Antithrombotics and bleeding risk: paradoxical findings

Can an antithrombotic drug prevent bleeding? For cerebral cavernous malformations (CCMs), a study in The Lancet Neurology by Susanna Zuurbier and colleagues1Zuurbier SM Hickman CR Tolias CS et al.Association between long-term antithrombotic therapy and risk of intracranial haemorrhage from cerebral cavernous malformations: a population-based cohort study, systematic review, and meta-analysis.Lancet Neurology. 2019; (published online Aug 7.)http://dx.doi.org/10.1016/S1474-4422(19)30231-5Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar suggests that, paradoxically, it might. CCMs, also called cavernous angiomas or cavernomas, are small vascular lesions that are detected in up to 0·2% of the general population2Morris Z Whiteley WN Longstreth Jr, WT et al.Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis.BMJ. 2009; 339b3016Crossref PubMed Scopus (419) Google Scholar and can cause focal neurological deficits or seizures. Clinicians typically avoid antithrombotics in these patients because CCMs are prone to bleeding, with an approximate risk of bleeding of 0·8–1·6% per year for asymptomatic lesions and 3·6–6·2% per year for symptomatic lesions, depending on location.3Horne MA Flemming KD Su IC et al.Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data.Lancet Neurology. 2016; 15: 166-173Summary Full Text Full Text PDF PubMed Scopus (108) Google Scholar However, avoiding antithrombotics is becoming increasingly difficult because of expanding indications for their use and an ageing population.4Adelborg K Grove EL Sundboll J Laursen M Schmidt M Sixteen-year nationwide trends in antithrombotic drug use in Denmark and its correlation with landmark studies.Heart. 2016; 102: 1883-1889Crossref PubMed Scopus (34) Google Scholar In this cohort study, systematic review, and meta-analysis, the authors used data from the Scottish Audit of Intracranial Vascular Malformations and the published literature to establish whether antithrombotic use was associated with new focal neurological deficits or bleeding.1Zuurbier SM Hickman CR Tolias CS et al.Association between long-term antithrombotic therapy and risk of intracranial haemorrhage from cerebral cavernous malformations: a population-based cohort study, systematic review, and meta-analysis.Lancet Neurology. 2019; (published online Aug 7.)http://dx.doi.org/10.1016/S1474-4422(19)30231-5Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar Patients were identified by screening of all radiology reports within a defined geographical area (Scotland, UK) for diagnosed CCMs. Active surveillance was then used to identify patients who had either new episodes of documented bleeding or new focal neurological deficits in the absence of new bleeding, as well as treatment with antithrombotics. Despite the widely held clinical concern that antithrombotic drugs could increase the risk of bleeding, the findings from the study suggested the opposite. There were fewer episodes of new bleeding or new focal neurological deficits over a mean follow-up of 11·6 years in the patients given antithrombotics (one [2%] of 61 patients) than in those who did not take antithrombotics (29 [12%] of 239). The adjusted hazard ratio (HR) of 0·12 (95% CI 0·02–0·88) was remarkably low, given that HRs that small are rarely seen in clinical research. In secondary prevention trials, for example, aspirin prevents recurrent stroke with an HR of 0·83.5Baigent C Blackwell L Collins R et al.Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.Lancet. 2009; 373: 1849-1860Summary Full Text Full Text PDF PubMed Scopus (2512) Google Scholar Therefore, potential sources of bias should be considered. The most plausible source of bias could be confounding by indication. That is, if clinicians mostly use antithrombotics in patients at lower risk for haemorrhage, but not in patients at higher risk, then a spurious association might be detected between antithrombotic use and lower recurrence of haemorrhages. To mitigate this risk for bias, the authors adjusted for type of presentation and brainstem location,3Horne MA Flemming KD Su IC et al.Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data.Lancet Neurology. 2016; 15: 166-173Summary Full Text Full Text PDF PubMed Scopus (108) Google Scholar the two factors that influence bleeding risk that would also be known to the treating clinician and might have influenced their treatment decisions. There was no change in the HR after adjustment. A series of subgroup and sensitivity analyses provide additional reassurance that the findings are consistent with the conclusion that antithrombotics might be protective in these patients. In each analysis, the estimates were in the same direction, with a clinically relevant effect, although not statistically significant, possibly because of the small sizes of the groups or the small number of events. These analyses included patients taking anticoagulants (none of 10 patients), individuals with intracerebral haemorrhage at presentation (adjusted HR 0·41, in 52 patients), and when antithrombotic therapy was analysed as a time-dependent covariate (adjusted HR 0·30). Importantly, when the outcome was restricted to intracerebral haemorrhage only, the direction of effect was similar but not significant (one [2%] of 62 patients vs 18 [8%] of 238; log-rank p=0·070). Furthermore, a systematic review of six other published and unpublished studies showed similar findings, with fewer intracerebral haemorrhages in the patients on antithrombotics.1Zuurbier SM Hickman CR Tolias CS et al.Association between long-term antithrombotic therapy and risk of intracranial haemorrhage from cerebral cavernous malformations: a population-based cohort study, systematic review, and meta-analysis.Lancet Neurology. 2019; (published online Aug 7.)http://dx.doi.org/10.1016/S1474-4422(19)30231-5Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar Are these findings plausible on the basis of current knowledge of the pathophysiology of CCMs? Histologically, these lesions consist of dilated thin-walled vascular channels lined by endothelium, with no or minimal intervening brain tissue, surrounded by gliosis and haemosiderin.6Raychaudhuri R Batjer HH Awad IA Intracranial cavernous angioma: a practical review of clinical and biological aspects.Surg Neurol. 2005; 63: 319-328Summary Full Text Full Text PDF PubMed Scopus (113) Google Scholar Thrombi within these channels are seen in about a half to three-quarters of cases.7Frischer JM Pipp I Stavrou I Trattnig S Hainfellner JA Knosp E Cerebral cavernous malformations: congruency of histopathological features with the current clinical definition.J Neurol Neurosurg Psychiatry. 2008; 79: 783-788Crossref PubMed Scopus (36) Google Scholar, 8Abe M Fukudome K Sugita Y Oishi T Tabuchi K Kawano T Thrombus and encapsulated hematoma in cerebral cavernous malformations.Acta Neuropathologica. 2005; 109: 503-509Crossref PubMed Scopus (12) Google Scholar It is plausible that thrombosis could impair venous drainage or trigger inflammation, with expression of metalloproteinases, leading to increased pressure and breakdown of the extracellular matrix, with consequent bleeding. The findings from this study provide some reassurance that clinicians can use antithrombotics safely, if clearly indicated, in patients with CCMs—particularly when the patient is asymptomatic and excision or radiosurgery is not indicated or not possible.9Akers A Al-Shahi Salman R Awad IA et al.Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel.Neurosurgery. 2017; 80: 665-680Crossref PubMed Scopus (133) Google Scholar Perhaps antithrombotics could even be used as a treatment for CCMs, although it would be presumptuous to do so based only on uncontrolled observational evidence. A clinical trial of antithrombotics is well justified by the findings of this observational study, and hopefully will be done. EES reports personal fees from Portola Pharmaceuticals and Alnylam Pharmaceuticals, outside the submitted work. Long-term antithrombotic therapy and risk of intracranial haemorrhage from cerebral cavernous malformations: a population-based cohort study, systematic review, and meta-analysisAntithrombotic therapy use is associated with a lower risk of intracranial haemorrhage or focal neurological deficit from cerebral cavernous malformations than avoidance of antithrombotic therapy. These findings provide reassurance about safety for clinical practice and require further investigation in a randomised controlled trial. Full-Text PDF Open Access

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