Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Indeed it's a hard nut to crack!!
- Dr Fatai Kunle Salawu,FMCP,FWACP (19 August 2005)
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No universal rule
- Mahamood Basharuthulla (20 August 2005)
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primary intracerebral haemorrhage and very high risk of embolic stroke
- Fernando Pita, Catia Carmona (26 August 2005)
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Warfarin or aspirin for stroke prevention? - using decision models to aid complex decision making.
- Nicola L Anderson, Richard Fuller, Nigel Dudley (30 August 2005)
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Primary intracerebral haemorrhage or haemorrhagic transformation of an ischaemic infarct?
- Madeleine A Purchas (12 September 2005)
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Author's reply
- Mushtaq Wani (12 September 2005)
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RE: Should a patient with primary intracerebral haemorrhage receive
- David M Wilson, MI Wiggam (5 October 2005)
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Re: Primary intracerebral haemorrhage or haemorrhagic transformation of an ischaemic infarct?
- Mushtaq Wani (10 October 2005)
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Re: RE: Should a patient with primary intracerebral haemorrhage receive
- Mushtaq Wani (17 October 2005)
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Dr Fatai Kunle Salawu,FMCP,FWACP, Consultant neurologist Specialist Hospital,Maiduguri.Nigeria
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I cannot agree more with the team managing this unfortunate man with a "nest full of problems."Indeed,I have had a similar case and my hands were tied,so I think it's time neurologists around the world found a gold standard solution to it as it were.As it is really frustrating for the doctors caring for such patients and seeing them deteriorating before their eyes. Competing interests: None declared |
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Mahamood Basharuthulla, Consultant Physician and Cardiologist Bangalore 560078-India
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Dear sir, This is a topic keeps coming up frequently in clinical practice where the patient is under General Physician,.The neurologist, neuro srgeon, cardiologist and Haematologists have their own interptation and opnion about anticoagulation therapy in such patients. As there are no set rules, therfore there is always a difference of opinion and at the end should there be any complications, then specialist express their concern and even blame each other. I do believe the authers are absolutely right in suggesting a proper further studies and set guide lines.Till then the treating physician will have to decide the treatment as per the individual case to the best of his/or her judegement. yours sincerely Dr Mahamood Basharuthulla ,MD,FACP, FRCP-GLasg, FRCP-I Consultant Physician and Cardiologist. Bangalore-India Competing interests: None declared |
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Fernando Pita, Neurologist Servico Neurologia, Hospital Garcia de Orta, 2800 Almada, Portugal, Catia Carmona
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I think the authors miss an important clinical point in their discussion: What to do in the acute phase with patients anticoagulated, with very high risk of embolic stroke who suffer primary intracerebral haemorrhage. Patients with cardiac mechanical valvular prosthesis have a very high risk of cardio-embolism, with an incidence of 4% / patient / year of embolic stroke or complicated peripheral embolism (with necessity of surgery or death of the patient). With antiplatelet therapy the incidence drops to 2.2% / patient / year, and with oral anticoagulation 1% / patient / year (1). The risk of intracranial haemorrhage in anticoagulated patients is about 1 - 2 % / year (2), bigger (4 to 10 x) for INR values > 3,5 (3). Age and leukoaraiosis are added risk factors for haemorrhage. (4), and its frequency and gravity are directly correlated with the value of INR. (5) After primary intracerebral haemorrhage, in the acute set, it is common sense to revert anticoagulation, but for how long should it be withhold, and how to reintroduce it in a safe way? There are few studies (3, 5, 6, 7, 8) in patients with primary intracerebral haemorrhage and very high risk of embolic stroke, because even in neurointensive reference units the incidence is low, around 2.5 patients year. (2, 5, 6) Two studies have been realized in two neurointensive units in reference centers (Mayo Clinic, Rochester, Minnesota and University Hospital of Heidelberg) and have very different conclusions: The study from Mayo Clinic (2, 6) collected retrospectively 141 patients from a 23 years period. In the acute set anticoagulation was reversed with vitamin K and fresh plasma and withhold for a median period of 10 days (0- 30) and reintroduced with Heparin or