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When should antiplatelet therapy be restarted after cerebral hemorrhage?

 Last Update: 2021-11-01
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In May 2019, Lancet magazine published an article on when to restart antithrombotic therapy for patients with spontaneous intracerebral hemorrhage, titled "Effects of antiplatelet therapy afterstroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Research Introduction

Research Introduction Research Introduction

1.
Research background

1.
Research background 1.
Research background

Antiplatelet therapy is the cornerstone of primary and secondary prevention of ischemic stroke and coronary artery disease .

In high-income countries, up to one-third of patients with spontaneous cerebral hemorrhage are taking antithrombotic drugs when they develop cerebral hemorrhage
.

These patients are usually also at risk of ischemic vascular events.
Therefore, clinicians are usually faced with the decision of whether to restart antithrombotic therapy

Antiplatelet therapy is the cornerstone of primary and secondary prevention of ischemic stroke and coronary artery disease .

2.
Research methods

2.
Research method 2.
Research method

The Stop or Restart Antithrombotic Therapy in Patients with Cerebral Hemorrhage (RESTART) study is a prospective, randomized, open-label, blinded endpoint, parallel controlled trial conducted in 122 hospitals in the UK
.

Patients ≥18 years of age who had spontaneous intracranial hemorrhage and survived for more than 24 hours were enrolled and were receiving antithrombotic therapy (antiplatelet or anticoagulation therapy) to prevent occlusive vascular disease when cerebral hemorrhage occurred

3.
Research results

3.
Research results 3.
Research results

From May 22, 2013 to May 31, 2018, a total of 537 cases of cerebral hemorrhage were taking antithrombotic therapy (1/2 taking aspirin, about 1/4 taking clopidogrel, and nearly 1/5 taking oral For patients with anticoagulants, the median time from the onset of cerebral hemorrhage to randomization was 76 (29-146) days
.

Among them, 268 cases were assigned to the antiplatelet therapy group, and 269 cases were assigned to the antiplatelet therapy group

During the follow-up, 4 patients who died before discharge were excluded
.

For the primary endpoint, the proportion of recurrent intracranial hemorrhage events in the antiplatelet therapy group and the antiplatelet therapy group was 4% (12/268) vs 9% (23/268) (adjusted HR 0.

During the follow-up, 4 patients who died before discharge were excluded

Sensitivity analysis of the main outcomes was performed, and on the basis of the recurrence of spontaneous symptomatic intracranial hemorrhage, the following were added: ①Symptomatic stroke or stroke of uncertain subtype; ②Death of unknown cause, reduced the two main outcomes on the adjusted or unadjusted model The proportion of events is the same.
Restarting antiplatelet therapy after intracranial hemorrhage does not increase the risk of hemorrhagic stroke recurrence as a whole.
It is even found that antiplatelet therapy may reduce the risk of recurrent intracranial hemorrhage.
The underlying mechanism is worthy of further study
.

During the follow-up, the KM curve of the first recurrence of intracranial hemorrhage showed that the antiplatelet therapy was initiated vs.
the antiplatelet therapy group, and the corrected HR was 0.
51 (95% CI 0.
25 to 1.
03, P= 0.
060), but the symptoms recurred after 2 years The cumulative incidence of sexual bleeding events was basically stable in both groups, indicating that extended follow-up time had little effect on the main outcome (Figure 1)
.

During follow-up, the first occurrence of intracranial hemorrhage recurrence KM curves show start antiplatelet therapy vs antiplatelet therapy group did not start, after 0.
51 corrected the HR (95% CI0.
25 ~ 1.
03, P = 0.
060), P but relapsed after 2 years The cumulative incidence of symptomatic bleeding events was basically stable in both groups, indicating that extended follow-up time had little effect on the main outcome, but the cumulative incidence of symptomatic bleeding events that recurred after 2 years was basically stable in both groups, indicating that extended follow-up time was effective The main outcome has little effect (Figure 1)
.

In order to explore the impact of antiplatelet therapy on the main outcome, the study presupposed some subgroups.
Through the analysis of the prespecified subgroups, no heterogeneity was found in the main outcome of antiplatelet therapy in different subgroups of patients (Figure 2)
.

No heterogeneity was found in the main outcome of antiplatelet therapy in different subgroups of patients (Figure 2)

3.
Research conclusion

3.
Research conclusion 3.
Research conclusion

For patients receiving antithrombotic therapy (antiplatelet or anticoagulation therapy) to prevent spontaneous intracranial hemorrhage in patients with occlusive vascular disease, the use of antiplatelet therapy does not increase the risk of recurrence of cerebral hemorrhage, and can reduce the incidence of occlusive vascular events
.
In general, antiplatelet therapy is beneficial for the secondary prevention of such patients
.
For patients receiving antithrombotic therapy (antiplatelet or anticoagulation therapy) to prevent spontaneous intracranial hemorrhage in patients with occlusive vascular disease, the use of antiplatelet therapy does not increase the risk of recurrence of cerebral hemorrhage, and can reduce the incidence of occlusive vascular events
.
In general, antiplatelet therapy is beneficial for the secondary prevention of such patients
.

