Challenging Antiplatelet Therapy for Small Vessel Stroke Through Genetics

HomeStrokeVol. 55, No. 4Challenging Antiplatelet Therapy for Small Vessel Stroke Through Genetics Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBChallenging Antiplatelet Therapy for Small Vessel Stroke Through Genetics Guido J. Falcone and Daniel Woo Guido J. FalconeGuido J. Falcone Correspondence to: Guido J. Falcone MD, ScD, MPH, Department of Neurology, Yale School of Medicine, Suite 1N, 100 York St, New Haven, CT 06511. Email E-mail Address: [email protected] Department of Neurology (G.J.F.), Yale School of Medicine, New Haven, CT. Center for Brain and Mind Health (G.J.F.), Yale School of Medicine, New Haven, CT. and Daniel WooDaniel Woo https://orcid.org/0000-0002-2466-7155 Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, OH (D.W.). Originally published25 Mar 2024https://doi.org/10.1161/STROKEAHA.124.046111Stroke. 2024;55:943–945This article is a commentary on the followingDoes Thrombosis Play a Causal Role in Lacunar Stroke and Cerebral Small Vessel Disease?Cerebral small vessel disease (CSVD) encompasses a spectrum of highly prevalent vasculopathies affecting the brain's microvasculature, leading to a variety of clinical manifestations.1 Among the primary subtypes of CSVD, cerebral amyloid angiopathy2 and deep perforator arteriopathy,3 the latter frequently referred to as hypertension-related vasculopathy or lipohyalinosis, are the most significant. Deep perforator arteriopathy, in particular, has garnered considerable attention in recent years due to its substantial contribution to morbidity and mortality. This arteriopathy is implicated in numerous clinical presentations, including lacunar ischemic stroke (also known as small vessel ischemic stroke), spontaneous intracerebral hemorrhage, cognitive decline and dementia, parkinsonism, and late-life depression.4 Despite increasing awareness of its clinical significance, deep perforator arteriopathy remains a subject of intense debate, particularly regarding its pathophysiology and the optimization of therapeutic strategies. This controversy stems partly from the likely heterogeneous nature of the pathobiological processes ascribed to it. At least 2 distinct mechanisms are involved: arteriolosclerosis, primarily induced by chronic hypertension, and a branch orifice microatheromatous disease, resulting from the cumulative effects of various vascular risk factors.5 Of note, these are not pure phenotypes and oftentimes manifest together. This complexity highlights the need for a nuanced understanding of the disease's pathophysiology to develop more effective treatment modalities.See related article, p 934The complex pathophysiology and consequent scientific debate surrounding CSVD have profound clinical ramifications, particularly in the management of lacunar ischemic strokes. While there is a consensus on the critical role of aggressive blood pressure control in these patients, the approach toward antithrombotic therapies remains controversial for secondary prevention in lacunar stroke cases. This uncertainty partly arises from a dearth of clinical trials specifically aimed at investigating secondary prevention strategies for lacunar stroke. A notable exception is the SPS3 (Secondary Prevention of Small Subcortical Strokes) clinical trial, which compared aspirin alone to a combination of aspirin and clopidogrel in patients with magnetic resonance imaging–confirmed lacunar strokes.6 The trial's findings were significant: while long-term dual antiplatelet therapy did not substantially reduce the recurrence of strokes, it notably increased the risks of hemorrhagic complications and raised mortality rates by 50%. Remarkably, trials focusing solely on single antiplatelet therapy post-lacunar stroke have not been conducted, underscoring the existing gaps in the evidence base that informed the SPS3 trial. Confronted with these findings, the medical community now faces a complex dilemma: whether to invest substantial resources in unraveling the simpler question of aspirin's efficacy in this context or to channel these resources toward exploring more contemporary issues. These modern queries could include investigating the role of inflammation and anti-inflammatory agents in the onset, severity, and progression of CSVD.7 This decision is critical, as it will shape future research directions and potentially redefine therapeutic strategies in managing this intricate and challenging aspect of stroke medicine.The challenging landscape of clinical research in CSVD and deep perforator arteriopathy necessitates innovative approaches to unravel the pathophysiological underpinnings of these conditions, particularly concerning causality. Population genetics emerges as a formidable tool in this endeavor, offering unique insights into complex diseases where common genetic variation significantly contributes to pathophysiology. Lacunar stroke, with genetic association studies indicating that common genetic variants account for up to 30% of its risk,8 serves as an example for the application of these genetic tools. Within