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Aspirin combined with P2Y12 receptor antagonist dual antiplatelet therapy (DAPT) has been widely used in the treatment of cardiovascular diseases
.
While DAPT reduces the risk of ischemia, it also increases the risk of bleeding.
Intracranial hemorrhage (ICH) is the most serious complication
.
The incidence of ICH is not high (0.
2%-0.
3% per year), but its mortality rate is as high as 60%, and the base of cardiovascular disease patients is large, and its cumulative burden may be huge
.
Patients with a history of stroke or transient ischemic attack (TIA) are at higher risk of developing ICH when receiving dual antibody therapy
.
Risk prediction models can help clinicians assess the risk of DAPT for patients with a history of stroke/TIA
.
In July 2021, Dr.
Andrew CT Ha published a review on JACC, summarizing the epidemiology, risk factors, risk prediction models and treatment options of ICH related to antiplatelet drugs
.
Epidemiology of ICH Currently, the global age-standardized incidence of cerebral hemorrhage and subarachnoid hemorrhage is about 55 persons per 100,000 person-years, and the lifetime risk of hemorrhagic stroke among adults worldwide is about 8.
2%
.
Although the diagnosis and treatment of ICH have improved in recent years, the risk of its occurrence has not changed significantly
.
Studies have shown that patients treated with antiplatelet drugs are more likely to have severe clinical manifestations of ICH
.
The use of antiplatelet drugs is associated with greater baseline bleeding and a higher risk of increased bleeding (OR: 1.
85; 95% CI: 1.
37-2.
50)
.
Compared with patients receiving single antiplatelet therapy (SAPT), patients with cerebral hemorrhage who received DAPT had a higher mortality rate
.
Trauma is an important mechanism of ICH related to antiplatelet therapy, but it has not been fully understood
.
At least 50% of patients hospitalized for traumatic brain injury (TBI) experienced ICH, and about 11% of patients admitted for TBI received antiplatelet medication
.
Risk of ICH caused by antiplatelet therapy For patients undergoing percutaneous coronary intervention (PCI), acute coronary syndrome (ACS), high-risk chronic coronary artery disease, and recent history of stroke or TIA, DAPT can reduce stroke and myocardial infarction It is better than SAPT in terms of risk
.
The pharmacological effects of clopidogrel and prasugrel are irreversible, while the antiplatelet effect of ticagrelor is reversible
.
The results of the meta-analysis showed that compared with aspirin monotherapy, the risk of ICH in patients receiving DAPT increased by 42%
.
The PEGASUS-TIMI 54 trial showed that for patients with a history of subacute myocardial infarction (1-3 years), compared with aspirin monotherapy, patients who received extended DAPT therapy (median 33 months) had a higher risk of ICH
.
The THEMIS trial showed that compared with aspirin monotherapy, prolonging DAPT (median 39.
9 months) increased the patient's risk of ICH (0.
7% vs 0.
5%; HR: 1.
71; 95% CI: 1.
18-2.
48)
.
Studies have shown that compared with aspirin monotherapy, patients treated with aspirin + ticagrelor have a higher risk of ICH (0.
51% vs 0.
34%; hazard ratio: 1.
59; 95% CI: 1.
06-2.
39; P = 0.
02)
.
In the DAPT randomized trial comparing different P2Y12 receptor antagonists, compared with clopidogrel, patients treated with prasugrel/ticagrelor had a higher risk of ICH, but the difference was not statistically significant
.
A meta-analysis of risk factors for ICH related to antiplatelet therapy showed that East Asian race (RR: 1.
84; 95% CI: 1.
04-3.
27) and low body mass index <25 kg/m2 (RR: 1.
84; 95% CI: 1.
04- 3.
27) It is related to the increased risk of ICH
.
Some studies have shown that stroke (ischemic/hemorrhagic) or history of TIA is an important risk factor for ICH related to antiplatelet therapy
.
In a pooled analysis of six trials evaluating the use of antiplatelet drugs in patients with a history of stroke/TIA, ICH accounted for 26% (392/1530) of all major bleeding events
.
In this patient population, DAPT treatment increased the risk of major bleeding by 70% compared with aspirin monotherapy
.
When doctors use antiplatelet therapy (especially DAPT) for patients with a history of stroke/TIA, they must consider carefully
.
Currently, there are several predictive models that can predict the risk of ICH in antiplatelet-treated patients with a history of stroke/TIA
.
The S2TOP-BLEED score can be used to predict major bleeding or ICH.
