Wang Yongjun's team CHANCE-2 climbs to the top of NEJM to guide new strategies for secondary stroke prevention Interview with authors

On October 28, 2021, the New England Journal of Medicine (NEJM) published online the CHANCE-2 study results of Professor Wang Yongjun’s team from Beijing Tiantan Hospital, Capital Medical University In patients with CYP2C19 inactivated alleles, ticagrelor combined with aspirin is more effective than clopidogrel combined with aspirin in preventing stroke recurrence.
The former has a 23% lower stroke recurrence rate than the latter within 90 days
.

About 60% of Asians carry the above-mentioned inactivation sites, so this result is of great value for the secondary prevention of stroke in Asian populations

Professor Wang Yongjun's team

Professor Wang Yongjun announced the main results of CHANCE-2 in the form of an oral report at the 2021 World Stroke Conference (WSC) Late Breaking Trials at 6:30 pm Beijing time on the 28th
.

This is the second researcher-initiated clinical trial (IIT) published by Wang Yongjun's team at NEJM after the CHANCE study published in 2013

"NEJM Frontiers in Medicine" recently interviewed Professor Wang Yongjun on the publication process of CHANCE-2, how to carry out high-level research and international cooperation, etc.

View details , see end of the article we will continue to launch clinical research methods courses, so stay tuned

You announced in your lecture at the end of March that the results of the CHANCE-2 test will be submitted to NEJM.
Why do you have such confidence?

You announced in your lecture at the end of March that the results of the CHANCE-2 test will be submitted to NEJM.
Why do you have such confidence?

Our team published the results of the CHANCE trial in NEJM in 2013, confirming that clopidogrel combined with aspirin treatment can effectively reduce the risk of stroke recurrence in the Chinese population
.

Subsequent subgroup analysis showed that the proportion of patients carrying the CYP2C19 inactivated allele in the Chinese population was 58.

In 2017, our team published in Circulation a meta-analysis of carrying CYP2C19 inactivated alleles and clopidogrel to prevent stroke recurrence.
Professor Tabassome Simon, a famous French pharmacogenetics expert, wrote a review and pointed out that prospective trials should be carried out to verify the results of the meta-analysis.

.

Of course, genotype-guided antiplatelet therapy has different conclusions in the prevention of cardiovascular events, which brings some risks to our research
.

But these few studies only involve the cardiovascular field after all, not the research carried out for stroke

In an analysis published in BMJ in 2019, we and international experts jointly advocated that the efficacy and feasibility of CYP2C19 inactivated alleles for secondary stroke prevention still need to be verified by randomized controlled trials
.

In 2020, NEJM published the results of the THALES trial that our team participated in ( see details ).
A review written by Professor Peter Rothwell at the same time also pointed out that the CHANCE-2 trial has two dual antiplatelet strategies in patients with transient ischemic attack or mild stroke.
A head-to-head comparison of the curative effect of the drug is carried out, and the results are worth looking forward to
.

This once again proves the importance of the CHANCE-2 test

check the details

In terms of clinical trial design, what aspects do you think are easily overlooked?

In terms of clinical trial design, what aspects do you think are easily overlooked?

The first is to determine which clinical data must be collected and tested
.

On the premise that the primary endpoint of the analysis is met, the less clinical data collected, the better, because the less clinical data, the easier the control of the trial development, and the higher the quality of the trial

The second is to carry out pre-tests
.

Through multiple rounds of demonstration in the early stage, the scientific problem of the test plan has been solved, but the feasibility problem needs to be answered through pre-tests

Can you share some tips for smoothly carrying out clinical trials?

Can you share some tips for smoothly carrying out clinical trials?

The first is the need to evaluate the feasibility of the test, which I have answered earlier
.

The second is the need to have an experienced team
.
From CHANCE to CHANCE-2 test, we have built a particularly combatable project management team, the project manager has rich experience and outstanding ability
.
Project management personnel can provide support to each sub-center at any time to ensure that the sub-center completes tasks in accordance with the requirements of the project team
.