the realm of population genetics, Mendelian randomization (MR) studies have gained prominence as a robust method to establish causal relationships.9 Traditional research in human diseases has often been bifurcated into observational studies, which can suggest causative factors but are inherently limited by design, and randomized clinical trials, which provide causal evidence but are constrained by logistical complexities, extensive time requirements, and significant resource demands. MR studies adeptly bridge this gap, providing a level of causal evidence that sits between observational studies and randomized clinical trials. MR functions as a specialized form of instrumental variable analysis, using a factor (the instrument) that is strongly associated with the exposure of interest and not related to the outcome to examine exposure-disease associations with minimal confounding risk. Genetic risk variants, distributed randomly during meiosis and closely linked to specific human traits and diseases, serve as ideal instruments in this context in that later life traits do not affect how the variants are distributed at conception. Thus, patients are randomized at birth to having or not having candidate variants but also diet, exercise, and pharmaceutical treatments are theoretically randomized at conception (those events are unlikely to have any bearing on meiosis). If, for example, variants for thrombosis are randomized at birth and thrombosis is not associated with lacunar stroke, then the variants should be equally distributed between those with and without lacunar stroke. Notably, MR studies are useful not only in providing supportive causal evidence for specific exposure-disease associations but also in dispelling the existence of presumed associations as causal. This dual utility underscores the value of MR studies in guiding the development of targeted and effective interventions in the complex field of CSVD and deep perforator arteriopathy research. Importantly, recent reports indicate that treatments evaluated in clinical trials backed by human genetic evidence have a significantly higher likelihood of progressing from phase I studies to Food and Drug Administration approval.10In this edition of Stroke, Koohi et al11 present an important MR study examining the role of thromboembolism in the pathogenesis of lacunar stroke. This research aims to provide support for the use of antiplatelet agents in preventing lacunar strokes, given their efficacy in thrombosis prevention. The authors capitalized on a large genome-wide association study of venous thromboembolism, which encompassed 81 190 cases, to select appropriate genetic instruments for their analysis. Specifically, they pinpointed 119 genetic risk variants independently associated with an increased risk of venous thromboembolic events. These identified genetic variants were then evaluated against various types of ischemic stroke using results from GIGASTROKE. This comprehensive genome-wide association study of stroke, the largest to date in its field, included 10 804 cases of cardioembolic stroke, 6399 cases of large-artery stroke, and 6811 cases of lacunar stroke. Beyond these associations, the study also assessed brain magnetic resonance imaging markers indicative of CSVD in individuals without a stroke history, as evaluated in the UK Biobank. These markers included white matter hyperintensities and diffusion tensor imaging metrics, specifically mean diffusivity and fractional anisotropy.In their investigation, the authors found that genetically determined risk for venous thrombosis exhibited associations with certain ischemic stroke subtypes, while showing no correlation with others. Notably, the presence of genetically determined venous thrombosis was linked with a 32% increased risk of cardioembolic ischemic stroke and a 41% elevated risk of large-artery ischemic stroke. These associations align with the anticipated role of thrombosis in these stroke subtypes, thought to occur due to blood flow stasis in the left heart chambers or through in situ thrombosis on the damaged epithelium of atherosclerotic plaques. Conversely, the study revealed no significant link between genetically determined venous thrombosis risk and lacunar ischemic strokes. As indicated above, this subtype of stroke is marked by inconclusive evidence regarding the involvement of thrombotic mechanisms. Corroborating these findings, the study also reported no association between genetically instrumented thrombosis and the 3 key brain magnetic resonance imaging markers of CSVD evaluated in the study. Critically, the robustness of these findings is underscored by their consistency across 4 distinct MR methodologies. This comprehensive approach strengthens the conclusion that while thrombotic mechanisms may play a significant role in certain ischemic stroke subtypes, their involvement in lacunar strokes and related CSVD may be limited. These insights offer valuable clarity in understanding the pathophysiology of different ischemic stroke subtypes and could have significant implications for targeted stroke prevention