How does HR-NICE antiplatelet therapy go smoothly?

Introduction my country is one of the countries with the heaviest stroke burden in the world, and the population base of high-risk non-disabling ischemic cerebrovascular events (HR-NICE) is huge.

As compared with other types of stroke patients, the HR-NICE population has an increased risk of recurrence and death.
Many studies and guidelines support early intensive antiplatelet therapy.

However, over time, the risk of recurrence in HR-NICE patients decreases.
Considering the balance between reducing the risk of recurrence and maintaining a low risk of bleeding, the acute phase and long-term secondary prevention antiplatelet treatment regimens should be different1.

This article aims to explore how to transform antiplatelet therapy strategies from acute to long-term secondary prevention for the HR-NICE population.

my country's HR-NICE population base is huge and the risk of early recurrence is high.
my country is one of the countries with the most serious burden of cerebrovascular disease in the world.
The mortality rate of cerebrovascular disease is five times that of North America.

Ischemic stroke is the most common type of cerebrovascular disease in my country, accounting for about 77.
8% of all strokes3.

After the onset of ischemic stroke, according to its severity and clinical consequences, it is divided into disabling and non-disabling.

Most patients who have a non-disabling ischemic cerebrovascular event (NICE) are in an unstable state, and their NICE recurrence is at high risk of becoming a serious stroke, and once recurrence, the prognosis is extremely poor, which is called high-risk non-disabling Ischemic Cerebrovascular Event (HR-NICE) 2.

 According to my country's 2016 edition of the "Guidelines for the Diagnosis and Treatment of High-Risk Non-disabling Ischemic Cerebrovascular Events", high-risk TIA (ABCD2≥4 points) and mild stroke with an onset time of less than 24 hours belong to HR-NICE4.

Epidemiological research results show that in my country, there are 23.
9 million people with transient ischemic attack (TIA), of which 78% are high-risk groups (ABCD2 score ≥ 4 points); among the 11 million existing stroke patients, Light strokes accounted for 46.
4%3. It can be seen that the population base of HR-NICE patients in my country is huge.

Not only that, the risk of early recurrence of HR-NICE is high, and the risk of stroke recurrence within 30 days of patients is as high as 7% to 12%5.

 Therefore, HR-NICE should be the key population for stroke prevention and control in my country.

Targeted treatment of HR-NICE patients will greatly reduce the disability and death caused by cerebrovascular disease, and greatly reduce the disease burden of cerebrovascular disease3.

HR-NICE has a high risk of early recurrence, and secondary prevention needs to be initiated as soon as possible to reduce stroke recurrence6.

The British EXPRESS study showed that active intervention as soon as possible after stroke can significantly reduce the 90-day stroke recurrence risk by 80% compared with delayed intervention; compared with delayed intervention, the early intervention group did not increase the risk of intracranial hemorrhage or other hemorrhage7.

In addition, early active and intensive intervention can significantly reduce the number of days and costs of hospitalization for patients, and significantly reduce the disability rate for 6 months8.

my country's 2018 edition of the "Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke" and the 2014 edition of the "Chinese Expert Consensus on Antiplatelet Therapy for Transient Ischemic Attack and Mild Stroke" also emphasized that secondary prevention should be implemented from the acute phase6,9 .

 Antiplatelet therapy is an important intervention in the secondary prevention of stroke.

So, from the acute phase to the long-term secondary prevention, how should the clinic develop antiplatelet treatment strategies for the HR-NICE population? In the acute phase of HR-NICE, intensive antiplatelet therapy has more benefits.
Previous studies have confirmed that for HR-NICE and other stroke patients with high risk of recurrence, early aspirin-based dual antiplatelet therapy is more effective than monoclonal antibody platelet therapy Reduce the risk of stroke recurrence1.

 The CHANCE study is the first multi-center, randomized, double-blind, parallel controlled trial to confirm the benefit of short-term dual antiplatelet therapy in the HR-NICE population.

