Published on March 14, 2014
Stroke IV thrombolysis beyond limitations; case series and review of literature
Review Article Stroke IV thrombolysis beyond limitations; case series and review of literature Mukesh Sharma a, *, Mudgerikar Sucheta a , Andani Naresh b a Senior Consultant, Department of Neurology, Apollo Hospital, Ahmedabad, India b Junior Registrar, Department of Neurology, Apollo Hospital, Ahmedabad, India a r t i c l e i n f o Article history: Received 5 August 2013 Accepted 7 August 2013 Available online 12 September 2013 Keywords: Thrombolytic therapy Intravenous recombinant tissue- type plasminogen activator (IV rtPA) Alteplase Ischemic stroke Hyperglycemia a b s t r a c t Background: Thrombolytic therapy with intravenous alteplase for ischemic stroke is restricted by guidelines, because of the risk of hemorrhage, especially in the brain, and only a small number of selected patients are being treated. Findings from meta analyses and post licensing experience suggest that more subjects, who otherwise have a poor predicted outcome without treatment, might beneﬁt from intravenous. Methods: We retrospectively assessed clinical safety of the IV stroke thrombolysis beyond guidelines in 20 patients out of 140 total patients thrombolysed by IV rtPA in our depart- ment. Patient eligible for thrombolysis within 3 h were selected by CT or MRI and beyond 3 h only by MRI brain. Imaging study was done at the time of presentation and after 24 h to rule out symptomatic ICH. Finding: We have not recorded any symptomatic ICH in any patients which we thrombo- lysed beyond guideline. Two patients had asymptomatic hemorrhagic transformation. Conclusion: This document does not intend to change the guidelines but reviews the liter- ature on the use of intravenous alteplase for stroke beyond guidelines and in particular conditions which help in more and more patients can be beneﬁted by stroke thrombolysis. Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. 1. Introduction Thrombolytic therapy is the only available medical treatment for acute ischemic stroke that has been proven to be effective. Intravenously administered recombinant tissue plasminogen activator (rtPA) has been shown to improve the long-term functional outcome1,2 and is recommended for the treatment of eligible acute stroke patients.3e5 However, due to the risk of major bleeding, particularly in the brain, patients need to be carefully selected on the basis of eligibility criteria. These have been largely adopted from the inclusion and exclusion criteria used in the randomized clinical trials.6,7 There is increasing evidence that the commonly used intravenous recombinant tissue-type plasminogen activator (IV rtPA) eligibility criteria are sometimes too restrictive and limit the use of thrombolysis in acute stroke. A number of recent studies have reported that treatment of patients with common IV rtPA exclusion criteria does not result in an increased complication rate or in worse outcome.8,9 The purpose of this review is to gather the available literature on the use of intravenous alteplase for stroke beyond the guidelines and in situations not well covered by the guidelines and put forth our experience in this matter. * Corresponding author. E-mail address: firstname.lastname@example.org (M. Sharma). Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/apme a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 1 1 e2 1 6 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2013.08.004
1.1. Beyond 4.5 h We have thrombolysed three patients between 4.5 and 6 h on the basis of diffusion and clinical mismatch. One patient showed hemorrhagic transformation without symptomatic worsening [Fig. 1]. Pooled analysis of data from the National Institute of Neurological Disorders and Stroke (NINDS) trials (parts 1 and 2, 3-h window),5 the 2 European Cooperative Acute Stroke Study (ECASS) trials (6-h window),7,10 and the 2 Alteplase Thrombolysis for Acute Non-interventional Ther- apy in Ischemic Stroke (ATLANTIS) trials (part A, 6-h window and part B, 5-h window),6,11 suggest a potential beneﬁt from treatment beyond 3 h. The odds ratio for a favorable outcome was 1.40 (95% CI, 1.05e1.85) for patients treated between 3 and 4.5 h, and 1.15 (0.90e1.47) for those treated between 4.5 and 6 h. What the pooled analysis clearly demonstrated is that the sooner alteplase is given to stroke patients, the greater the beneﬁt, especially if started within 90 min. The adage “time is brain”, which has now become widely familiar in the medical community, should be further promoted in the general public. 1.2. Age 80 or older We have thrombolysed four patients above the age of 80 years and none of them developed intracranial bleed. Because most studies excluded patients above age 80, the risk of SICH (Se- vere Intracerebral hemorrhage) in this population has not been well studied. However, in the Canadian Alteplase for Stroke Effectiveness Study, which was included in this review, and 1 additional study which did not meet inclusion criteria for this review, the rate of SICH in rtPA-treated patients older than 80 years was not different from patients younger than 80.12 Moreover, in the NINDS tPA trial, which had no upper age limit in the latter part of the study, no association between age and SICH was found. In a recent systematic review that compared stroke outcome after rtPA in older versus younger patients no increased risk of SICH was found with advancing age.13 These data suggest that acute stroke patients above 80 should not be excluded from treatment with tPA based on their SICH risk. 1.3. Age 18 or less The clinical trials did not enroll persons under the age of 18 years. We have thrombolysed one patient with RHD (Rheumatic Heart Disease), AF below 18 years of age with consent without any complication. Only a few cases, ranging in age from 12 to 16 years, have been reported to have received rtPA.14 There were no complications and all had a good outcome. 