Warfarin. They concluded that is safe to stop anticoagulation for one to two weeks because they had few complications (0 % haemorrhages and 3 a 5% embolisms), but 43% of the patients died from unknown reasons, because there was no cerebral or cardiac imaging control (maybe from hemorrhagic or embolic complications). The study from Heidelberg (2, 5), collected retrospectively 15 patients from a 5 years period and is more homogeneous. In all patients anticoagulation was also reverted in the acute set, with reinstitution of Heparin in the first day in 73% of patients. This strategy has an apparent higher incidence of complications (20 % haemorrhages and 20 % embolisms) but with a significant lower mortality (6.5%). Hemorrhagic complications occurred in those patients without normalization of INR (< 1.5). Embolic complications occurred in those patients without therapeutic values after Heparin reintroduction. In conclusion, oral anticoagulation should be reverted in the acute set in patients with a primary intracerebral haemorrhage and very high risk of embolic stroke and reintroduction should be, if possible, precocious with unfractionated IV heparin without bolus. 1. Crawley F, Bevan D, Wren D. Management of intracranial bleeding associated with anticoagulation: balancing the risk of further bleeding against thromboembolism from prosthetic heart valves. J Neurol Neurosurg Psychiatry. 2000;69:396-398. 2. Werner H. The Dilemma of Reinstituting Anticoagulation for Patients With Cardioembolic Sources and Intracranial Hemorrhage: How Wide Is the Strait Between Skylla and Karybdis? Arch Neurol. 2000;57:1682-1684. 3. Leker RR, Abramsky O. Early anticoagulation in patients with prosthetic heart valves and intracerebral hematoma. Neurology.1998;50:1489-1491. 4. Ferro J. Cardioembolic stroke: an update. The Lancet Neurology. 2003:Vol.2; 177-188. 5. Bertram M, Bonsanto M, Hacke W, Schwab S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrage and urgent need for anticoagulation. J Neurol. 2000; 247:209-214. 6. PhanTG, Hoh M, Wijdicks EFM. Safety of discontinuation of anticoagulation in patients with intracranial hemorrage at high thromboembolic risk. Arch Neurol. 2000:57;1710-1713. 7. Eckman MH, Rosand J, Knudsen KA, et al. Can patients be anticoagulated after intracerebral hemorrage? A decision analysis. Stroke. 2003; 34:1710- 1716. 8. Butler A, Tait RC. Restarting Oral Anticoagulation after intracerebral hemorrage - response Stroke.2004;35: 5-6. Competing interests: None declared |
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Nicola L Anderson, SpR Elderly Medicine Department of Elderly Medicine, St James' University Hospital, Leeds, LS9 7TF., Richard Fuller, Nigel Dudley
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There is no prospect of “large scale, well designed trials” taking place to provide the answers to the questions posed by Dr Wani’s 55 year old man who had both an infarct and an intracerebral bleed.[1] Both doctors and patients are cautious when it comes to the use of antithrombotic agents following intracerebral haemorrhage, and besides there are so many potential variables in terms of degree of risk of both infarction and bleeding that the required numbers would not be able to be recruited.[2,3] The alternative approach is the use of a decision analysis model such as that constructed by Eckman and colleagues, but their Markov model is clearly too detailed and cumbersome for day to day clinic use.[4] In co-operation with decision modelling colleagues in Leeds and South Africa, we have constructed a less complex model using requisite decision theory. This can be used on a laptop in a clinic setting to aid the clinical judgment of a doctor; results from its use are to be presented later in the year at the Autumn meeting of the British Geriatrics Society. Using the clinical information provided by Dr Wani, a sensitivity analysis using our model suggests the decision to use warfarin for stroke prevention is the wrong choice and aspirin would have been the preferable option. [1] Wani M, Nga E, Navaratnasingham R. Should a patient with primary intracerebral haemorrhage receive antiplatelet or anticoagulant therapy? BMJ 2005;331:439 – 42 [2] Fuller R, Dudley N, Blacktop J. Avoidance hierarchies and preferences for anticoagulation – semi-qualitative analysis of older patients’ views about stroke prevention and the use of warfarin. Age and Ageing 2004;33:1 – 4. [3] Lip GY, Zarifis RD, Watson RD, Beevers DG. Physician variation in the management of patients with atrial fibrillation. Heart 1996;75:200 – 5. [4] Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagulated after intracerebral haemorrhage? A decision analysis. Stroke 2003;34:1710 – 6. Competing interests: None declared |
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Madeleine A Purchas, SpR medicine for the elderly Royal Cornwall Hospitals Trust, Truro TR1 3LJ
