carry 1 or 2 CYP inactivating alleles

Ticagrelor, a cyclopentyltriazole pyrimidine (CPTP) oral antiplatelet drug, is a non-competitive and direct antagonist of P2Y12 receptors, and is a non-prodrug, so it does not need to be metabolized by the liver Activation can take effect directly, reversibly binds to P2Y12 ADP receptor, inhibits receptor signaling and subsequent platelet activation, and can achieve antithrombotic efficacy earlier in acute treatment, and is not affected by metabolic enzymes.

Who can benefit from aspirin + ticagrelor? Who can benefit from aspirin + ticagrelor?

According to the previous CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) study and POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) study, both domestic and foreign guidelines recommend NIHSS score ≤3 points and onset time <24h Patients with 21 days of clopidogrel combined with aspirin can be treated with clopidogrel combined with aspirin, which is the gold standard recognized at home and abroad, but whether patients with NIHSS score of 4-5 can benefit from it is still controversial

According to the previous CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) study and POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) study, both domestic and foreign guidelines recommend NIHSS score ≤3 points and onset time <24h Patients with 21 days of clopidogrel combined with aspirin can be treated with clopidogrel combined with aspirin, which is the gold standard recognized at home and abroad, but whether patients with NIHSS score of 4-5 can benefit from it is still controversial

According to the results of a THALES study published in NEJM on July 16, 2020 (VOL.

Cumulative incidence of recurrent stroke or death risk, DOI: 10.

Cumulative incidence of recurrent stroke or death risk, DOI: 10.

The research team has since published its latest subgroup analysis online in JAMA Neurology on July 9, 2021, concluding that JAMA compared with patients with mild ischemic stroke in patients with moderate ischemic stroke in The benefit of ticagrelor plus aspirin or aspirin monotherapy was consistent, with no further increased risk of intracranial hemorrhage or other serious bleeding events

Kaplan-Meier Event Curve Plot of Primary Efficacy Endpoint (Stroke or Death) by Treatment Allocation and Baseline National Institutes of Health Stroke Scale (NIHSS) Group, DOI: 10.

Kaplan-Meier Event Curve Plot of Primary Efficacy Endpoint (Stroke or Death) by Treatment Allocation and Baseline National Institutes of Health Stroke Scale (NIHSS) Group, DOI: 10.
1001/jamaneurol.
2021.
2440

The results of this study showed that the efficacy and safety of ticagrelor combined with aspirin in the treatment of moderate ischemic stroke were similar to those in the treatment of mild ischemic stroke.
Although some data were not statistically significant, moderate ischemic stroke could be observed.
There is a trend for patients to benefit more when they receive ticagrelor in combination with aspirin, so the U.
S.
Food and Drug Administration ( FDA ) has also approved the relevant indications
.

The results of this study showed that the efficacy and safety of ticagrelor combined with aspirin in the treatment of moderate ischemic stroke were similar to those in the treatment of mild ischemic stroke.
Although some data were not statistically significant, moderate ischemic stroke could be observed.
There is a trend for patients to benefit more when they receive ticagrelor in combination with aspirin, so the U.
S.
Food and Drug Administration ( FDA ) has also approved the relevant indications
.
Statistical Administration FDA

How safe is ticagrelor?

How safe is ticagrelor? How safe is ticagrelor?

In the SOCRATES trial, ticagrelor was not superior to aspirin in reducing the risk of the composite endpoint of stroke and myocardial infarction
.
However, in the PRINCE trial, ticagrelor combined with aspirin showed greater efficacy in preventing
recurrent stroke at 90 days .
In the THALES trial, ticagrelor combined with aspirin showed better efficacy, but there were some safety concerns
.
Recently, the CHANCE 2 trial published results comparing ticagrelor plus aspirin versus clopidogrel plus aspirin for secondary stroke prevention in carriers of the CYP2C19 loss-of-function allele
.
All of these trials showed more bleeding events, although there was no statistical difference
.
However, the three trials also raised concerns about the safety of ticagrelor combined with aspirin
.

