Expert consensus on the standardized use of antiplatelet agents in the secondary prevention of ischemic stroke/transient ischemic attack.
A large number of clinical studies have demonstrated the efficacy of antiplatelet therapy in the secondary prevention of ischemic stroke/transient ischemic attack (TIA), and national evidence-based guidelines strongly recommend antiplatelet therapy as a primary measure in the secondary prevention of TIA and will continue to be updated based on new evidence. However, there is still a significant gap between clinical practice and guidelines. First, guideline recommendations are often derived from summaries of evidence from large-scale clinical studies, and sometimes the design of large-scale clinical trials is such that they do not reflect individual risk variability, leaving a discrepancy between clinical practice and guideline adherence. Second, a close reading of the evidence from large-scale clinical studies, especially the results of representative post hoc subgroup analyses, as they reflect individual risk variability, makes the content of guidelines clearer and easier to follow. Hongquan Liu, Brain Center, Jiangsu Provincial Hospital of Integrative Medicine
The 2002 International Antithrombotic Clinical Trials Collaborative Group (ATT) meta-analysis of people with a history of prior ischemic stroke/TIA at a mean of 29 months of onset showed a reduction of (36±6) serious vascular events per 1000 patients treated, including a reduction of (25±5) non-fatal stroke recurrences per 1000 patients treated, with the benefit far outweighing the risk of bleeding. Therefore, for noncardiogenic ischemic stroke, antiplatelet agents are recommended to prevent stroke recurrence and cannot be replaced by any other agents. Studies have shown that the risk of stroke recurrence within 7 d after TIA/mini-stroke is 8-12%, suggesting that stroke prevention in patients with TIA or mini-stroke should be started early. The evidence base for the use of antiplatelet agents in the acute phase comes from the International Stroke Trial (IST) and the China Acute Stroke Trial (CAST). The results of the meta-analysis of these two trials, each comprising approximately 20 000 patients with acute ischemic stroke who were started on aspirin 160 mg/d or 300 mg/d within 48 h of onset, showed a reduction of 7 nonfatal ischemic strokes and 4 deaths per 1000 cases treated, but an increase of 2 bleeding cases, for a net benefit of approximately 1% in the combined analysis. A recent retrospective study confirmed that early initiation of secondary stroke prevention reduced the risk of stroke recurrence by approximately 80% within 90 d in patients with TIA and mini-stroke, with acute management including stroke assessment, antihypertensive therapy, antiplatelet therapy, and carotid endarterectomy. These studies provide evidence that early use of antiplatelet agents can prevent stroke recurrence. A study of 290 patients with TIA in the Oxford Community Planning Study showed that major vascular events remained high 10 years after TIA. An epidemiological study in Beijing showed that the incidence of first or recurrent ischemic stroke increased at an average rate of 8.7% per year from 1984 to 2004, suggesting that antiplatelet agents should be used long-term.
Recommendation 1
1. In patients with non-cardiogenic embolism of ischaemic stroke/TIA (cerebral atherosclerotic, luminal and of unknown etiology), antiplatelet agents are recommended to reduce the risk of recurrent stroke or other vascular events and cannot be replaced by any other drug.
2. Antiplatelet therapy should be initiated as early as possible after ischemic stroke/TIA
3. If there is no contraindication, antiplatelet agents should be used long-term
The following is the main evidence-based evidence for the use of different antiplatelet agents.
1. Aspirin: In numerous different studies with placebo controls, the efficacy of aspirin (50-325 mg/d) in preventing vascular events was 13% (6-19%), and increasing the dose did not increase the efficacy but increased the risk of bleeding. The efficacy of aspirin in preventing stroke recurrence and major vascular events is limited, and there are adverse effects such as gastrointestinal reactions and aspirin asthma, so there is a need to find more effective and safer therapeutic agents.
The European Stroke Prevention Study-2 (ESPS-2) enrolled 6602 patients with ischemic stroke/TIA and demonstrated that the combination of extended-release disopyramide (200 mg) and aspirin (25 mg) (2 times/d) reduced the RR of stroke recurrence by 23% compared with aspirin alone (P=0.006), with no significant increase in bleeding risk. There was no significant increase in the risk of bleeding . Headache was a common adverse effect of the combination of extended-release dipyridamole and aspirin.