Advanced age and use of DAPT (aspirin + clopidogrel) are the strongest determinants of increased risk
.
If the S2TOP BLEED scores of 55-65, 65-75, and 75-85-year-old patients exceed 13, 11, and 8, respectively, their annualized ICH risk is estimated to be greater than 1.
0%
.
For the annualized ICH risk, 1.
0% is a critical value.
Beyond this critical value, the benefits of antithrombotic therapy may be offset.
The S2TOP-BLEED prediction rule can help clinicians balance the effects of antiplatelet therapy in previous stroke/TIA patients.
Risks and benefits
.
Intracranial-B2LEED3S score can predict the risk of ICH in patients with ischemic stroke treated with antiplatelet drugs
.
A score ≥5 indicates an annualized ICH risk ≥1%
.
It should be noted that the discriminative ability of these scores is not strong (C statistic: 0.
53-0.
65), and has not been verified in patients with acute ischemic stroke/TIA
.
For patients with acute ischemic stroke/TIA, the high bleeding risk score should not be used as a reason for suspending DAPT
.
The rich data of DAPT-related bleeding comes from the PCI field, and there are a number of published risk prediction models with a fairly good discriminative ability (C statistic: 0.
63-0.
70)
.
However, the prediction results of these models are hemorrhage, not ICH, and whether they can be used to predict the risk of ICH is currently unclear
.
Prevention and management of ICH All cases of ICH require early intervention.
Among ICH patients receiving antiplatelet therapy, interventions that can quickly reverse drug activity may reduce the severity of bleeding and promote early neurosurgical treatment
.
So far, there is no clinical therapy that can quickly reverse the effect of antiplatelet drugs
.
Existing therapies for patients with antiplatelet-related ICH include: hemostatic drugs (recombinant activating factor VII, fibrinogen concentrate, factor XIII), antifibrinolytic drugs (such as tranexamic acid), platelet transfusion, and desmotherapy Pressure hormone, serum albumin, platelet-rich plasma, adsorbents (for ticagrelor), monoclonal antibody fragments (Bentracimab for ticagrelor)
.
These treatment options require further prospective clinical trials to determine their efficacy
.
In addition, in vitro studies have shown that platelet transfusion can partially reverse the antiplatelet effects of clopidogrel or prasugrel, but in vivo research data is lacking
.
At present, clinical practice guidelines do not recommend nor oppose platelet transfusion in patients with ICH related to antiplatelet therapy
.
Bentracimab is a monoclonal antibody fragment that binds to ticagrelor and its main circulating active metabolites with high affinity
.
In a phase I trial, intravenous Bentracimab reversed the antiplatelet effect of ticagrelor quickly (within 5 minutes), continuously (up to 20 hours), and substantially (about 80%)
.
Based on the above results, Bentracimab was granted a breakthrough therapy designation by the U.
S.
FDA in 2019 for reversing the antiplatelet effect of ticagrelor for emergency hemostasis clinically
.
The best time to resume antiplatelet therapy after ICH is not yet clear
.
The RESTART trial randomized patients who experienced cerebral hemorrhage while receiving antithrombotic therapy, and either recovered (patients started to recover SAPT 2.
5 months after cerebral hemorrhage) or avoided using antiplatelet drugs
.
No difference in the recurrence rate of symptomatic spontaneous intracerebral hemorrhage was observed between the two groups, and the bleeding rate of patients in the antiplatelet therapy group had a tendency to decrease
.
Ongoing randomized trials (RESTART-Fr and STATICH) will expand the evidence base for this important clinical issue
.
Due to the lack of guidance from randomized controlled trial data, DAPT should be avoided as far as possible in patients after ICH
.
Conclusion DAPT has ischemic protection for patients with cardiovascular diseases, but it is also accompanied by an increase in the risk of major bleeding events, of which ICH is the most destructive bleeding complication
.
For certain high-risk patients, such as those with a history of stroke/TIA, the risk of ICH associated with DAPT must be carefully considered
.
Risk prediction models can help doctors make trade-offs and develop individualized treatment plans for patients at high risk of bleeding
.
In current clinical practice, there is no drug that can quickly and effectively reverse the antiplatelet effect of P2Y12 receptor antagonists, and drugs that reverse the antiplatelet effect of ticagrelor are under study
.
Literature source: Ha ACT, Bhatt DL, Rutka JT, et al.
Intracranial Hemorrhage During Dual Antiplatelet Therapy: JACC Review Topic of the Week.
J Am Coll Cardiol.
2021 Sep 28; 78(13): 1372-1384.
doi: 10.