In the SOCRATES trial, ticagrelor was not superior to aspirin in reducing the risk of the composite endpoint of stroke and myocardial infarction
.
However, in the PRINCE trial, ticagrelor combined with aspirin showed greater efficacy in preventing
recurrent stroke at 90 days .
In the THALES trial, ticagrelor combined with aspirin showed better efficacy, but there were some safety concerns
.
Recently, the CHANCE 2 trial published results comparing ticagrelor plus aspirin versus clopidogrel plus aspirin for secondary stroke prevention in carriers of the CYP2C19 loss-of-function allele
.
All of these trials showed more bleeding events, although there was no statistical difference
.
However, the three trials also raised concerns about the safety of ticagrelor combined with aspirin
.
myocardial infarction prevention

Based on this, the neurology team of Huashan Hospital Affiliated to Fudan University conducted a meta-analysis of pooled data from PRINCE, THALES and CHANCE 2 trials
.
Considering the differences between THALES and the other two trial interventions, the authors' team performed subgroup analyses of PRINCE and CHANCE 2
.
The results were published in Stroke & Vascular Neurology
.

Based on this, the neurology team of Huashan Hospital Affiliated to Fudan University conducted a meta-analysis of pooled data from PRINCE, THALES and CHANCE 2 trials
.
Considering the differences between THALES and the other two trial interventions, the authors' team performed subgroup analyses of PRINCE and CHANCE 2
.
The results were published in Stroke & Vascular Neurology
.

The analysis found that in the ticagrelor plus aspirin group, the relative risk (RR) for all bleeding events was 1.
86 (95% CI 1.
39 to 2.
49)
.

The analysis found that in the ticagrelor plus aspirin group, the relative risk (RR) for all bleeding events was 1.
86 (95% CI 1.
39 to 2.
49)
.

Forest plot of bleeding events
.
(A) Forest plot for all bleeding events; (B) Forest plot for intracranial hemorrhage; (C) Forest plot for moderate to severe bleeding events; (D) Forest plot for fatal bleeding events
.
A, aspirin; C+A, clopidogrel plus aspirin; T+A, ticagrelor plus aspirin, DOI: 10.
1136/svn-2021-001423

Forest plot of bleeding events
.
(A) Forest plot for all bleeding events; (B) Forest plot for intracranial hemorrhage; (C) Forest plot for moderate to severe bleeding events; (D) Forest plot for fatal bleeding events
.
A, aspirin; C+A, clopidogrel plus aspirin; T+A, ticagrelor plus aspirin, DOI: 10.
1136/svn-2021-001423

Further analysis of the published data from these trials by the authors' team suggests that the combination of ticagrelor with aspirin may increase the rate of bleeding events
.

Further analysis of the published data from these trials by the authors' team suggests that the combination of ticagrelor with aspirin may increase the rate of bleeding events
.
Combining ticagrelor with aspirin may increase the incidence of bleeding events
.

The main concern with ticagrelor plus aspirin since the SOCRATES trial was the higher risk of all bleeding events and severe to moderate bleeding events
.
In the PRINCE trial, the authors' team noted that any bleeding events were higher in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group (p=0.
007) , especially in minor bleeding events (p=0.
003)
.
The CHANCE 2 trial showed a similar trend toward an increase in the rate of bleeding events, but not for the risk of major bleeding
.

The main concern with ticagrelor plus aspirin since the SOCRATES trial was the higher risk of all bleeding events and severe to moderate bleeding events
.
In the PRINCE trial, the authors' team noted that any bleeding events were higher in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group (p=0.
007) , especially in minor bleeding events (p=0.
003)
.
The CHANCE 2 trial showed a similar trend toward an increase in the rate of bleeding events, but not for the risk of major bleeding
.

The authors' team noted differences in treatment duration, which may alter the balance of benefits and risks
.
In the POINT trial, the authors' team found that if treatment continued for 90 days, patients taking clopidogrel plus aspirin had a lower risk of major ischemic events, but a higher risk of major bleeding than patients taking aspirin alone
.
However, the first CHANCE trial showed that taking a lower loading dose of clopidogrel plus aspirin for only 21 days reduced the risk of subsequent stroke events without increasing the risk of bleeding compared with patients taking aspirin alone
.
The results of these two randomized controlled trials (RCTs) may suggest that by reducing the loading dose and duration of DAPT, bleeding risk may be further reduced
.