and treatment strategies.This study presents a significant implication, as highlighted by the authors: it offers human genetic evidence suggesting that thrombosis may not play a crucial role in the development of lacunar strokes and clinically silent CSVD. Consequently, this raises doubts about the effectiveness of antithrombotic agents, such as aspirin, in preventing future lacunar strokes. The robustness of these conclusions is underpinned by several strengths of the study: comprehensive stroke subtyping, the concurrent evaluation of lacunar stroke and neuroimaging markers of CSVD, the integration of data from multiple studies, and substantial statistical power in both identifying genetic instruments for thromboembolism and assessing the impact of genetically determined thrombosis on stroke risk. These findings challenge the prevailing notion of the role of thrombosis in lacunar stroke, casting doubt on the rationale for using aspirin or similar antiplatelet treatments. These findings pave the way for a pivotal discussion about future directions in clinical trials concerning lacunar stroke. The SPS3 trial, which compared aspirin alone to a combination of aspirin and clopidogrel, operated under the assumption that thrombosis contributed to lacunar strokes and necessitated some form of antiplatelet therapy. The results of this genetic study call this assumption into question and suggest the potential value of a trial incorporating a placebo arm. Such a trial would fundamentally reshape our understanding of lacunar stroke treatment and could lead to significant revisions in clinical guidelines, emphasizing the need for evidence-based approaches tailored to the specific pathophysiology of different stroke subtypes.An important limitation of this study, duly acknowledged by the researchers, lies in the use of venous thromboembolism as the model for identifying genetic instruments to study thrombosis. Venous thromboembolism may not completely represent the thrombotic processes occurring in the arterial system, particularly within the small vessels of the brain that, when occluded, result in lacunar strokes. Although current genetic evidence suggests a significant overlap in the pathophysiology of venous thromboembolism and arterial thrombosis,12 it is conceivable that the unique aspects of arterial thrombosis could still justify the use of antithrombotic agents. This limitation highlights a valuable direction for future research: investigating whether a genetically determined propensity for arterial thrombosis correlates with an increased risk of lacunar strokes. Such research could provide a more nuanced understanding of the role of thrombosis in lacunar stroke pathogenesis and potentially inform more targeted therapeutic approaches. This line of inquiry would be important in distinguishing the specific thrombotic mechanisms at play in different vascular territories and stroke subtypes, thereby refining the clinical application of antithrombotic treatments.In conclusion, Koohi et al employ MR analyses to investigate the role of thromboembolism in the etiology of lacunar strokes. Utilizing robustly powered genetic association studies, the team identified genetic risk variants that heighten the risk of venous thromboembolism. They then assessed the cumulative causal effect of these variants on the risk of lacunar stroke, ultimately finding no significant associations. This key finding delivers causal evidence that thrombosis may not play a substantial role in the occurrence of lacunar stroke. Consequently, it underscores the need for further research to ascertain the appropriateness of antithrombotic agents in the aftermath of such strokes. We note that, until such research is completed, it is reasonable to continue the current practice of prescribing long-term antiplatelet monotherapy in this scenario. Beyond these specific results and their possible clinical implications, this study exemplifies the value of leveraging population genetics tools in deepening our understanding of complex human disease like stroke. In particular, MR analyses stand out as a powerful method to substantiate causality in specific exposure-disease relationships. By bridging the gap between observational studies and clinical trials, MR provides a unique and valuable perspective in the exploration of disease pathophysiology and the development of targeted therapeutic interventions.Disclosures None.FootnotesFor Disclosures, see page 945.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Guido J. Falcone MD, ScD, MPH, Department of Neurology, Yale School of Medicine, Suite 1N, 100 York St, New Haven, CT 06511. Email guido.falcone@yale.eduREFERENCES1. Markus HS, de Leeuw FE. Cerebral small vessel disease: Recent advances and future directions.Int J Stroke. 2023; 18:4–14. doi: 10.1177/17474930221144911CrossrefGoogle Scholar2. Biffi A, Greenberg SM. Cerebral amyloid angiopathy: a systematic review.J Clin Neurol. 2011; 7:1–9. doi: 10.3988/jcn.2011.7.1.1CrossrefMedlineGoogle Scholar3. Wardlaw JM, Smith C, Dichgans M. 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