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The New England Journal of Medicine (NEJM) published today officially published the CHANCE-2 study led by Professor Wang Yongjun from Beijing Tiantan Hospital, Capital Medical University
.
"NEJM Frontiers of Medicine" specially invited James Grotta, director of stroke research at Memorial Hermann Hospital and neurologist, to write a review to interpret the significance of CHANCE-2 research and related clinical issues that still need to be explored
.
Grotta, as the first and corresponding author, published a clinical study on the role of mobile stroke unit in first aid for patients with acute ischemic stroke in the NEJM published on September 9 this year (see related reading at the end of the article for details)
.
James C Grotta Stroke Research and Mobile Stroke Unit Memorial Hermann Hospital, Texas Medical Center has relied on aspirin for decades.
By combining aspirin with clopidogrel, recurrent strokes in high-risk patients have been drastically reduced in the past few years
.
Much of this progress stems from research conducted in China
.
In China, the incidence of stroke and recurrent stroke is an important public health issue, and China has a large amount of infrastructure needed to conduct multi-center clinical trials [1-3]
.
However, the "fault" is that most Asian patients do not genetically have the ability to convert clopidogrel into its active metabolite [4]
.
The mechanism of ticagrelor is similar to clopidogrel, but does not require metabolic activation, so it is a reasonable solution to this problem
.
However, for patients with cardiovascular disease who do not carry cytochrome p450 (CYP) alleles and therefore do not have the ability to metabolize clopidogrel, using ticagrelor instead of clopidogrel has obtained conflicting results [5-7], and Ticagrelor may increase bleeding complications [8-10]
.
In this context, the CHANCE-2 study [11] published by NEJM in the New England Journal of Medicine on December 30, 2021 provides clinicians with long-awaited and very important clear results
.
For Chinese Han patients who carry at least one CYP inactivated allele and start treatment within 24 hours after the onset of non-cardiogenic high-risk TIA or mild stroke, patients who receive aspirin combined with ticagrelor within 90 days The recurrence rate of stroke (6% vs.
7.
6%; hazard ratio, 0.
77; 95% CI, 0.
64 to 0.
94) was lower than that of patients receiving aspirin combined with clopidogrel, and the incidence of severe bleeding in the former did not increase (both groups Both are 0.
3%)
.
Previous studies have shown that the above-mentioned dual antiplatelet therapy has the most obvious benefit during the first 21 days, and continued medication afterwards will only increase the risk of bleeding [1,9], so both groups discontinued aspirin after 21 days
.
Importantly, this test has observed positive results in patients with 1 (intermediate metabolizer) and 2 (slow metabolizer) CYP alleles
.
Figure 1.
Cumulative incidence of stroke [11] These results are of great significance.
As to whether clinical practice applied to a large number of patients should be changed accordingly, the answer is yes
.
In China, stroke is the leading cause of death and disability, and 60% of Asians carry 1 or 2 CYP alleles
.
In addition, on the basis of previous studies on patients with TIA and mild stroke [1,9,10], the results of the CHANCE-2 study confirmed that in patients without obvious cardiogenic embolism, the pathogenesis of recurrent stroke is Sensitive to higher-intensity antiplatelet therapy
.
This is especially true for patients with a heavier burden of intracranial or extracranial atherosclerosis [12]
.
Although not studied in CHANCE-2, the additional benefits of ticagrelor compared to clopidogrel may be greater in this population
.
We can also use further genetic studies to more accurately determine the Asian stroke patients who benefit the most from the use of ticagrelor instead of clopidogrel
.
The genetic characteristics of CYP studied in CHANCE-2 may only lead to partial clinical efficacy differences after clopidogrel administration [13]
.
Table 1.
Efficacy and safety outcomes [11] Before deciding whether to use ticagrelor and which patients should use ticagrelor, there are still some obstacles and practical problems that need to be resolved
.
Point-of-care genotyping is not universal, and its cost is uncertain.
In addition, the market price comparison of ticagrelor and clopidogrel is also uncertain
.
Therefore, a cost-benefit analysis is required
.
This type of analysis should not only compare the use of clopidogrel in each patient with the selection of ticagrelor or clopidogrel based on the results of the genotype test, but also compare the routine use of clopidogrel with routine use of ticagrelor (both groups are not Perform genotype testing)
.