Q&A

Q &A

Q1: What are the characteristics of the study?

Q1: What are the characteristics of the study? Q1: What are the characteristics of the study?

A1 : This study is a practical, multi-center, prospective, randomized, open-label, blinded endpoint, parallel group controlled trial
.

A1 : This study is an A1 practical, multi-center, prospective, randomized, open-label, blinded endpoint, parallel-group controlled trial
.

Q2: What is an effective RCT?

Q2: What is an effective RCT? Q2: What is an effective RCT?

A2: "Pragmatic" means pragmatic, which can reflect the influence of real-world RCTs.
The counterpart of pragmatic test is explanatory test
.
In actual clinical practice, patients often have multiple diseases and receive multiple treatments at the same time.
The final effect is the combined effect of the research intervention and various other treatment factors.
RCTs often formulate strict selection and exclusion criteria, resulting in insufficient representation of research subjects , Limiting its conclusions to the general population
.
The small number of cases, short research time, and many medication conditions and design limitations lead to differences in research results from the real clinical environment, which cannot provide sufficient decision-making information
.
Effective randomized controlled trials have the following characteristics: ①Broad selection criteria to ensure that conclusions can be extrapolated to the maximum; ②Multiple outcomes, including functional status and utilization of medical services
.
The research is carried out under actual clinical medical conditions; ③Intervene in conventional treatment as little as possible
.

A2: "Pragmatic" means pragmatic, which can reflect the influence of real-world RCTs.
The counterpart of pragmatic test is explanatory test
.
In actual clinical practice, patients often have multiple diseases and receive multiple treatments at the same time.
The final effect is the combined effect of the research interventions and various other treatment factors.
RCTs often formulate strict selection and exclusion criteria, resulting in insufficient representation of research subjects , Limiting its conclusions to the general population
.
The small number of cases, short research time, and many medication conditions and design limitations lead to differences in research results from the real clinical environment, which cannot provide sufficient decision-making information
.
A2: Effective randomized controlled trials have the following characteristics: ①Broad selection criteria to ensure that conclusions can be extrapolated to the maximum; ②Multiple outcomes, including functional status and utilization of medical services
.
The research is carried out under actual clinical medical conditions; ③Intervene in conventional treatment as little as possible
.
Effective randomized controlled trials have the following characteristics: ①Broad selection criteria to ensure that conclusions can be extrapolated to the maximum; ②Multiple outcomes, including functional status and utilization of medical services
.
The research is carried out under actual clinical medical conditions; ③Intervene in conventional treatment as little as possible
.

Q3: "open label" and "blinded endpoint" seem to be two opposite experimental designs.
Are they contradictory?

Q3: "open label" and "blinded endpoint" seem to be two opposite experimental designs.
Are they contradictory? Q3: "open label" and "blinded endpoint" seem to be two opposite experimental designs.
Are they contradictory?

A3: Open label: It refers to a trial in which neither the investigator nor the subject is blinded, and both parties know the real drug delivery situation
.
In the study, treatment allocation is open to participants, clinicians, primary and secondary care staff, and local researchers
.
The trial coordinator did not know the treatment assignment
.
When analyzing the outcome event, the identity of the participant, treatment allocation, and drug use were masked, that is, the blinded endpoint
.
Blinding is one of the basic principles of RCT, but not all research must be used or can be implemented
.
In open trials, blinding cannot be implemented, but group concealment can still be implemented
.
At the same time, consider blinding the outcome assessors, data monitoring and statistical analysis personnel
.
Its advantage is that it is easy to design and implement, the researcher understands the grouping situation, and it is convenient to deal with the research object in time.
Its main disadvantage is that it is prone to bias
.

A3: Open label: A3: It refers to a trial in which neither the investigator nor the subject is blinded, and both parties know the real drug administration situation
.
In the study, treatment allocation is open to participants, clinicians, primary and secondary care staff, and local researchers
.
The trial coordinator did not know the treatment assignment
.
When analyzing the outcome event, the identity of the participant, treatment allocation, and drug use were masked, that is, the blinded endpoint
.
Blinding is one of the basic principles of RCT, but not all research must be used or can be implemented
.
In open trials, blinding cannot be implemented, but group concealment can still be implemented
.
At the same time, consider blinding the outcome assessors, data monitoring and statistical analysis personnel
.
Its advantage is that it is easy to design and implement, the researcher understands the grouping situation, and it is convenient to deal with the research object in time.
Its main disadvantage is that it is prone to bias
.