3. Clopidogrel: Non-cardiogenic ischemic stroke is not due to the same etiology. Intracranial and extracranial cerebral atherosclerosis occurs at a high frequency of about 40% to 50% in patients with ischemic stroke/TIA in China and is an independent risk factor for recurrent ischemic stroke. Patients with intracranial atherosclerosis have a recurrence rate of ischemic stroke of 12%-24% in year 1 and up to 14%-30% in years 2 and 3 with aspirin or warfarin 13, suggesting that more effective antiplatelet agents should be given to these patients. The Clopidogrel versus Aspirin for the Prevention of Ischemic Events (CAPRIE) study enrolled 19 185 patients with myocardial infarction (MI), ischemic stroke (6431 patients (33.5%) with ischemic stroke events within 1 week to 6 months), or peripheral vascular disease and compared the secondary prevention of clopidogrel (75 mg/d) with that of aspirin (325 mg/d). Clopidogrel was found to be slightly more effective than aspirin, with clopidogrel further reducing ischemic event RR by 8.7% (p=0.043) compared to aspirin, and its overall safety was at least comparable to that of moderate doses of aspirin . A post hoc subgroup analysis showed that in 496 patients with severe ischemic time with MT or ischemic stroke (23.4% of all patients), clopidogrel treatment for 3 years reduced the RR of MI, stroke, or vascular death by 14.9% and the absolute risk (AR) by 3.4% compared with aspirin (P=0.045), suggesting a significant advantage of clopidogrel for symptomatic arterial disease in patients at high risk of recurrence. atherosclerotic patients with a high risk of recurrence . In addition, in diabetic patients, clopidogrel showed a further reduction in MI, stroke events and vascular death (RR11.9%, P=0.042) than aspirin, also showing an advantage. In a newly completed trial of the effectiveness of secondary stroke prevention in 20,332 patients with ischemic stroke/TIA, the study did not meet the prespecified non-inferiority test and the combination of extended-release dipyridamole and aspirin was comparable to clopidogrel in preventing stroke and vascular events. The risk of intracranial hemorrhage was significantly higher with extended-release dipyridamole in combination with aspirin than with clopidogrel (risk ratio 1.42); headache was a common adverse event, thereby reducing patient compliance , and side effects of clopidogrel included gastrointestinal reactions, but were slightly lower than those of aspirin, and ticlopidine, another thienopyridine derivative similar to clopidogrel, also reduced the recurrence of serious vascular events and was superior to Aspirin, but increases the risk of rash and diarrhea, and in particular significantly increases the risk of granulocytopenia .
4. Clopidogrel in combination with aspirin: Combination of aspirin and clopidogrel versus clopidogrel alone after recent ischemic stroke or TIA in high-risk patients (MATCH) study enrolled 7599 patients with recent ischemic stroke or TIA who had at least one of the following risk factors: history of ischemic stroke, MI, angina, diagnosed peripheral arterial disease, or diabetes mellitus. The results showed that the combination of aspirin and clopidogrel did not further reduce the risk of ischemic stroke, MI, vascular death, or rehospitalization compared with clopidogrel alone, but increased the risk of life-threatening or severe bleeding . The Combination of Clopidogrel and Aspirin Compared to Aspirin Alone for Prevention of Atherothrombotic Events (CHARISMA) study enrolled 15,609 patients at high risk for symptomatic vascular disease (coronary heart disease, ischemic stroke, or peripheral arterial disease) or asymptomatic disease and showed that the combination of aspirin and clopidogrel did not further reduce the risk of MI, stroke, or vascular cause of death compared with aspirin alone. risk of death. A subgroup analysis showed that the combination of aspirin and clopidogrel was not superior to aspirin alone in asymptomatic high-risk patients; however, in 12 153 patients with MI, ischemic stroke, or peripheral arterial disease (78% overall, 37% of whom had ischemic stroke or TIA), the combination of aspirin and clopidogrel reduced the RR of MI, ischemic stroke, or vascular death by 12% (p<0.05). The combination of aspirin and clopidogrel decreased the RR of MI, ischemic stroke, or vascular death by 12% (P = 0.04), and there was a significant increase in moderate