Although the additional benefits of ticagrelor compared with clopidogrel may be small without genotype selection, in all eligible Asian patients with TIA or stroke, ticagrelor is used directly instead of chlorine The only disadvantage of Pidogrel is the increased cost of the drug because the risk has not increased, and most people in this population are genetically resistant to clopidogrel
.
We do not yet know whether these results are applicable to people other than Asians
.
A large-scale international study compared aspirin combined with ticagrelor and aspirin monotherapy in similar patients (including 43% of Asians)
.
The study showed that there was no difference between the results of Asian patients and patients other than Asians
.
However, although the incidence of recurrent ischemic events of ticagrelor is slightly lower, this advantage is offset by the increase in the incidence of severe bleeding, but the incidence of severe bleeding is still very low (0.
5%) [10]
.
In the previous stroke secondary prevention study of clopidogrel combined with aspirin, which mainly included patients other than Asians, the dual antiplatelet therapy group (0.
9%) had an increase in severe bleeding compared with the aspirin monotherapy group (0.
4%) The amplitude is similar [9]
.
Therefore, for people other than Asians, given that only a small number of patients carry inactivated alleles, the benefit-risk ratio of ticagrelor combined with aspirin may not be excellent, and it is not very attractive as an alternative to clopidogrel
.
In view of the above considerations, before extrapolating CHANCE-2 results outside of Asia, it is necessary to compare the benefits, risks, and costs of aspirin combined with ticagrelor and aspirin combined with clopidogrel in other populations outside of Asia
.
In short, CHANCE-2 provides important new data, which will undoubtedly change the treatment of high-risk TIA and mild stroke patients in Asia, and promote further analysis and research on a global scale
.
References 1.
Wang Y, Wang Y, Zhao X, et al.
Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.
N Engl J Med 2013;369:11-19.
2.
Wang Y, Chen W, Lin Y, et al.
Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet reactivity in patients with minor stroke or transient ischaemic attack: Open label, blinded endpoint, randomised controlled phase II trial.
BMJ 2019;365:l2211.
3.
Wang Y, Zhao X, Lin J, 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;316:70-78.
4.
Pan Y, Chen W, Xu Y, et al.
Genetic polymorphisms and clopidogrel efficacy for acute ischemic stroke or transient ischemic attack: a systematic review and meta-analysis.
Circulation 2017;135:21-33.
5.
Notarangelo FM, Maglietta G,Bevilacqua P, et al.
Pharmacogenomic approach to selecting antiplatelet therapy in patients with acute coronary syndromes: the PHARMCLO trial.
J Am Coll Cardiol 2018;71:1869-1877.
6.
Claassens DMF, Vos GJA, Bergmeijer TO, et al.
A genotype- guided strategy for oral P2Y12 inhibitors in primary PCI.
N Engl J Med 2019;381:1621-1631.
7.
Pereira NL, Farkouh ME, So D, et al.
Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial.
JAMA 2020;324:761-771.
8.
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.
9.
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.
10.
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.
11.
Wang Y, Meng X, Wang A et al.
Ticagrelor versus clopidogrel in CYP2C19 loss-of-function carriers with stroke or TIA.
N Engl J Med 2021;385:2520-30.
12.
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.
13.
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.
Copyright information draftTicagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA.
N Engl J Med 2020;383:207-217.
11.
Wang Y, Meng X, Wang A et al.
Ticagrelor versus clopidogrel in CYP2C19 loss-of-function carriers with stroke or TIA.
N Engl J Med 2021;385:2520-30.
12.
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.
13 .
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.
Copyright information -Med) and the New England Journal of Medicine (NEJM) jointly created "NEJM Frontiers in Medicine" translation, writing or commissioningTicagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA.
N Engl J Med 2020;383:207-217.
11.
Wang Y, Meng X, Wang A et al.
Ticagrelor versus clopidogrel in CYP2C19 loss-of-function carriers with stroke or TIA.
N Engl J Med 2021;385:2520-30.
12.
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.
13 .
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.
Copyright information -Med) and the New England Journal of Medicine (NEJM) jointly created "NEJM Frontiers in Medicine" translation, writing or commissioningDenison 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.
13.
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.
Copyright information NEJM Frontiers in Medicine Translation, writing or manuscriptDenison 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.
13.
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.
Copyright information NEJM Frontiers in Medicine Translation, writing or manuscript
.
The Chinese translation of the full text and the included diagrams are exclusively authorized by the NEJM Group
.
If you need to reprint, please leave a message or contact nejmqianyan@nejmqianyan.
cn
.
