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Editor's note: Recently, the 7th European Stroke Organization Conference (ESOC) in 2021 It was successfully held in the form of an online virtual meeting. On September 3rd, Professor R. Al-Shahi Salman announced the 3.5-year follow-up results of the RESTART study, which once again confirmed the safety of restarting antiplatelet therapy after cerebral hemorrhage. The results were simultaneously published online JAMA Neurology .
Anti-platelet therapy is the cornerstone of secondary prevention of ischemic stroke, but how to re-antithrombotic therapy for stroke patients who have suffered cerebral hemorrhage during antithrombotic therapy has been quite controversial. Early initiation of antithrombotic therapy may cause hematoma enlargement and later bleeding recurrence. Should patients with this type of cerebral hemorrhage give up antithrombotic therapy or restart? And when is the best time to restart? These problems have plagued clinicians for a long time. The main venue of the 2019 ESOC Opening Ceremony, Professor Rustam Al-Shahi Salman, University of Edinburgh, UK, published the RESTART (The REstart or STop Antithrombotics Randomised Trial) study, which observed the effect of restarting antiplatelet therapy after bleeding on bleeding recurrence and its prevention The net benefit of vascular occlusion events. The research results were simultaneously published online in LANCET magazine.
ESOC 2019 Professor Rustam Al-Shahi Salman published RESTART
RESTART: Antiplatelet therapy for patients with cerebral hemorrhage after stroke, restart or give up?
research method
RESTART study is a prospective, randomized, open-label, blinded endpoint, parallel controlled trial conducted in 122 hospitals in the UK.Include patients ≥18 years of age with spontaneous intracranial hemorrhage who survived for more than 24 hours, who were receiving antithrombotic therapy (antiplatelet or anticoagulation therapy) to prevent occlusive vascular disease when cerebral hemorrhage occurred, and antithrombotic therapy was terminated after cerebral hemorrhage occurred . Participants were randomly assigned to the two groups with or without antiplatelet therapy at a ratio of 1:1. The primary endpoint is fatal or non-fatal recurrent symptomatic intracranial hemorrhage, and the secondary endpoint is the composite endpoint of all major bleeding events and major occlusive vascular events.
study results
From May 22, 2013 to May 31, 2018, a total of 537 patients who were receiving antithrombotic therapy at the time of cerebral hemorrhage occurred were enrolled. The median value from cerebral hemorrhage to randomization The time is 76 days. The average age is 72 years old, predominantly white (92%). 62% of the participants had cerebral hemorrhage, 88% of the participants had at least one ischemic event in the past, and 3/4 of the participants had a history of hypertension.
From the Kaplan-Meier survival analysis model, for the primary endpoint, the antiplatelet therapy group has a tendency to reduce the recurrence of symptomatic intracerebral hemorrhage (sICH) but there is no significant statistical significance [12 (4%) vs. 23 (9%) ), aHR 0.51 (95% CI: 0.25 to 1.03); P=0.060, Figure 1], a composite secondary endpoint, initiation of antiplatelet therapy seems to reduce non-fatal myocardial infarction, non-fatal stroke (ischemic, The incidence of hemorrhagic or unexplained) or vascular death (aHR 0.65, 95% CI: 0.44 to 0.95, P = 0.025).
Figure 1 KM curve of the first recurrent symptomatic intracerebral hemorrhage during follow-up
Primary endpoint subgroup analysis, non-lobe hemorrhage initiated antithrombotic therapy can reduce sICH events by 69%, but lobe hemorrhage did not Increased the risk of sICH recurrence [0.75 (0.30~1.87)], and there was no interaction between the bleeding site and antiplatelet therapy (Figure 2).
Figure 2 Preset subgroup analysis of the risk of first recurrent symptomatic intracranial hemorrhage Hemorrhage (CMB) site (brain lobe vs. other sites),The correlation between the number (0~1 vs. 2~4 vs. ≥5) and stroke recurrence. A total of 254 (48%) participants in this imaging subgroup underwent MRI before randomization (122 in the antiplatelet group vs. 132 in the control group), and the median time from onset to MRI was 55 days. 40% had cerebral hemorrhage, 93 cases (40%) had ≥2 CMB, 62 cases (26%) had ≥5 CMB; 47 cases (20%) were likely to have cerebral amyloid angiopathy (CAA), 30 cases (13%) were possible CAA.
subgroup analysis found that CMB significantly increased the risk of stroke recurrence [sICH: HR=3.62 (95% CI 1.34~9.79); ischemic stroke: HR 1.92 (0.83~4.46)], and the number of CMB was linear with stroke recurrence Related, this is similar to previous observational studies. However, antiplatelet therapy does not increase the risk of the main outcome associated with CMB cerebral hemorrhage. There was no interaction between antiplatelet therapy and the number and location of CMB (all P interaction>0.05). In addition, antiplatelet application did not increase the risk of recurrence of cerebral hemorrhage accompanied by CAA.