bleeding, but not in the risk of severe bleeding. These two results tell us that the CHARISMA study showed that adding clopidogrel to aspirin in patients with high-risk ischemic stroke increased efficacy, whereas the MATCH study showed that adding aspirin to clopidogrel in patients with high-risk ischemic stroke did not increase efficacy further. The CAPRIE study has demonstrated that clopidogrel is more effective than aspirin in high-risk patients, and from the overall benefit perspective we can only conclude that clopidogrel should be used in high-risk patients without long-term dual antiplatelet therapy. Plaque vulnerability or artery-to-artery embolism is an important pathogenetic mechanism leading to cerebral atherosclerotic ischemic stroke/TIA, and such patients are at high risk of recurrence. Clinical studies have found that the presence of microembolic signals in cerebral blood flow in patients with carotid and intracranial atherosclerosis is an independent risk factor for ischemic stroke recurrence, especially early recurrence, and that effective and rapid stabilization of plaque to reduce emboli is beneficial in preventing ischemic stroke recurrence. In 107 patients with symptomatic carotid stenosis with microembolic signatures treated with aspirin (75 mg) in combination with clopidogrel (first dose 300 mg and 75 mg/d thereafter) in the CARESS study, the RR of microembolic signatures at 24 h was reduced in the combination group compared with the aspirin group alone The risk of ischemic stroke was reduced by 25.2% at 24 h (P = 0.078) and 37.3% at day 7 (P = 0.011), and the risk of hourly microembolic frequency was reduced by 62.17% at 24 h (P < 0.001) and 61.2% at day 7 (P = 0.001), with a trend toward a reduced risk of ischemic stroke at short-term follow-up and no increased risk of bleeding. The efficacy of clopidogrel in combination with aspirin for the prevention of recurrent events in non-ST-segment elevation acute coronary (coronary) syndromes (CURE) compared with aspirin alone showed a 20.1% reduction in RR of MI, non-fatal stroke and vascular death over 3-12 months of treatment . Randomized controls confirmed that combined aspirin and clopidogrel treatment significantly reduced MI and death events after coronary stenting compared with aspirin alone (OR 0.23, 95% CI 0.11-0.49, P=0.0001).
5. Cilostazol: In a Japanese placebo-controlled study of cilostazol for prevention of ischemic stroke recurrence, an intention-to-treat (ITT) analysis of 1067 patients showed a significant reduction in RR (OR 42.3, 95%, CI: 10.3-62.9, p=0.0127), and no clinically significant adverse drug reactions were found with cilostazol . A recent randomized double-blind controlled study in China with 720 cases confirmed that cilostazol was as effective as aspirin in preventing ischemic stroke, but with a significantly reduced risk of bleeding . However, the sample sizes of both studies were small and further studies with larger sample sizes are needed.
Other: Oral anticoagulants [international normalized ratio (INR) 2.0C3.0] can reduce the risk of recurrent stroke in patients with non-valvular atrial fibrillation (whether permanent, chronic, or paroxysmal) and most other types of cardiogenic embolism, but relatively low doses of antiplatelet agents may be considered for those with contraindications.
Recommendation 2
1. Clopidogrel (75 mg/d), aspirin (50-325 mg/d), and extended-release dipyridamole (200 mg) in combination with aspirin (25 mg) (2 doses/d) may be the antiplatelet agents of choice.
2. Individualized treatment based on the benefits, risks and costs of various antiplatelet agents
3. Prefer clopidogrel (75 mg/d) for atherosclerotic ischemic stroke/TIA and prior history of cerebral infarction, coronary artery disease, diabetes mellitus or peripheral vascular disease
4. In patients with unstable angina, no Q-wave MI or coronary stenting, clopidogrel and aspirin combination (clopidogrel 300mg first dose, 75mg/d thereafter) + aspirin (75-150mg/d) should be given for 9-12 months
5.For recent cerebral artery stenting, clopidogrel 300mg first dose, thereafter clopidogrel (75mg/d) combined with aspirin (75~150mg/d) for 30d, change to clopidogrel alone (75mg/d) for 9~12 months, re-evaluate the risk before deciding the next antiplatelet drug choice (IIa, C).
6. Patients with cardiogenic cerebral embolism who are not amenable to anticoagulation should be given antiplatelet therapy.