Timing of Antiplatelet Resumption After Intracerebral Hemorrhage: A Sophie’s Choice

HomeStrokeVol. 54, No. 2Timing of Antiplatelet Resumption After Intracerebral Hemorrhage: A Sophie’s Choice Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTiming of Antiplatelet Resumption After Intracerebral Hemorrhage: A Sophie’s Choice Pargol Balali, Aristeidis H. Katsanos and Ashkan Shoamanesh Pargol BalaliPargol Balali https://orcid.org/0000-0002-5895-577X Division of Neurology, Department of Medicine, McMaster University/Population Health Research Institute, Hamilton, Canada. Search for more papers by this author , Aristeidis H. KatsanosAristeidis H. Katsanos https://orcid.org/0000-0002-6359-0023 Division of Neurology, Department of Medicine, McMaster University/Population Health Research Institute, Hamilton, Canada. Search for more papers by this author and Ashkan ShoamaneshAshkan Shoamanesh Correspondence to: Ashkan Shoamanesh, MD, Associate Professor of Medicine (Neurology) Marta and Owen Boris Chair in Stroke Research and Care, Director of the Hemorrhagic Stroke Research Program, McMaster University/Population Health Research Institute Hamilton, ON, Canada. Email E-mail Address: ashkan.shoamanesh@phri https://orcid.org/0000-0002-2802-1626 Division of Neurology, Department of Medicine, McMaster University/Population Health Research Institute, Hamilton, Canada. Search for more papers by this author Originally published9 Jan 2023https://doi.org/10.1161/STROKEAHA.122.041466Stroke. 2023;54:546–548This article is a commentary on the followingEarly Antiplatelet Resumption and the Risks of Major Bleeding After Intracerebral HemorrhageOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 9, 2023: Ahead of Print One of the key tenets of secondary prevention of intracerebral hemorrhage (ICH) is the avoidance of offending agents. However, this principle is simpler in theory than in practice as patients with ICH often necessitate ischemic vascular preventative treatments that could increase the risk of ICH recurrence, such as antithrombotic and lipid-lowering therapies, for competing comorbid ischemic vaso-occlusive or thromboembolic diseases.1–3 To complicate matters further, it is becoming increasingly apparent that patients with ICH are at a heightened risk of major thrombotic vascular events, particularly over the first months following ICH.4 Accordingly, whether ICH survivors with competing ischemic vascular diseases should resume ischemic vascular preventative treatments and, if yes, the optimal timing of their resumption are active areas of controversy and investigation.See related article, p 537Fortunately, randomized trials are beginning to provide some guidance in this regard. RESTART (Restart or Stop Antithrombotics Randomised Trial) was a phase 2 trial that randomized 537 patients with ICH who were taking antithrombotic medication to start or avoid antiplatelet therapy.5 Patients assigned to antiplatelet treatment in this trial had a 35% relative risk reduction in the pre-specified secondary outcome of major adverse vascular events without suggestion of an increased risk of recurrent ICH. Although inconclusive and requiring validation in an adequately powered main phase trial, RESTART’s findings are reassuring and suggest that any potential increased risk of recurrent ICH from antiplatelet resumption is unlikely to negate their established protective effect on ischemic vascular events. On the basis of these results, recent ICH guidelines state that it may be reasonable to (re)initiate antiplatelet treatment in ICH survivors where indicated for secondary prevention of ischemic vascular events.6,7 However, guidelines do not currently define the optimal timing of antiplatelet (re)initiation following ICH. Although RESTART eligibility allowed randomization as early as 24 hours following the index event, the median time from the qualifying ICH to randomization was 76 days,5 and there remains a paucity of evidence in this regard. Arguments supporting early resumption of antiplatelet therapy following ICH are that hemostasis is often achieved within 24 hours and hematoma expansion is exceedingly rare beyond this timeframe (in the absence of coagulopathy),8 existing experience with safely initiating chemoprophylactic dosing of low molecular weight heparin as early as 48 hours following ICH,9 the relatively low risk of early recurrent ICH, and the high risk of early major occlusive vascular events in ICH survivors.4 Proponents of later