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Editor - The evidence based case report by Wani et al was a thorough and systematic review of the available evidence regarding antiplatelet or anticoagulant therapy in patients with primary intracerebral haemorrhage. I would value the authors comments regarding a recent patient in our care where anticoagulation was felt to be necessary in a patient with an intracerebral haemorrhage. A 70 year old man was admitted with a 2 day history of pleuritic chest pain and shortness of breath. He had a history of sudden onset right hemiparesis with dysarthria 10 days previously which had resolved almost completely over 2 days. He was awaiting an outpatient computed tomogram (CT) scan of the head. He had a past medical history of hypertension, hypercholesterolaemia, and a previous cerebrovascular event 16 years ago, from which he had fully recovered. CT pulmonary angiogram confirmed bilateral pulmonary emboli. CT of his head showed an area in the left basal ganglia consistent with a resolving intracerebral haemorrhage. The scans were discussed further at our Xray meeting. There was also evidence of several old infarcts on the CT, and the possibility of haemorrhagic transformation of an ischaemic infarct was discussed. In light of this discussion it was felt that the benefits of anticoagulation outweighed the risks, although we accepted that there remained a very significant element of risk. Wani et al raised the issue that in their case haemorrhagic transformation of an infarct was possible. Their scan was performed about 90 hours after the onset of neurological symptoms, whereas ours was at approximately 11 days. It is usually adviseable to scan within 14 days so as to be able to distinguish between infarct and haemorrhage. I am unaware of the commonest time after the onset of symptoms for haemorrhagic transformation to occur. Do the authors know the answer to this, and how often is it possible to distinguish between primary or secondary haemorrhage from CT evidence? The advent of thrombolysis may of course alter the occurence of such patients: if all are scanned within 3 hours of onset of symptoms, we may not see haemorrhagic transformation of ischaemic strokes, except as a complication of treatment. Competing interests: None declared Editorial note
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Mushtaq Wani, Consultant, Stroke Medicine Morriston Hospital, Swansea, SA6 6NL
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Re: primary intracerebral haemorrhage and very high risk of embolic stroke Thank you Dr Pita for your comments which highlight further dilema in managing patients with prosthetic valves who have suffered an intracranial haemorrhage. Although this setting was not the main theme of our clinical review, the issue has been briefly touched upon. Some of the references you've cited have also been quoted. Re: Warfarin or aspirin for stroke prevention? - using decision models to aid complex decision making. 12 September 2005 Thank you Dr Anderson for your comment. I agree trials in this area are very difficult to conduct but I would not rule out the possiblity although I personally do not have any experience in conceptualising/formualting any multicentre trials. Decision-making models could be an alternative which again I would prefer to see to be put to the test before being recommended as a standard. I would be keen to see your paper on this issue; perhaps you'll be kind enough to mail me when it is ready. Competing interests: None declared |
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David M Wilson, SpR Stroke Unit Belfast City Hospital Belfast City Hospital, Lisburn Rd, Belfast, BT9 7AB, MI Wiggam
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Editor - We congratulate Wani et al, on their discussion of the evidence base for antiplatelet and anticoagulant treatment in their patient with primary intracerebral haemorrhage [1]. We were surprised however, at the final decision to start warfarin, given that the patient had a large disabling stroke. As pointed out in their discussion, secondary prevention studies in atrial fibrillation have included mostly patients with TIA or minor stroke. The European Atrial fibrillation Trial study group defined a minor stroke as grade 3 or less on the modified Rankin scale; patients with a large disabling stroke were excluded [2]. When attempting to apply evidence-based medicine to individuals, we need to consider not only the outcome of the trial, but also inclusion and exclusion criteria. If we apply so-called evidence-based interventions to patients whose characteristics do not correspond to the trial population, then we leave evidence-based medicine behind and enter the realms of speculation. D Wilson SpR, MI Wiggam Consultant Stroke Unit, Belfast City Hospital, Lisburn Rd, Belfast, BT9 7AB [1] Wani M, Nga E, Navaratnasingham R. Should a patient with primary intracerebral haemorrhage receive antiplatelet or anticoagulant therapy? BMJ 2005;331:439 – 42 [2] EAFT (European Atrial fibrillation Trial) Study Group: Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993;342:1255-1262 Competing interests: None declared |