1016 /j.
jacc.
2021.
07.
048.
PMID: 34556323.
.
While DAPT reduces the risk of ischemia, it also increases the risk of bleeding.
Intracranial hemorrhage (ICH) is the most serious complication
.
The incidence of ICH is not high (0.
2%-0.
3% per year), but its mortality rate is as high as 60%, and the base of cardiovascular disease patients is large, and its cumulative burden may be huge
.
Patients with a history of stroke or transient ischemic attack (TIA) are at higher risk of developing ICH when receiving dual antibody therapy
.
Risk prediction models can help clinicians assess the risk of DAPT for patients with a history of stroke/TIA
.
In July 2021, Dr.
Andrew CT Ha published a review on JACC, summarizing the epidemiology, risk factors, risk prediction models and treatment options of ICH related to antiplatelet drugs
.
Epidemiology of ICH Currently, the global age-standardized incidence of cerebral hemorrhage and subarachnoid hemorrhage is about 55 persons per 100,000 person-years, and the lifetime risk of hemorrhagic stroke among adults worldwide is about 8.
2%
.
Although the diagnosis and treatment of ICH have improved in recent years, the risk of its occurrence has not changed significantly
.
Studies have shown that patients treated with antiplatelet drugs are more likely to have severe clinical manifestations of ICH
.
The use of antiplatelet drugs is associated with greater baseline bleeding and a higher risk of increased bleeding (OR: 1.
85; 95% CI: 1.
37-2.
50)
.
Compared with patients receiving single antiplatelet therapy (SAPT), patients with cerebral hemorrhage who received DAPT had a higher mortality rate
.
Trauma is an important mechanism of ICH related to antiplatelet therapy, but it has not been fully understood
.
At least 50% of patients hospitalized for traumatic brain injury (TBI) experienced ICH, and about 11% of patients admitted for TBI received antiplatelet medication
.
Risk of ICH caused by antiplatelet therapy For patients undergoing percutaneous coronary intervention (PCI), acute coronary syndrome (ACS), high-risk chronic coronary artery disease, and recent history of stroke or TIA, DAPT can reduce stroke and myocardial infarction It is better than SAPT in terms of risk
.
The pharmacological effects of clopidogrel and prasugrel are irreversible, while the antiplatelet effect of ticagrelor is reversible
.
The results of the meta-analysis showed that compared with aspirin monotherapy, the risk of ICH in patients receiving DAPT increased by 42%
.
The PEGASUS-TIMI 54 trial showed that for patients with a history of subacute myocardial infarction (1-3 years), compared with aspirin monotherapy, patients who received extended DAPT therapy (median 33 months) had a higher risk of ICH
.
The THEMIS trial showed that compared with aspirin monotherapy, prolonging DAPT (median 39.
9 months) increased the patient's risk of ICH (0.
7% vs 0.
5%; HR: 1.
71; 95% CI: 1.
18-2.
48)
.
Studies have shown that compared with aspirin monotherapy, patients treated with aspirin + ticagrelor have a higher risk of ICH (0.
51% vs 0.
34%; hazard ratio: 1.
59; 95% CI: 1.
06-2.
39; P = 0.
02)
.
In the DAPT randomized trial comparing different P2Y12 receptor antagonists, compared with clopidogrel, patients treated with prasugrel/ticagrelor had a higher risk of ICH, but the difference was not statistically significant
.
A meta-analysis of risk factors for ICH related to antiplatelet therapy showed that East Asian race (RR: 1.
84; 95% CI: 1.
04-3.
27) and low body mass index <25 kg/m2 (RR: 1.
84; 95% CI: 1.
04- 3.
27) It is related to the increased risk of ICH
.
Some studies have shown that stroke (ischemic/hemorrhagic) or history of TIA is an important risk factor for ICH related to antiplatelet therapy
.
In a pooled analysis of six trials evaluating the use of antiplatelet drugs in patients with a history of stroke/TIA, ICH accounted for 26% (392/1530) of all major bleeding events
.
In this patient population, DAPT treatment increased the risk of major bleeding by 70% compared with aspirin monotherapy
.
When doctors use antiplatelet therapy (especially DAPT) for patients with a history of stroke/TIA, they must consider carefully
.
Currently, there are several predictive models that can predict the risk of ICH in antiplatelet-treated patients with a history of stroke/TIA
.
The S2TOP-BLEED score can be used to predict major bleeding or ICH.
Advanced age and use of DAPT (aspirin + clopidogrel) are the strongest determinants of increased risk
.