Unauthorized translation is an infringement, and the copyright owner reserves the right to pursue legal liabilities
.
.
"NEJM Frontiers of Medicine" specially invited James Grotta, director of stroke research at Memorial Hermann Hospital and neurologist, to write a review to interpret the significance of CHANCE-2 research and related clinical issues that still need to be explored
.
Grotta, as the first and corresponding author, published a clinical study on the role of mobile stroke unit in first aid for patients with acute ischemic stroke in the NEJM published on September 9 this year (see related reading at the end of the article for details)
.
James C Grotta Stroke Research and Mobile Stroke Unit Memorial Hermann Hospital, Texas Medical Center has relied on aspirin for decades.
By combining aspirin with clopidogrel, recurrent strokes in high-risk patients have been drastically reduced in the past few years
.
Much of this progress stems from research conducted in China
.
In China, the incidence of stroke and recurrent stroke is an important public health issue, and China has a large amount of infrastructure needed to conduct multi-center clinical trials [1-3]
.
However, the "fault" is that most Asian patients do not genetically have the ability to convert clopidogrel into its active metabolite [4]
.
The mechanism of ticagrelor is similar to clopidogrel, but does not require metabolic activation, so it is a reasonable solution to this problem
.
However, for patients with cardiovascular disease who do not carry cytochrome p450 (CYP) alleles and therefore do not have the ability to metabolize clopidogrel, using ticagrelor instead of clopidogrel has obtained conflicting results [5-7], and Ticagrelor may increase bleeding complications [8-10]
.
In this context, the CHANCE-2 study [11] published by NEJM in the New England Journal of Medicine on December 30, 2021 provides clinicians with long-awaited and very important clear results
.
For Chinese Han patients who carry at least one CYP inactivated allele and start treatment within 24 hours after the onset of non-cardiogenic high-risk TIA or mild stroke, patients who receive aspirin combined with ticagrelor within 90 days The recurrence rate of stroke (6% vs.
7.
6%; hazard ratio, 0.
77; 95% CI, 0.
64 to 0.
94) was lower than that of patients receiving aspirin combined with clopidogrel, and the incidence of severe bleeding in the former did not increase (both groups Both are 0.
3%)
.
Previous studies have shown that the above-mentioned dual antiplatelet therapy has the most obvious benefit during the first 21 days, and continued medication afterwards will only increase the risk of bleeding [1,9], so both groups discontinued aspirin after 21 days
.
Importantly, this test has observed positive results in patients with 1 (intermediate metabolizer) and 2 (slow metabolizer) CYP alleles
.
Figure 1.
Cumulative incidence of stroke [11] These results are of great significance.
As to whether clinical practice applied to a large number of patients should be changed accordingly, the answer is yes
.
In China, stroke is the leading cause of death and disability, and 60% of Asians carry 1 or 2 CYP alleles
.
In addition, on the basis of previous studies on patients with TIA and mild stroke [1,9,10], the results of the CHANCE-2 study confirmed that in patients without obvious cardiogenic embolism, the pathogenesis of recurrent stroke is Sensitive to higher-intensity antiplatelet therapy
.
This is especially true for patients with a heavier burden of intracranial or extracranial atherosclerosis [12]
.
Although not studied in CHANCE-2, the additional benefits of ticagrelor compared to clopidogrel may be greater in this population
.
We can also use further genetic studies to more accurately determine the Asian stroke patients who benefit the most from the use of ticagrelor instead of clopidogrel
.
The genetic characteristics of CYP studied in CHANCE-2 may only lead to partial clinical efficacy differences after clopidogrel administration [13]
.
Table 1.
Efficacy and safety outcomes [11] Before deciding whether to use ticagrelor and which patients should use ticagrelor, there are still some obstacles and practical problems that need to be resolved
.
Point-of-care genotyping is not universal, and its cost is uncertain.
In addition, the market price comparison of ticagrelor and clopidogrel is also uncertain
.
Therefore, a cost-benefit analysis is required
.
This type of analysis should not only compare the use of clopidogrel in each patient with the selection of ticagrelor or clopidogrel based on the results of the genotype test, but also compare the routine use of clopidogrel with routine use of ticagrelor (both groups are not Perform genotype testing)
.
Although the additional benefits of ticagrelor compared with clopidogrel may be small without genotype selection, in all eligible Asian patients with TIA or stroke, ticagrelor is used directly instead of chlorine The only disadvantage of Pidogrel is the increased cost of the drug because the risk has not increased, and most people in this population are genetically resistant to clopidogrel
.