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Mushtaq Wani, Consultant, Stroke Medicine Morriston Hospital, Swansea, SA6 6NL
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Thank you Dr Purchas for your comments and questions. Firstly, the dilemma whether to anticoagulate your patient who had significant pulmonary embolism (presumably as a complication of immobility from stroke - haemorrhagic or haemorrhagic transformation) is akin to our case. The only difference is whereas anticoagulation in our case would have been preventive in your case it was a therapeutic challenge. Clearly on balance there was no other option but to anticoagulate to prevent imminent cardiorespiratory decompensation. Surgical embolectomy followed by inferior venacaval filter insertion to prevent further thromboembolism is a possible option but rarely practical. Secondly, the Royal College of Physician guidelines on investigation of stroke, second edition, recommend a computorised tomogram (CT) of head as soon as possible within 24 hours at the most (even earlier in certain situations) unless there are good clinical reasons for not doing so.[1] Differentiating an ischaemic from haemorrhagic stroke becomes difficult after a week or even earlier. Of course we are all struggling to achieve the standard and have most of our patients scanned within 24 hours. Thirdly, asymptomatic haemorrhagic transformation (HT) is not uncommon. Autopsy studies document higher rate (51% - 71%) in cardioembolic stroke (presumably larger infarcts) than in non-embolic stroke (thrombotic – artery to artery; 2-21%).[2-4] Sequential CT imaging has shown a lower incidence of 2-26% (probably not detecting smaller haemorrhages).[5-7] Horning et al showed a higher occurrence (43% in 28 of 65 cases).[8] As already mentioned in our paper gradient-echo MR imaging has the scope of detecting very minute haemorrhages even at a later stage.[9,10] Okada et al recorded a 40.6% HT during the month after cardio-embolic stroke with a strong relation to vessel reopening which was of 94.9% on follow-up angiography at 20 days (median) in 56 of 59 patients.[11] Age >70 years (50.8% versus 25.9% in <50 years) and moderate and large infarct size (50% and 51.5% versus 2.9% in smaller infarcts) were other major contributory factors to HT. Interestingly thrombolytic and anticoagulant agents (very small numbers) did not affect the incidence of HT (40% versus 40.7%) although the haematomas tended to be much larger. A study which used serial CT imaging (within first 6 hours and then again at 36 to 48 hours) and transcranial doppler (on admission, 6, 12, 24 and 48 hours) of stroke showed spontaneous recanalisation at 6 hours in 18.8% (10/53 cases).[12] 52.8% (28/53 cases) recanalised after 6 hours. HT was detected in 32% (17/53 cases) within first 48 hours. Proximal MCA occlusion, hypodensity≥33% and delayed recanalisation (>6 hours) were significantly associated with HT. None of the 10 cases who recanalised in less than 6 hours developed HT. 58% (11/19) of those who recanalised between 6 and 12 hours and 50% (3/6) of those who recanalised between 12 and 24 hours developed HT. On the other hand only 3 of 15 (20%) patients who did not recanalise had HT. The presence of HT was not related to neurological deterioration at 48 hours. Only PH2 haemorrhagic transformation (haematoma>30% of infracted area with significant mass effect) was associated with any significant neurological deterioration. Fiorelli et al also did not show any significant neurological deterioration associated with HI1 (petechial haemorrhage without space-occupying effect), HI2 (more confluent petechiae without space-occupying effect), or PH1 (haematoma>30% of infracted area with mild space-occupying effect) transformation as compared to the absence of HT in the European Cooperative Acute Stroke Study I (ECASS I).[13] Again Berger et al confirmed that only parenchymal haematoma type 2 (PH2 ) caused symptomatic clinical deterioration.[14] In the NINDS t-PA trial which used 3-hour therapeutic window 6.4% (20/312) of treatment group and 0.64% (2/312) of control group developed symptomatic intracranial haemorrhages at 36 hours from initiation of treatment.[15] Clinical symptoms occurred within 24 hours in all. 10 haemorrhages were fatal (1 in placebo patient). There were 21 asymptomatic haemorrhages (13 in t-PA – 4.1% and 8 – 2.5% in placebo patients) during first 36 hours detected on the safety 24-hour CT. In short, HT spontaneous or thrombolysis-induced is not uncommon but only large PH2 haematomas seem to be clinically important. HT also seems to be related to the timing of recanalisation of an occluded vessel. 