A total of 5,170 patients from 114 centers were enrolled in the study, comparing the combination of aspirin (loading dose 75-300 mg, 75 mg/d thereafter, for 21 days) with clopidogrel (loading dose 300 mg, 75 mg/d thereafter, for 90 days) or On the basis of aspirin (loading dose 75-300mg, thereafter 75mg/d, lasting 90d) combined with placebo to treat the safety and effectiveness of HR-NICE patients whose onset time is within 24h.

The results showed that compared with aspirin monotherapy, aspirin combined with clopidogrel treatment within 24 hours after the onset of onset can reduce the risk of recurrence and the incidence of disabling recurrence events in HR-NICE patients within 90 days, a relative reduction of 32% (double antibody Group 8.
2% vs.
monotherapy group 11.
7%, HR=0.
68, [95%CI: 0.
57-0.
81], P＜0.
001), and did not increase the risk of intracranial and extracranial hemorrhage (0.
3% vs 0.
3%, P=0.
73) 10, 11.

The results of the POINT study published in the New England Journal also confirmed the efficacy of an antiplatelet therapy program based on aspirin combined with clopidogrel in European and American patient populations.

At the same time, through the analysis of the treatment time course of POINT, the researchers determined that the treatment plan corresponds to a greater short-term clinical benefit, that is, the optimal treatment time course is 21 days, which is consistent with the treatment time course in the CHANCE study12.

 Since then, the dual antiplatelet treatment plan based on aspirin combined with clopidogrel has been recommended by major authoritative guidelines including the United States, Canada and China, and has become the standard treatment plan for the acute phase of HR-NICE.

HR-NICE patients have the highest risk of recurrence in the early stages of onset, and their risk of recurrence will decrease over time.

The ultimate benefit of antiplatelet therapy depends on the balance between reducing the risk of recurrence and maintaining a low risk of bleeding.
Therefore, intensive antiplatelet therapy may not be suitable for long-term secondary prevention in HR-NICE patients1. The 2014 edition of the "Guidelines for the Secondary Prevention of Ischemic Stroke and Transient Ischemic Attack in China" recommends that acute non-cardiogenic TIA or mild type with a high risk of stroke recurrence (ABCD2 score ≥ 4) within 24 hours of onset should be given as soon as possible Patients with ischemic stroke (NIHSS score ≤ 3 points) were treated with aspirin combined with clopidogrel for 21 days (Ⅰ, A).

Thereafter, aspirin or clopidogrel alone can be used as the first-line drug for long-term secondary prevention (I, A)13.

 However, the guideline recommendation does not mean that it can be extrapolated to all patients.
Based on the characteristics of stroke patients in my country, who is a more suitable long-term antiplatelet therapy for the HR-NICE population in my country? Based on the characteristics of Chinese patients, aspirin is preferred for long-term secondary prevention in the HR-NICE population as the veteran in the field of antiplatelet therapy.
As early as 1997, large trials (CAST and IST) studies have confirmed that oral aspirin within 48 hours after stroke can significantly reduce follow-up The mortality or disability rate at the end of the period reduces recurrence9.

A 2016 study that included 12 studies on the use of aspirin for secondary prevention of TIA or acute ischemic stroke (AIS) confirmed that aspirin can continue to significantly reduce stroke recurrence in both the general population and patients with TIA and mild stroke.
Risk 14.

 Figure 1 Aspirin can continue to significantly reduce the risk of stroke recurrence for both the general population and TIA and mild stroke patients.
14 Clopidogrel is another commonly used antiplatelet drug and its main source of recognition in the field of stroke antiplatelet therapy In the publication of CAPRIE results.

CAPRIE is a head-to-head, randomized, double-blind clinical study comparing the efficacy of aspirin and clopidogrel monotherapy.

The study included 19,185 patients with new-onset AIS, myocardial infarction (MI) or peripheral arterial disease who were randomly given aspirin 325 mg/d or clopidogrel 75 mg/d.

The results showed that compared with the aspirin group, the relative risk of AIS, MI or vascular death in the clopidogrel group was reduced by 8.
7% (95%CI: 0.
3-16.
5). However, the subgroup analysis data of the study showed that the end-point risk ratio of AIS patients in the clopidogrel group was only reduced by 7.
3%, and the reduction was not statistically significant (P=0.
26)15.