resumption counter these arguments by noting the association between antiplatelet treatment and greater rates of acute hematoma expansion,8 the modest effect size of antiplatelet therapy on annualized vascular events,10 and the potential for blood-brain barrier breakdown represented by peripheral contrast enhancement on neuroimaging for up to 6 weeks following the ictus.11In an attempt to address this knowledge gap, in the current issue of Stroke, Liu and colleagues12 report the results of an analysis of the Taiwan National Health Insurance Research Database between 2008 and 2017 comparing the risks of major hemorrhagic and occlusive vascular events between early (within 30 days of the index ICH) and late (31 to 365 days) antiplatelet resumption in ICH survivors taking antiplatelets at the time of their hemorrhage.12 Patients with atrial fibrillation, heart failure, anticoagulant use, and those who developed cardiovascular events or died prior to re-initiation of antiplatelet treatment were excluded. In 1584 (843 early and 741 late treatment groups) patients identified to meet study eligibility criteria in the National Health Insurance Research Database, the authors found no difference in the primary outcome of recurrent ICH after propensity score matching amongst patients restarted on antiplatelet treatment in the early versus late groups (3.12% versus 3.27%; adjusted HR, 0.97 [95% CI, 0.52–1.80]). Additionally, there were no statistically significant differences between the 2 groups in the secondary outcomes of all-cause mortality, major occlusive vascular events, and ischemic stroke at 1-year follow-up. However, subgroup analyses suggested a reduced risk of ischemic stroke with early resumption of antiplatelet therapy amongst patients with chronic kidney disease, as well as reduced rates of all-cause mortality and major hemorrhagic events with early resumption in patients without preexisting cerebrovascular disease. In sensitivity analyses, the unadjusted rates of recurrent ICH were similar between patients resuming antiplatelet treatment between 1–14 days (n=556; 4.5%), 15–30 days (n=287; 4.9%), and 31–365 days (n=741; 3.4%) following their ICH and virtually identical after propensity score matching. All-cause mortality was lower in patients that were resumed on antiplatelet therapy within 1–14 days versus 15–30 days of their ICH.Overall, the results suggest that antiplatelet treatment can be safely resumed early following ICH and may provide clinical benefit if resumed as early as within the first 2 weeks. The authors should be commended for providing evidence in an area that has not been previously systematically studied. However, some important limitations should be considered when interpreting their results. The first is that observational datasets are substantially prone to confounding by indication and, thus, are not reliable sources on which to base treatment decisions. For instance, it could easily be the case that patients who had their antiplatelet treatment resumed early were those whom physicians felt most comfortable doing so due to their perceived lower risk of ICH recurrence, and propensity score matching is an imperfect method for trying to adjust for such imbalances. Apart from unknown confounders, national databases are particularly prone to these biases because they often lack the level of granularity required to adjust for key variables of interest. The present analysis was unable to adjust for potential imbalances in quality of blood pressure control following the index hemorrhage, ICH location, hematoma size, and neuroimaging markers of heightened risk of recurrent ICH. For instance, patients with lobar ICH and cortical superficial siderosis are particularly at greater risk of early ICH recurrence.13 Moreover, vascular risk factors exist within a broad spectrum of disease duration, severity, and medical optimization that cannot be adequately captured and adjusted through binary variables. Hence, the simplistic elegance of the randomized trial for producing well-balanced groups of patients with respect to their risks of health outcomes where the unconfounded effect of an intervention can be tested.14 Furthermore, 99 patients were excluded from the analyses on the basis of having developed cerebrovascular events or death prior to antiplatelet resumption. As ischemic vascular events can be front loaded following ICH, excluding such patients could have biased their findings towards the late window. Lastly, the