3-hour thrombolytic window in the NINDS trial might explain the lower incidence of symptomatic haemorrhagic transformation. Haemorrhagic transformation can be difficult to distinguish from Primary intracerebral haemorrhage (PICH). Demonstration of a new haemorrhage on CT in a patient with previously documented ischaemic infarct who has clinically deteriorated would be an obvious HT. Minor non -confluent haemorrhage within a larger infarct would also be a reasonable assumption of an HT. However, at first presentation, a large PICH with surrounding oedema can be difficult to distinguish from a primary infarct with a large haemorrhagic transformation within it. I am not aware if any other imaging techniques other than possibly gradient-echo MR imaging could help differentiate the two; perhaps our neuroradiology colleagues might be able to comment. In NINDS trial PICH was diagnosed on CT as a typical homogeneous, hyperdense lesion with a sharp border with or without oedema or mass effect. A haemorrhagic infarct (HT) was defined as an acute infarction with punctuate or variable hypodensity/hyperdensity with an indistinct border. The difficulty of differentiating a confluent hyperdensity within an infarct from a PICH was recognised.[15] The trial does not make it clear how many PICH or HT were excluded at randomisation.[16] Lastly, I agree with you that with the advent of thrombolysis we are less likely to see haemorrhagic transformation at 3 hours and perhaps even later. Since in practice routine CT imaging after thrombolysis is not recommended most haemorrhagic transformation diagnosed will be symptomatic with clinical deterioration (deterioration in level of consciousness, increased weakness, headache, increased blood pressure or heart rate).[15] References: 1. National clinical guidelines for stroke; second edition June 2004. Prepared by the Intercollegiate Stroke Working Party. (www.rcplondon.ac.uk/pubs/books/stroke/stroke_guidelines_2ed.pdf) 2. Fisher CM, Adams RD. Observation on brain embolism with special reference to the mechanism of hemorrhagic infarction. J Neuropathol Exp Neurol 1951;10:92-94 3. Lodder J, Kryne-Kubat B, Broekman J. Cerebral hemorrhagic infarction at autopsy: Cardiac embolic cause and the relationship to the cause of death. Stroke 1986;17:626-629. 4. Jorgenscn L, Torvik A. Ischemic cerebrovascular disease in an autopsy series. Part 2. Prevalence, location, pathogenesis, and clinical course of cerebral infarcts. / Neurol Set 1969;9:285-320. 5. Hakim AM, Ryder-Cooke A, Melanson D. Sequential computerized tomographic appearance of strokes. Stroke 1983;14:893-895. 6. Weisberg LA. Nonseptic cardiogenic cerebral embolic stroke: Clinical-CT correlations. Neurology 1985;35:896-898. 7. Furlan AJ, Cavalier SJ, Hobbs RE, Weinstein MA, Modic MT. Hemorrhage and anticoagulation after nonseptic brain infarction. Neurology (NY) 1982;32:280-282. 8. Hornig CR, Dorndorf W, Agnoli AL. Hemorrhagic infarction - A prospective study. Stroke 1986;17:179-185. 9. Tsushima Y, Aoki J, Endo K. Brain microhaemorrhages detected on T2*- weighted gradient-echo MR images. Am J Neuroradiol 2003;24:88-96. 10. Kidwell C, Saver J, Villablanca P, Duckwiler G, et al. Magnetic resonance imaging detection of microbleeds before thrombolysis; an emergency application. Stroke 2002;33:95-98. 11. Okada Y, Yamaguchi T, Minematsu K, Miyashita T, Sawada T, Sadoshima S, Fujishima M, Omae T. Hemorrhagic transformation in cerebral embolism. Stroke. 1989;20:598–603. 12. Molina CA, Montaner J, Abilleira S, Ibarra B, Romero F, Arenillas JF, Alvarez-Sabín J. Timing of spontaneous recanalization and risk of hemorrhagic transformation in acute cardioembolic stroke. Stroke. 2001;32:1079-1084. 13. Fiorelli M, Bastianello S, von Kummer R, del Zoppo GJ, Larrue V, Lesaffre E, Ringleb AP, Lorenzano S, Manelfe C, Bozzao L. Hemorrhagic transformation within 36 hours of a cerebral infarct: relationship with early clinical deterioration and 3-month outcome in the European Cooperative Acute Stroke Study I (ECASS I) cohort. Stroke. 1999;30:2280–2284. 14. Christian Berger, Marco Fiorelli, Thorsten Steiner, Wolf-Rüdiger Schäbitz, Luigi Bozzao, Erich Bluhmki, Werner Hacke, Rüdiger von Kummer. Hemorrhagic transformation of ischemic brain tissue; asymptomatic or symptomatic? Stroke. 2001;32:1330-1335. 15. The NINDS rt-PA Stroke Study Group. Intracerebral hemorrhage after intravenous rt-PA therapy for ischemic stroke. Stroke. 1997;28:2109–2118. 16. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587. Competing interests: None declared |
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Mushtaq Wani, Consultant, Stroke Medicine Morriston Hospital, Swansea, SA6 6NL
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Thank you Dr Wilson and Dr Wiggam. We agree that the secondary prevention trials of anticoagulation in atrial fibrillation have mostly included minor strokes and TIAs. There is also paucity of information as to the optimum time of anticoagulation in these situations and except International Stroke Trial most have not included larger stroke acutely. We have acknowledged our inability to manage the case with full confidence due to a lot of uncertainties surrounding the area which we think is in need of further research. Competing interests: None declared |
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