Third, regular training
.
We have established a research network with more than 2,000 sub-centers, and we train the staff of the sub-centers every year to improve their understanding of clinical trials and their ability to carry out clinical trials
.
Some doctors involved in clinical research are likely to confuse the different requirements of clinical practice and clinical trials, and therefore lead to serious violations of the trial protocol
.
For example, during the CHANCE trial, we found that a research center did not strictly follow the process to carry out the trial and applied for randomization before signing the informed consent form.
Therefore, we disqualified the center from participating in CHANCE
.
Therefore, we must train them repeatedly to establish the correct concept of clinical trials
.

Fourth, choose units that are more motivated to participate in clinical trials and have a strong sense of responsibility
.
Tiantan Hospital, as the lead unit of the experiment, often chooses prefecture-level hospitals as sub-centers, so that it is highly representative and each sub-center also has a high degree of enthusiasm
.
We require each branch center to set up a full-time or part-time research coordinator who is responsible for project progress control, communication with the center, and problem solving
.
All scientific research coordinators will receive at least half a year of training at the National Neurological Diseases Clinical Medical Research Center, and master the skills required to carry out clinical trials through training
.

Fifth, pay attention to details
.
Taking CHANCE-2 as an example, in order to ensure that different doctors in each research center can implement uniform standards, the project management team has released more than ten volumes of Standard Operating Procedure Manual (SOP), which lists the operation methods of each step in detail
.
In this standard operating procedure, we even list the packaging boxes of each combined medication in detail to facilitate the implementation of the research participants in each center
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Each center can ensure that the test execution will not deviate from the test plan as long as they follow the standard operating procedures
.

How did you establish close cooperation with internationally renowned experts?

How did you establish close cooperation with internationally renowned experts?

We participated for the first time in an international multi-center trial sponsored by the industry led by an American professor in 2002.
During the trial, the US Food and Drug Administration sent personnel to the clinical trial site for verification
.
The verification proves that the quality of clinical trials in our center meets international standards
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We also received the highest quality award and the fastest progress award for global clinical trials issued by the sponsor of this trial
.
Participation in this experiment has established our center's position in the eyes of internationally renowned experts
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My cooperation with the well-known American expert Professor Claiborne Johnston began with a clinical trial CASTIA, which failed to carry out as expected.
During the program discussion and training, we began to collide with some sparks of cooperation
.
Since the CHANCE trial, we have gradually integrated into the international stroke antithrombotic community
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The CHANCE trial and the POINT trial designed by Professor Johnston were approved almost simultaneously ( see details ).
The CHANCE trial protocol stipulates that clopidogrel combined with aspirin will be treated for 21 days, while the POINT trial will be treated for 90 days
.
At that time, Professor Johnston's team raised objections to the 21-day treatment period, but later time-course analysis results confirmed that the best dual-antibody treatment period was 21 days
.

check the details

After this academic discussion, Professor Johnston and other foreign experts have more trust in our data and are more willing to cooperate with us
.
For example, as a core member, we have participated in a number of international multi-center trials such as SOCRATES and THALES, and the research results have been published on NEJM
.

How can young doctors take the first step in clinical trials and gradually improve?

How can young doctors take the first step in clinical trials and gradually improve?

Young doctors should first learn more and should participate more in multi-center trials initiated by other researchers, especially in international multi-center trials
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First learn how clinical trials work, and then learn how to design clinical trials, and gradually grow
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At present, China is also strengthening its support for young doctors to carry out exploratory research
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A considerable number of young doctors still lack the basic theory of clinical research, so I suggest that they read more articles on clinical research methodology, including clinical epidemiology, statistics, and research design
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After you have laid the foundation for these three aspects, you will feel very different when you read NEJM articles
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Doctors who do not understand research design like to read the conclusions, while doctors who are familiar with research design will pay attention to the research method of the article
.
Capital Medical University established the Department of Clinical Epidemiology and Clinical Trials in 2020 with the purpose of cultivating clinical trial talents with professional qualities
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What experience can you share during the submission of CHANCE-2 articles to the New England Journal of Medicine?