If the S2TOP BLEED scores of 55-65, 65-75, and 75-85-year-old patients exceed 13, 11, and 8, respectively, their annualized ICH risk is estimated to be greater than 1.
0%
.
For the annualized ICH risk, 1.
0% is a critical value.
Beyond this critical value, the benefits of antithrombotic therapy may be offset.
The S2TOP-BLEED prediction rule can help clinicians balance the effects of antiplatelet therapy in previous stroke/TIA patients.
Risks and benefits
.
Intracranial-B2LEED3S score can predict the risk of ICH in patients with ischemic stroke treated with antiplatelet drugs
.
A score ≥5 indicates an annualized ICH risk ≥1%
.
It should be noted that the discriminative ability of these scores is not strong (C statistic: 0.
53-0.
65), and has not been verified in patients with acute ischemic stroke/TIA
.
For patients with acute ischemic stroke/TIA, the high bleeding risk score should not be used as a reason for suspending DAPT
.
The rich data of DAPT-related bleeding comes from the PCI field, and there are a number of published risk prediction models with a fairly good discriminative ability (C statistic: 0.
63-0.
70)
.
However, the prediction results of these models are hemorrhage, not ICH, and whether they can be used to predict the risk of ICH is currently unclear
.
Prevention and management of ICH All cases of ICH require early intervention.
Among ICH patients receiving antiplatelet therapy, interventions that can quickly reverse drug activity may reduce the severity of bleeding and promote early neurosurgical treatment
.
So far, there is no clinical therapy that can quickly reverse the effect of antiplatelet drugs
.
Existing therapies for patients with antiplatelet-related ICH include: hemostatic drugs (recombinant activating factor VII, fibrinogen concentrate, factor XIII), antifibrinolytic drugs (such as tranexamic acid), platelet transfusion, and desmotherapy Pressure hormone, serum albumin, platelet-rich plasma, adsorbents (for ticagrelor), monoclonal antibody fragments (Bentracimab for ticagrelor)
.
These treatment options require further prospective clinical trials to determine their efficacy
.
In addition, in vitro studies have shown that platelet transfusion can partially reverse the antiplatelet effects of clopidogrel or prasugrel, but in vivo research data is lacking
.
At present, clinical practice guidelines do not recommend nor oppose platelet transfusion in patients with ICH related to antiplatelet therapy
.
Bentracimab is a monoclonal antibody fragment that binds to ticagrelor and its main circulating active metabolites with high affinity
.
In a phase I trial, intravenous Bentracimab reversed the antiplatelet effect of ticagrelor quickly (within 5 minutes), continuously (up to 20 hours), and substantially (about 80%)
.
Based on the above results, Bentracimab was granted a breakthrough therapy designation by the U.
S.
FDA in 2019 for reversing the antiplatelet effect of ticagrelor for emergency hemostasis clinically
.
The best time to resume antiplatelet therapy after ICH is not yet clear
.
The RESTART trial randomized patients who experienced cerebral hemorrhage while receiving antithrombotic therapy, and either recovered (patients started to recover SAPT 2.
5 months after cerebral hemorrhage) or avoided using antiplatelet drugs
.
No difference in the recurrence rate of symptomatic spontaneous intracerebral hemorrhage was observed between the two groups, and the bleeding rate of patients in the antiplatelet therapy group had a tendency to decrease
.
Ongoing randomized trials (RESTART-Fr and STATICH) will expand the evidence base for this important clinical issue
.
Due to the lack of guidance from randomized controlled trial data, DAPT should be avoided as far as possible in patients after ICH
.
Conclusion DAPT has ischemic protection for patients with cardiovascular diseases, but it is also accompanied by an increase in the risk of major bleeding events, of which ICH is the most destructive bleeding complication
.
For certain high-risk patients, such as those with a history of stroke/TIA, the risk of ICH associated with DAPT must be carefully considered
.
Risk prediction models can help doctors make trade-offs and develop individualized treatment plans for patients at high risk of bleeding
.
In current clinical practice, there is no drug that can quickly and effectively reverse the antiplatelet effect of P2Y12 receptor antagonists, and drugs that reverse the antiplatelet effect of ticagrelor are under study
.
Literature source: Ha ACT, Bhatt DL, Rutka JT, et al.
Intracranial Hemorrhage During Dual Antiplatelet Therapy: JACC Review Topic of the Week.
J Am Coll Cardiol.
2021 Sep 28; 78(13): 1372-1384.
doi: 10.
1016 /j.
jacc.
2021.
07.
048.
PMID: 34556323.