Therefore, whether the conclusions of the CAPRIE study can be extended to the AIS patient population still needs to be explored in future studies.

In addition, clopidogrel is a prodrug, which needs to be converted into active metabolites by the CYP450 enzyme system in the body to exert its antiplatelet effect.
Therefore, its curative effect is affected by the CYP2C19LOF gene16.

A meta-analysis of 4,762 patients with ischemic stroke or TIA treated with clopidogrel found that compared with non-carriers, the risk of stroke and compound vascular events in CYP2C19LOF carriers was significantly increased by 92%17.

At the same time, the subgroup analysis of the CHANCE research shows that the proportion of CYP2C19 LOF gene carriers in my country accounts for about 58.
8%, which is much higher than that of other races18.

 Figure 2 Compared with non-carriers, carriers of CYP2C19 LOF gene have a significantly increased risk of stroke and complex vascular events by 92%.
17 Aspirin is irreversible through the presence of cyclooxygenase (COX) active part of serine residues in platelets.
The acetylation reaction inactivates enzymes and inhibits the metabolism of arachidonic acid (AA), thereby reducing the production of thromboxane A2 (TXA2), which has a strong effect on platelet aggregation, and finally achieves the purpose of inhibiting platelet aggregation16.

A study included 570 patients with AIS who were treated with clopidogrel on the basis of aspirin at an early stage for 30 days, and then randomly divided into aspirin monotherapy group or clopidogrel monotherapy group to evaluate the effect of CYP2C19 LOF gene on the efficacy of antiplatelet drugs It turned out that in patients receiving aspirin monotherapy, the CYP2C19 polymorphism was not associated with the main outcome19.

Therefore, regardless of the mechanism or the results of clinical studies, it has not been found that the efficacy of aspirin is affected by the CYP2C19 LOF gene.

 Figure 3 Unlike clopidogrel, the process of aspirin is not affected by CYP2C19 gene polymorphism.
16 Some experts pointed out that the choice of long-term secondary prevention drugs for stroke should be based on relative effectiveness, safety, cost, patient characteristics and patient preferences.
Basic 20.

Therefore, when choosing HR-NICE long-term secondary prevention antiplatelet therapy drugs, on the basis of efficacy and safety, consideration should also be given to drug economy, patient characteristics, and patient preferences.

The choice of antiplatelet drugs that meet the needs of patients may be more conducive to improving patients' compliance with long-term medication, thereby improving the long-term prognosis of patients.

The 2014 edition of the "Guidelines for the Secondary Prevention of Ischemic Stroke and Transient Ischemic Attack in China" also pointed out that the drug compliance of secondary prevention in patients with ischemic stroke or TIA affects the clinical prognosis of stroke patients (Ⅱ, B) ) 13.

 From the perspective of cost, according to my country's 2020 National Medical Insurance Drug List (Western Medicines), aspirin belongs to the medical insurance category A drug, and the economic burden of long-term use is low21.

In 2020, a study on the clinical comprehensive evaluation of basic drugs for the elderly in my country was published.
The study selected some drugs commonly used by the elderly in my country from November 2016 to March 2018, and integrated the safety and effectiveness of the drugs.
Scoring and ranking in terms of drug economy, clinical value, medication compliance of medical staff, and patient medication compliance, and the results found that aspirin is the antiplatelet drug with the highest comprehensive score22.

 Therefore, considering all aspects of drug efficacy, gene polymorphism, safety, Chinese patient characteristics and patient compliance, aspirin may be a better choice for long-term secondary prevention of HR-NICE patients in my country.

To sum up, my country's HR-NICE has a huge population base and a high risk of early recurrence.
Effective prevention and control for this type of population will help reduce the burden of stroke disease in my country.

For HR-NICE patients, it is reasonable to combine clopidogrel with aspirin in the acute phase of antiplatelet therapy.

When switching to long-term secondary prevention, considering the balance between reducing the risk of recurrence and maintaining a low risk of bleeding, antiplatelet monotherapy is more recommended.

In terms of comprehensive efficacy, gene polymorphism, safety, patient characteristics and compliance, aspirin may be a more suitable long-term antiplatelet monotherapy option for the HR-NICE patient population in my country.

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