The authors' team noted differences in treatment duration, which may alter the balance of benefits and risks
.
In the POINT trial, the authors' team found that if treatment continued for 90 days, patients taking clopidogrel plus aspirin had a lower risk of major ischemic events, but a higher risk of major bleeding than patients taking aspirin alone
.
However, the first CHANCE trial showed that taking a lower loading dose of clopidogrel plus aspirin for only 21 days reduced the risk of subsequent stroke events without increasing the risk of bleeding compared with patients taking aspirin alone
.
The results of these two randomized controlled trials (RCTs) may suggest that by reducing the loading dose and duration of DAPT, bleeding risk may be further reduced
.

At the same time, the authors' team believes that this meta-analysis has some limitations
.
The THALES trial was designed to compare ticagrelor plus aspirin versus aspirin, and two other trials compared ticagrelor plus aspirin versus clopidogrel plus aspirin
.
In addition, there were differences in study design
, endpoint definitions, and duration of follow-up .

At the same time, the authors' team believes that this meta-analysis has some limitations
.
The THALES trial was designed to compare ticagrelor plus aspirin versus aspirin, and two other trials compared ticagrelor plus aspirin versus clopidogrel plus aspirin
.
In addition, there were differences in study design
, endpoint definitions, and duration of follow-up .
Research design

Taken together, although all three trials analyzed supported the use of ticagrelor plus aspirin for secondary stroke prevention in patients who already had minor stroke or TIA, we cannot ignore the bleeding risk of this treatment
.
Clinicians need to balance the risk of bleeding with the benefit of preventing recurrent stroke in each patient who may require DAPT
.

Taken together, although all three trials analyzed supported the use of ticagrelor plus aspirin for secondary stroke prevention in patients who already had minor stroke or TIA, we cannot ignore the bleeding risk of this treatment
.
Although all three trials analyzed supported the use of ticagrelor plus aspirin for secondary stroke prevention in patients who already had minor stroke or TIA, we cannot ignore the bleeding risk of this treatment
.
Clinicians need to balance the risk of bleeding with the benefit of preventing recurrent stroke in each patient who may require DAPT
.

1.
Wang, Y.
, et al.
, Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA.
2021.

1.
Wang, Y.
, et al.
, Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA.
2021.

2.
Wang, Y.
, et al.
, Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack.
Jama, 2016.
316(1): p.
70 -8.

2.
Wang, Y.
, et al.
, Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack.
Jama, 2016.
316(1): p.
70 -8.

3.
Johnston, SC, et al.
, Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA.
N Engl J Med, 2020.
383(3): p.
207-217.

3.
Johnston, SC, et al.
, Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA.
N Engl J Med, 2020.
383(3): p.
207-217.

4.
Wallentin L, Becker RC, Budaj A, et al.
Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
N Engl J Med 2009;361:1045-1057.

4.
Wallentin L, Becker RC, Budaj A, et al.
Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
N Engl J Med 2009;361:1045-1057.

5.
Johnston SC, Easton JD, Farrant M, et al.
Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA.
N Engl J Med 2018;379:215-225.

5.
Johnston SC, Easton JD, Farrant M, et al.
Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA.
N Engl J Med 2018;379:215-225.

6.
Johnston SC, Amarenco P, Denison H, et al.
Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA.
N Engl J Med 2020;383:207-217.

6.
Johnston SC, Amarenco P, Denison H, et al.
Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA.
N Engl J Med 2020;383:207-217.

7.
Amarenco P, Denison H, Evans SR et al.
Ticagrelor added to aspirin in acute nonsevere ischemic stroke or transient ischemic attack of atherosclerotic origin.
Stroke 2020;51:3504-3513.

7.
Amarenco P, Denison H, Evans SR et al.
Ticagrelor added to aspirin in acute nonsevere ischemic stroke or transient ischemic attack of atherosclerotic origin.
Stroke 2020;51:3504-3513.

8.
Pan Y, Wangqin R, Li H, et al.
F2R polymorphisms and clopidogrel efficacy and safety in patients with minor stroke or TIA.
Neurology 2021;96:e1–e9.

8.
Pan Y, Wangqin R, Li H, et al.
F2R polymorphisms and clopidogrel efficacy and safety in patients with minor stroke or TIA.
Neurology 2021;96:e1–e9.

9.
https://mp.
weixin.
qq.
com/s/sD97XojdhrImZ62Py9tuHA

9.
https://mp.
weixin.
qq.
com/s/sD97XojdhrImZ62Py9tuHA

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