significant differences identified between subgroups in secondary analyses could have simply been chance findings due to multiple testing.The successor of RESTART, the phase 3 ASPIRING (Antiplatelet Secondary Prevention International Randomised Trial After Intracerebral Haemorrhage) comparing antiplatelet therapy against antiplatelet avoidance in ICH survivors, is currently in preparation. It aims to enroll over 4000 patients with ICH and subgroup analyses from this trial will hopefully ultimately further our understanding of optimal timing of antiplatelet (re)initiation and inform the design of future randomized trials aiming to specifically answer the question of early versus late resumption. Until the results of such trials are forthcoming, the present analysis by Liu and colleagues provides the best evidence that we have to date on the topic matter and reassurance to those amongst us who are presently resuming antiplatelet treatment early (often after 7 days and ensuring hematoma stabilization on neuroimaging) following ICH.Article InformationDisclosures Dr Shoamanesh reports grants from National Institutes of Health; grants from Canadian Institutes of Health Research; grants from Daiichi Sankyo Company; grants from Servier Affaires Medicales; grants from Octapharma USA, Inc; compensation from AstraZeneca for consultant services; grants from Heart and Stroke Foundation of Canada; compensation from Takeda Pharmaceutical Company for consultant services; and grants from Bayer. Dr Katsanos reports grant from the Canadian Institutes of Health Research.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Disclosures, see page 547.Correspondence to: Ashkan Shoamanesh, MD, Associate Professor of Medicine (Neurology) Marta and Owen Boris Chair in Stroke Research and Care, Director of the Hemorrhagic Stroke Research Program, McMaster University/Population Health Research Institute Hamilton, ON, Canada. Email ashkan.shoamanesh@phriReferences1. Sheth KN, Selim M. Focused update on vascular risk and secondary prevention in survivors of intracerebral hemorrhage.Stroke. 2022; 53:2128–2130. doi: 10.1161/STROKEAHA.122.039819LinkGoogle Scholar2. Puy L, Forman R, Cordonnier C, Sheth KN. Protecting the brain, from the heart: safely mitigating the consequences of thrombosis in intracerebral hemorrhage survivors with atrial fibrillation.Stroke. 2022; 53:2152–2160. doi: 10.1161/STROKEAHA.122.036888LinkGoogle Scholar3. Shoamanesh A, Selim M. Use of lipid-lowering drugs after intracerebral hemorrhage.Stroke. 2022; 53:2161–2170. doi: 10.1161/STROKEAHA.122.036889LinkGoogle Scholar4. Li L, Murthy SB. Cardiovascular events after intracerebral hemorrhage.Stroke. 2022; 53:2131–2141. doi: 10.1161/STROKEAHA.122.036884LinkGoogle Scholar5. Collaboration RESTART. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial.Lancet. 2019; 393:2613–2623. doi: 10.1016/S0140-6736(19)30840-2CrossrefGoogle Scholar6. Shoamanesh A, Patrice Lindsay M, Castellucci LA, Cayley A, Crowther M, de Wit K, English SW, Hoosein S, Huynh T, Kelly M, et al. 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Computerized tomography in intracranial hemorrhage.Arch Neurol. 1979; 36:422–426. doi: 10.1001/archneur.1979.00500430052007CrossrefMedlineGoogle Scholar12. Liu C-H, Wu Y-L, Hsu C-C, Lee T-H. Early antiplatelet resumption and the risks of major bleeding after intracerebral hemorrhage.Stroke. 2023; 54:537–545. doi: 10.1161/STROKEAHA.122.040500LinkGoogle Scholar13. Roongpiboonsopit D, Charidimou A, William CM, Lauer A, Falcone GJ, Martinez-Ramirez S, Biffi A, Ayres A, Vashkevich A, Awosika OO, et al. Cortical superficial siderosis predicts early recurrent lobar hemorrhage.Neurology. 2016; 87:1863–1870. doi: 10.1212/WNL.0000000000003281CrossrefMedlineGoogle Scholar14. Collins R, Bowman L, Landray M, Peto R. The magic of randomization versus the myth of real-world evidence.N Engl J Med. 2020; 382:674–678. doi: 10.1056/NEJMsb1901642CrossrefMedlineGoogle Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesEarly Antiplatelet Resumption and the Risks of Major Bleeding After Intracerebral HemorrhageChi-Hung Liu, et al. Stroke. 2023;54:537-545 February 2023Vol 54, Issue 2 Advertisement Article Information Metrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.122.041466PMID: 36621821 Originally publishedJanuary 9, 2023 KeywordsEditorialsantiplatelethematomaintracerebral hemorrhagepracticesecondary preventionPDF download Advertisement Subjects Intracranial Hemorrhage Thrombosis Treatment