We do not yet know whether these results are applicable to people other than Asians
.
A large-scale international study compared aspirin combined with ticagrelor and aspirin monotherapy in similar patients (including 43% of Asians)
.
The study showed that there was no difference between the results of Asian patients and patients other than Asians
.
However, although the incidence of recurrent ischemic events of ticagrelor is slightly lower, this advantage is offset by the increase in the incidence of severe bleeding, but the incidence of severe bleeding is still very low (0.
5%) [10]
.
In the previous stroke secondary prevention study of clopidogrel combined with aspirin, which mainly included patients other than Asians, the dual antiplatelet therapy group (0.
9%) had an increase in severe bleeding compared with the aspirin monotherapy group (0.
4%) The amplitude is similar [9]
.
Therefore, for people other than Asians, given that only a small number of patients carry inactivated alleles, the benefit-risk ratio of ticagrelor combined with aspirin may not be excellent, and it is not very attractive as an alternative to clopidogrel
.
In view of the above considerations, before extrapolating CHANCE-2 results outside of Asia, it is necessary to compare the benefits, risks, and costs of aspirin combined with ticagrelor and aspirin combined with clopidogrel in other populations outside of Asia
.
In short, CHANCE-2 provides important new data, which will undoubtedly change the treatment of high-risk TIA and mild stroke patients in Asia, and promote further analysis and research on a global scale
.
References 1.
Wang Y, Wang Y, Zhao X, et al.
Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.
N Engl J Med 2013;369:11-19.
2.
Wang Y, Chen W, Lin Y, et al.
Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet reactivity in patients with minor stroke or transient ischaemic attack: Open label, blinded endpoint, randomised controlled phase II trial.
BMJ 2019;365:l2211.
3.
Wang Y, Zhao X, Lin J, 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;316:70-78.
4.
Pan Y, Chen W, Xu Y, et al.
Genetic polymorphisms and clopidogrel efficacy for acute ischemic stroke or transient ischemic attack: a systematic review and meta-analysis.
Circulation 2017;135:21-33.
5.
Notarangelo FM, Maglietta G,Bevilacqua P, et al.
Pharmacogenomic approach to selecting antiplatelet therapy in patients with acute coronary syndromes: the PHARMCLO trial.
J Am Coll Cardiol 2018;71:1869-1877.
6.
Claassens DMF, Vos GJA, Bergmeijer TO, et al.
A genotype- guided strategy for oral P2Y12 inhibitors in primary PCI.
N Engl J Med 2019;381:1621-1631.
7.
Pereira NL, Farkouh ME, So D, et al.
Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial.
JAMA 2020;324:761-771.
8.
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.
9.
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.
10.
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.
11.
Wang Y, Meng X, Wang A et al.
Ticagrelor versus clopidogrel in CYP2C19 loss-of-function carriers with stroke or TIA.
N Engl J Med 2021;385:2520-30.
12.
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.
13.
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.
Copyright information draftTicagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA.
N Engl J Med 2020;383:207-217.
11.
Wang Y, Meng X, Wang A et al.
Ticagrelor versus clopidogrel in CYP2C19 loss-of-function carriers with stroke or TIA.
N Engl J Med 2021;385:2520-30.
12.
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.
13 .
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.
Copyright information -Med) and the New England Journal of Medicine (NEJM) jointly created "NEJM Frontiers in Medicine" translation, writing or commissioningTicagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA.
N Engl J Med 2020;383:207-217.
11.
Wang Y, Meng X, Wang A et al.
Ticagrelor versus clopidogrel in CYP2C19 loss-of-function carriers with stroke or TIA.
N Engl J Med 2021;385:2520-30.
12.
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.
13 .
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.
Copyright information -Med) and the New England Journal of Medicine (NEJM) jointly created "NEJM Frontiers in Medicine" translation, writing or commissioningDenison 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.
13.
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.
Copyright information NEJM Frontiers in Medicine Translation, writing or manuscriptDenison 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.
13.
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.
Copyright information NEJM Frontiers in Medicine Translation, writing or manuscript
.
The Chinese translation of the full text and the included diagrams are exclusively authorized by the NEJM Group
.
If you need to reprint, please leave a message or contact nejmqianyan@nejmqianyan.
cn
.
Unauthorized translation is an infringement, and the copyright owner reserves the right to pursue legal liabilities
.