RESTART imaging subgroup analysis results show the safety of antiplatelet therapy for secondary prevention with CMB. This seems to mean that antiplatelet therapy should be safe in patients with CMB. Given that the risk of ischemic recurrence of CMB is significantly higher than the risk of hemorrhage recurrence, the safety and effectiveness of antithrombotic drugs for the secondary prevention of cerebral hemorrhage with CMB deserve to be further confirmed by large sample RCT studies.
After two years, the RESTART study extended follow-up results announced
In order to monitor compliance, increase follow-up time, and improve the accuracy of the evaluation of the impact of antiplatelet therapy on recurrent intracranial hemorrhage and major vascular events, the investigator is right The follow-up of the RESTART study was extended to 7 years.
In this randomized clinical trial, after the initial follow-up ended on November 30, 2018, the annual follow-up was extended to November 30, 2020, with 537 participants [median age, 76.0 years; 360 (67.0%) Male; median time after onset of ICH,The median total follow-up time of 76.0 days] was 3.0 years (interquartile range, 2.0 to 5.0 years).
The proportion of recurrent cerebral hemorrhage in the antiplatelet therapy group (n=268) was 22 (8.2%), and the proportion of the antiplatelet therapy group [n=269 (1 person withdrew)] was 25 (9.3) %), no significant difference (aHR, 0.87; 95% CI: 0.49~1.55; P = 0.64). There was no significant difference in the incidence of major vascular events between the antiplatelet therapy group and the non-antiplatelet therapy group (26.8% vs. 32.5%, HR=0.79; 95% CI: 0.58~1.08; P = 0.14 ). (Table 1, Figure 3)
Table 1 The risk of the first major and secondary end points during the extended follow-up period
Figure 3 A: Risk of first occurrence of recurrent symptomatic cerebral hemorrhage; B: First occurrence of major blood vessels The risk of the event
Limitations
RESTART study sample size and the number of results are too small to be determined. Most participants are men. Adherence to assigned treatment declined over time, but even after up to 5 years of follow-up, adherence still exceeded 80% and appeared to be unaffected by the announcement of the primary endpoint. Some secondary composite endpoints, such as venous thromboembolism, may not be affected by antiplatelet therapy. Antiplatelet therapy mainly reduces the risk of occlusive arterial events by reducing platelet activation and aggregation. This mechanism may explain the early effects of antiplatelet therapy. It can be observed in major vascular events, but has no effect on other composite endpoints (Table 1). In addition, the general applicability of the findings to other populations is unclear.
These findings, together with published observational studies, provide a guarantee for the use of long-term antiplatelet therapy and antithrombotic therapy after intracranial hemorrhage. Since the publication of the main results of RESTART, the stroke guidelines have recommended that “for patients with indications for continuous antiplatelet therapy, it is reasonable to restart antiplatelet therapy (evidence level B).” However,During the long-term follow-up period after the announcement of the main results, no changes in participant compliance were observed. Therefore, patients and guidelines still need stronger and more definite evidence to change clinical practice.
Larger randomized clinical trials are needed to explore several existing problems of antiplatelet therapy after ICH, including whether the overall reduction of major vascular events after ICH is similar to that of non-ICH patients; the time after ICH and the effect of antiplatelet therapy Whether the duration will change these effects; whether the effects are different in other subgroups; whether antiplatelet therapy is beneficial to ICH survivors who have not previously used antithrombotic drugs or have not had a major vascular event.
Conclusion
After the final extended follow-up of the only published randomized clinical trial of antiplatelet therapy after ICH, no statistically significant risk of recurrent ICH or risk of major vascular events after restarting antiplatelet therapy was found A significant increase. If this program is to be used for secondary prevention of major vascular events , this discovery may provide some assurance for clinicians to use antiplatelet therapy after ICH.
▼References
[1] Al-Shahi Salman R, Murray GD, Dennis MS, et al. The REstart or STop Antithrombotics Randomised Trial (RESTART) after stroke due to intracerebral haemorrhage: statistical analysis plan for a randomised controlled trial. Trials. 2019;20(1):183. doi:10.1186/s13063-019-3270-2
[2] Al-Shahi Salman R, Dennis MS, Murray GD, et al; RESTART collaborators. The REstart or STop Antithrombotics Randomised Trial (RESTART) after stroke due to intracerebral haemorrhage: study protocol for a randomised controlled trial. Trials. 2018;19(1):162. doi:10.1186/s13063-018-2542-6
[3 ] RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet. 2019;393(10191):2613-2623. doi:10. 1016/S0140-6736(19 )30840-2
[4] Al-Shahi Salman R, Minks DP, Mitra D, et al; RESTART Collaboration. Effects of antiplatelet therapy on stroke risk by brain i maging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial. Lancet Neurol. 2019; 18(7):643-652. doi:10.1016/S1474-4422(19)30184- X
[5] RESTART Trial. Accessed August 17, 2021. http://www.RESTARTtrial.org
[6] Al-Shahi Salman R, Dennis MS,Sandercock PAG, et al.Effects of antiplatelet therapy after stroke caused by intracerebral hemorrhage:extended follow-up of the RESTART randomized clinical trial.JAMA Neurol. Published online September 3, 2021. doi:10.1001/jamaneurol.2021.2956
(Source: Editorial Department of "International Circulation")
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