Acute dual antiplatelet therapy for minor ischaemic stroke or transient ischaemic attackBMJ 2019; 364 doi: https://doi.org/10.1136/bmj.l895 (Published 28 February 2019) Cite this as: BMJ 2019;364:l895
- Yongjun Wang, professor1234,
- S Claiborne Johnston, professor5,
- Philip M Bath, professor6,
- James C Grotta, professor7,
- Yuesong Pan, researcher1234,
- Pierre Amarenco, professor8,
- Yilong Wang, professor1234,
- Tabassome Simon, professor91011,
- Jong Sung Kim, professor12,
- Jiann-Shing Jeng, professor13,
- Liping Liu, professor1234,
- Yi Lin, associate professor14,
- Ka Sing Lawrence Wong, professor15,
- David Wang, professor1617,
- Hao Li, professor1234
- 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- 2China National Clinical Research Center for Neurological Diseases, Beijing, China
- 3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- 4Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- 5Dean’s Office, Dell Medical School, University of Texas at Austin, Austin, TX, USA
- 6Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK
- 7Clinical Innovation and Research Institute, Memorial Hermann Hospital, Houston, TX, USA
- 8Department of Neurology and Stroke Center, Bichat University Hospital and Paris-Diderot, Sorbonne University, Paris, France
- 9Department of Clinical Pharmacology and Clinical Research Platform of East of Paris, Assistance Publique-Hôpitaux de Paris, Paris, France
- 10Department of Clinical Pharmacology, Sorbonne Université, Paris, France
- 11French Alliance for Cardiovascular Clinical Trials, Paris, France
- 12Department of Neurology, University of Ulsan, Asan Medical Center, Seoul, South Korea
- 13Department of Neurology and Stroke Center, National Taiwan University Hospital, Taipei, Taiwan
- 14Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- 15Division of Neurology, Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
- 16Illinois Neurological Institute Stroke Network, OSF Healthcare System, Peoria, IL, USA
- 17Department of Neurology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
- Correspondence to: Yongjun Wang
Recent research on antiplatelet therapy has advanced the knowledge of early, intensive treatment for recurrent stroke in minor ischaemic stroke or transient ischaemic attack
In patients with high risk, non-disabling ischaemic cerebrovascular events, including minor stroke and transient ischaemic attack, short term dual antiplatelet therapy should be given within 24 hours after the onset of symptoms and as early as possible
Further studies are needed to evaluate antiplatelet strategies, explore whether dual antiplatelet therapy could benefit broader patient population, and improve adherence of the recommended antiplatelet therapy
The risk of recurrent stroke and other vascular events is high in the first few weeks after index minor ischaemic stroke and high risk transient ischaemic attack (5-11.7%).12 Dual antiplatelet therapy (DAPT), comprising clopidogrel and aspirin, is an effective strategy for reducing recurrence.1 An expert panel from the MAGIC group (http://magicproject.org/) recently produced a strong rapid recommendation in The BMJ for starting DAPT within 24 hours of symptom onset and continuing for 10-21 days in patients with minor stroke or transient ischaemic attack.3 The evidence for this came from a systematic review and meta-analysis of published clinical trials.4 Most current international guidelines,5678 but not all,9 recommend early (within 24 hours) and short term (a duration of 21 days or 21-30 days) DAPT in patients with minor stroke or transient ischaemic attack (table 1).
Questions remain regarding choice of antiplatelet strategy, possibility of safe expansion of DAPT to a broader patient population, and adherence of patients to recommended antiplatelet therapy in clinical practice.
In the past five years, trials on acute antiplatelet treatment have focused on evaluating the efficacy and safety of more intensive treatment to prevent recurrent stroke after minor ischaemic stroke or high risk transient ischaemic attack. These include dual therapy versus monotherapy,12 triple versus dual antiplatelet treatment,10 and a potentially more potent agent (ticagrelor) compared with aspirin alone (table 2).111213 The findings of these studies have greatly advanced the antiplatelet strategy for secondary prevention of stroke in patients with minor ischaemic stroke or transient ischaemic attack.
Treatment population for DAPT
Patients who have a minor stroke or a transient ischaemic attack are at high risk of developing thrombosis and having ischaemic brain damage that could increase their risk of bleeding.1214 More intensive antiplatelet therapy could be effective and safe in these patients. The CHANCE and POINT trials compared the efficacy and safety of DAPT with clopidogrel plus aspirin against aspirin alone in patients with minor stroke (National Institutes of Health Stroke Scale (NIHSS) ≤3) or high risk transient ischaemic attack (ABCD2 score ≥4). The primary results from CHANCE1 and secondary analysis from POINT15 show that up to 21 days of dual antiplatelet therapy were both effective and safe (table 2), indicating that patients with minor stroke or high risk transient ischaemic attack are suitable for dual antiplatelet therapy with clopidogrel plus aspirin.