What experience can you share during the submission of CHANCE-2 articles to the New England Journal of Medicine?

In the first round of review, the editorial department returned more than 20 questions.
There were no questions that were particularly difficult to answer.
Among them, two questions were focused on, namely, the extrapolation of the conclusions and the influence of intracranial artery stenosis on the results
.

Most of the patients we enrolled were Han people, and there were very few minority patients
.
This is in line with the actual situation in China
.
After a detailed explanation, we will discuss this as a defect of this experiment
.
The universality and extrapolation of Chinese population data to the world need to be specifically stated, which has also been recognized by the NEJM editorial department
.

Since it has been reported that Chinese people have a higher incidence of intracranial artery stenosis than Western people, the editorial department needs to supplement the incidence of intracranial artery stenosis in CHANCE-2 population and its impact on the outcome
.
Since all subjects collected DICOM format data of cranial magnetic resonance, we took a few days to interpret and supplement the relevant data
.

Comparison of ticagrelor and clopidogrel in carriers of CYP2C19 alleles suffering from stroke or TIA

Comparison of ticagrelor and clopidogrel in carriers of CYP2C19 alleles suffering from stroke or TIA

Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA

Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA

Wang Y, Meng X, Wang A, et al.

DOI: 10.
1056/NEJMoa2111749

Summary

Summary

background

background

So far, ticagrelor and clopidogrel have not been widely compared for the secondary prevention of stroke in carriers of CYP2C19 inactivated alleles
.

method

method

We conducted a randomized, double-blind, placebo-controlled trial in 202 research centers in China.
This trial included patients with mild ischemic stroke or transient ischemic attack (TIA) and carrying the CYP2C19 inactivating allele Patient
.
We randomly divided the patients into groups at a ratio of 1:1 within 24 hours after their onset.
One group received ticagrelor (180 mg on day 1, 90 mg twice a day on days 2 to 90) and chlorine Pidogrel was treated with placebo, and the other group received clopidogrel (300 mg on day 1, 75 mg once a day on days 2 to 90) and ticagrelor placebo; the other two groups received placebo for 21 days Aspirin treatment
.
The main efficacy outcome was a new stroke, and the main safety outcome was severe or moderate bleeding, both of which were assessed for events within 90 days
.

result

result

A total of 11,255 patients were screened, 6412 patients were included in the trial, of which 3205 were assigned to the ticagrelor group and 3207 were assigned to the clopidogrel group
.
The median age of the patients was 64.
8 years old, women accounted for 33.
8%; 98.
0% were Han nationality
.
191 patients (6.
0%) in the ticagrelor group and 243 patients (7.
6%) in the clopidogrel group had a stroke within 90 days (hazard ratio, 0.
77; 95% confidence interval, 0.
64 to 0.
94; P=0.
008)
.
The direction of the secondary outcome is generally the same as the primary outcome
.
Severe or moderate bleeding occurred in 9 patients (0.
3%) in the ticagrelor group and 11 patients (0.
3%) in the clopidogrel group; there were 170 patients (5.
3%) and 80 patients (2.
5%) in the two groups, respectively Bleeding occurred
.

in conclusion

in conclusion

Among Chinese patients with mild ischemic stroke or TIA who carry the CYP2C19 inactivated allele, the 90-day stroke risk after ticagrelor is slightly lower than that of clopidogrel
.
There was no difference in the risk of severe or moderate bleeding between the two groups, but the total number of bleeding events in the ticagrelor group exceeded that in the clopidogrel group
.
(Funded by the Ministry of Science and Technology of the People's Republic of China; CHANCE-2 is registered at ClinicalTrials.
gov as NCT04078737
.
)