Q4: What is the minimization method when randomly grouping?

Q4: What is the minimization method when randomly grouping? Q4: What is the minimization method when randomly grouping?

A4: Dynamic random grouping refers to a method in which the probability of a research object being assigned to each group is dynamically adjusted according to certain conditions.
Minimization is one of the more common methods
.
The basic principle is: before the start of the trial, determine the factors that have an important impact on the outcome, and divide the new cases into the group that minimizes the difference in the distribution of these factors according to the distribution of factors affecting the prognosis of the included cases; When there is no difference in the distribution of these prognostic factors between groups, new cases will be randomly assigned with equal probability
.
The main advantage of the minimization method is to ensure that multiple prognostic factors are evenly distributed among the groups
.

A4: Dynamic random grouping refers to a method in which the probability of a research object being assigned to each group is dynamically adjusted according to certain conditions.
Minimization is one of the more common methods
.
The basic principle is: before the start of the trial, determine the factors that have an important impact on the outcome, and divide the new cases into the group that minimizes the difference in the distribution of these factors according to the distribution of factors affecting the prognosis of the included cases; When there is no difference in the distribution of these prognostic factors between groups, new cases will be randomly assigned with equal probability
.
A4: The main advantage of the minimization method is to ensure that multiple prognostic factors are evenly distributed among the groups
.

Q5: Why is the variable "probability of good 6-monthoutcome" added to the baseline characteristics?

Q5: Why is the variable "probability of good 6-monthoutcome" added to the baseline characteristics? Q5: Why is the variable "probability of good 6-monthoutcome" added to the baseline characteristics?

A5: Because the answers to the questions need to be balanced between the two groups, each has a 50% probability of occurrence
.
This variable comes from a predictive model study.
Methodological studies have confirmed that this simple predictive model can be used in epidemiological studies, such as stratification in trials or correction of case mixes
.

Q6: What is the significance of the sensitivity analysis of the main outcome in the study?

Q6: What is the significance of the sensitivity analysis of the main outcome in the study? Q6: What is the significance of the sensitivity analysis of the main outcome in the study?

A6: In clinical studies, after the researchers have performed the effect estimation, they usually have this question: How much will the outcome change if different methods of processing missing data are used? If you adjust for different levels of covariates, how big is the effect gap? If different criteria are used to define the outcome variables, how much will the conclusion shift? Issues such as these fall into the category of sensitivity analysis
.
Because the main outcome of the study was a negative result, the criteria for the main outcome may not be clear.
For example, in patients who died early, it was impossible to determine whether there was intracranial hemorrhage, so an uncertain endpoint was generated
.
Therefore, a sensitivity analysis was carried out on this basis
.

A6: In clinical research, after the researcher has performed the effect estimation, they usually have this question: How much will the outcome change if different missing data processing methods are used? If you adjust for different degrees of covariates, how big is the effect gap? If different criteria are used to define the outcome variables, how much will the conclusion shift? Issues such as these fall into the category of sensitivity analysis
.
A6: Because the main outcome of the study was a negative result, the criteria for the main outcome may not be clear.
For example, in patients who died early, it was impossible to determine whether there was intracranial hemorrhage, so an uncertain endpoint was generated
.
Therefore, a sensitivity analysis was carried out on this basis
.

discuss

Discuss discussion

The study originally planned to enroll 720 patients in the design plan.
After the one-year planned recruitment period was extended, the enrollment was terminated early due to various reasons, and the planned sample size was not reached.
The actual number of enrolled patients was 562
.
Due to the insufficient number of sample cases, the results may also be affected
.
Follow-up authors will continue to combine other relevant research results, such as the ongoing French randomized trial of restarting or stopping antithrombotic therapy (RESTART-Fr) and the antithrombotic therapy study after cerebral hemorrhage (STATICH), conduct a meta-analysis, and when appropriate Carry out a larger RCT trial to explore whether to initiate antiplatelet therapy and the best time to initiate antiplatelet therapy to further confirm the effect of antithrombotic therapy after cerebral hemorrhage
.

The study originally planned to enroll 720 patients in the design plan.
After the one-year planned recruitment period was extended, the enrollment was terminated early due to various reasons, and the planned sample size was not reached.
The actual number of enrolled patients was 562
.
Due to the insufficient number of samples, the results may also be affected
.
Follow-up authors will continue to combine other relevant research results, such as the ongoing French randomized trial of restarting or stopping antithrombotic therapy (RESTART-Fr) and the antithrombotic therapy study after cerebral hemorrhage (STATICH), conduct a meta-analysis, and when appropriate Carry out a larger RCT trial to explore whether to initiate antiplatelet therapy and the best time to initiate antiplatelet therapy to further confirm the effect of antithrombotic therapy after cerebral hemorrhage
.
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