Time window of starting antiplatelet therapy
Approximately 75-80% of recurrent strokes occur in the first two weeks after onset of the index stroke or transient ischaemic attack.12 Almost all guidelines recommend that antiplatelet therapy be given as soon as possible after the diagnosis of an ischaemic event. Five of the recent trials included patients that started treatment within 24 hours (table 2).12111213 Exploratory analysis of the TARDIS trial showed that intensive triple antiplatelet therapy could significantly reduce recurrence after mild stroke or transient ischaemic attack, or minor stroke alone, if started within 24 hours, but not if started after 24 hours (PM Bath, personal communication). This further supports the consensus that antiplatelet therapy should be given as soon as possible within 24 hours.
Duration of dual antiplatelet therapy
Risk of bleeding is the main harm of intensive dual or triple antiplatelet therapy. The CHANCE and POINT trials showed similar efficacy of DAPT with up to ~30% reduction of recurrent stroke (table 2), but the POINT trial also showed a 2.3-fold increase in the risk of major haemorrhage in the DAPT group compared with aspirin alone (P=0.02), whereas the CHANCE trial did not (P=0.73).12 This discrepancy is not completely understood, but a longer duration of DAPT (90 days in the POINT trial versus 21 days in the CHANCE trial) may be the explanation.16 A secondary time course analysis of the POINT trial provided further supportive evidence for the recent rapid recommendation.315 But more systematic studies are needed to determine how to choose the duration of DAPT more precisely—between 10 and 21 days in clinical practice.
Although DAPT with clopidogrel and aspirin is an effective strategy for secondary stroke prevention, some patients fail to respond. DAPT is not effective in patients with lacunar strokes,17 but is potent in patients with multiple acute infarctions or ipsilateral atherosclerotic stenosis.1819 Further studies are needed to thoroughly examine the effects of antiplatelet treatment on minor stroke or transient ischaemic attack with different causes and to identify those who will respond well.
Pharmacogenetics may also play an important role. A few genetic polymorphisms have been identified that might influence the metabolism of clopidogrel, which is a pro-drug that requires biotransformation to become an active metabolite and exert its effect.20 Carriers of the CYP2C19 loss of function alleles are less likely to benefit from clopidogrel.20 Although not recommended in current clinical practice, genetic testing may be considered to personalise antiplatelet therapy, especially in Asian populations, which have high prevalence of the CYP2C19 loss of function allele. Escalation of clopidogrel dosages or considering new antiplatelet agents (such as ticagrelor) could be alternatives for those carriers with CYP2C19 loss of function alleles. The efficacy, feasibility, and cost effectiveness of treatment for patients with minor stroke or transient ischaemic attack based on genetic testing requires further evaluation through randomised controlled trials.
The CHANCE trial and secondary data of POINT have shown that short term usage of dual antiplatelet therapy further reduced up to ~30% of recurrent stroke without increased major bleeding compared with aspirin alone. Clinicians and researchers are eager to know whether dual antiplatelet therapy can benefit a broader population of patients who are at high risk of new stroke. The SOCRATES trial implied that the patient population at slightly more severe risk (NIHSS ≤5) also benefited from ticagrelor compared with aspirin in reducing recurrent stroke as the secondary efficacy outcome (table 2).11 A recent meta-analysis indicated that DAPT was associated with reduced stroke recurrence among patients with acute non-cardioembolic ischaemic stroke or TIA when started within three days of ictus.21 DAPT might also be effective with acceptable safety in broader patient populations, such as those with more severe stroke (NIHSS 4-5) or in an expanded time window (within 72 hours of symptom onset). These matters need further evaluation in randomised controlled trials.
Whether a treatment is effective will eventually be influenced by patients’ adherence. Although short term DAPT was shown to be safe in patients with minor stroke or high risk transient ischaemic attack, concerns still exist for bleeding risk in clinical practice. Secondary analysis of the CHANCE trial showed that DAPT may increase the risk of non-intracranial haemorrhage in patients with minor strokes.22 Mild bleeding, such as skin bruises and gum bleeding, could influence physicians’ decisions and patients’ adherence to antiplatelet therapy. Further research is needed to improve adherence.
In summary, DAPT should be started as soon as possible within 24 hours of minor ischaemic stroke or high risk transient ischaemic attack and should be continued up to 21 days. The 21st day is the possible trade-off point to balance treatment effect and bleeding risk. Further studies are needed to evaluate novel and more precise antiplatelet therapy after minor ischaemic stroke and transient ischaemic attack.
Contributors and sources: YJW, SCJ, PMB, JCG, PA, YLW, JSK, JSJ, LPL, YL, KSL, and DW are experts in clinical research on stroke and transient ischaemic attack. TS is an expert in clinical pharmacology and pharmacogenetics in cardiovascular disease. YSP and HL have expertise in clinical research methodology and clinical research on stroke. This article arose from The BMJ’s roundtable discussion on antiplatelet therapy in ischaemic stroke and transient ischaemic attack on 7 December 2018. YJW is the guarantor.
Competing interests: We have read and understood BMJ policy on declaration of interests and declare that the study was supported by grants from the Ministry of Science and Technology of the People’s Republic of China (2016YFC0901001, 2016YFC0901002, 2017YFC1310901, 2018YFC1311700 and 2018YFC1311706), and grants from Beijing Municipal Commission of Health and Family Planning (No 2016-1-2041, SML20150502).
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.