1.4. Seizure at onset As it may be difﬁcult to differentiate ischemic stroke from postictal Todd paralysis by clinical examination and brain CT scan, current guidelines exclude patients with seizure at stroke onset. MRI or angiography can be used to conﬁrm the diagnosis of an acute ischemic process in the presence of concurrent seizures, and these patients can be treated. We have treated two patients with stroke with seizure at onset with intravenous rtPA with good results. 1.5. Hyperglycemia Two patients came in window period with sugar level more than 400 mg/dl. We started insulin infusion before sending patient to MRI and thrombolysed the patients after MRI brain without any post thrombolysis hemorrhage. Hyperglycemia may not only hamper the ﬁbrinolytic process, delaying alteplase-induced reperfusion of the ischemic penumbra, but treatment is also associated with increased cerebral hemorrhage and worse outcome. A retrospective analysis of 138 consecutive alteplase treated patients showed that the rate of hemorrhage already sharply increased above a glucose level >8.4 mmol/L. Levels >11.1 mmol/L were associated with a 25% symptomatic hem- orrhage rate.15 It remains to be determined whether aggressive therapy for glycemic control before reperfusion may improve the efﬁcacy and safety of thrombolytic therapy in these patients. 1.6. Thrombocytopenia One patient who perfectly ﬁtted criteria for thrombolysis was found to have platelets count 95,000/cmm. We checked PT and Fig. 1 e Post thrombolysis asymptomatic hemorrhagic transformation in two patients. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 1 1 e2 1 6212
APTT which were normal and thrombolysed within 90 min with excellent results. A very low platelet count (<100,000/ cmm) is a contraindication for the routine use of rtPA1 and thrombolytic trials have generally excluded these patients. Therefore, data are only available on patients with platelet counts exceeding 100,000/cmm. One study identiﬁed lower platelet counts as an independent risk factor for SICH.10 In the other 2 studies no association was found in either univariate or multivariate analyses.16,17 1.7. Deranged PT and APPT We have done one case with INR 3 and APPT twice than the control. In both cases thrombolysis was started very early, within 30 min of onset of stroke. We got PT and APTT reports when half the dose of alteplase had already been given. One of the patients showed dense MCA sign which recovered 24 h later on follow up CT scan. We have not found any literature about thrombolysis beyond INR I.7 and deranged APTT [Figs. 2 and 3]. 1.8. Severe stroke Patients with severe strokes (National Institute of Health Stroke Scale score >20) have a poor prognosis whether or not they are treated with alteplase. Because the risk of hemor- rhage is higher among this population, caution should be exercised. However, these patients may still beneﬁt from treatment, as shown in a post hoc analysis of the NINDS,1 and the pooled analysis of the NINDS, ECASS and ATLANTIS Fig. 2 e Dense MCA sign in high PT patient. Fig. 3 e Post IV rtPA dense MCA sign disappear. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 1 1 e2 1 6 213
trials.7,11 Posterior circulation stroke mainly basilar artery occlusion usually presented with more than 22 NIHHS score. We have experience in two such patients who had complete basilar block and recovered well after thrombolysis [Figs. 4 and 5]. 1.9. Mild or rapidly improving symptoms About one third of acute stroke patients with rapid improvement of neurological deﬁcit on arrival at the hospital develop severe subsequent deterioration.28,29 In 19 patients with rapidly improving symptoms, treatment with intrave- nous alteplase was associated with good outcome. These preliminary data suggest that withholding intravenous thrombolysis because of mild or improving symptoms may not always be justiﬁed. We have thrombolysed one patient in whom motor deﬁcit improved partially but sensory aphasia persisted. There was complete improvement in power post thrombolysis and speech improved well over 48 h. Another patient with right hemianopia and left P3 segment block improved completely post thrombolysis [Figs. 6 and 7]. 1.10. Intracranial aneurysm Uncomplicated thrombolysis with intravenous alteplase was reported in 2 stroke patients with unruptured cerebral aneu- rysms, and in another 2 patients with myocardial infarction who had previously been treated for cerebral aneurysm (1 clipped and 1 coiled). Five cases have been described with an intracranial aneurysm detected after intra-arterial thrombol- ysis for stroke; 2 had a fatal intracranial hemorrhage. Our patient was thrombolysed twice in 13 months without any complications [Fig. 8]. Fig. 4 e Basilar A. blocked. Fig. 5 e Post rtPA reopening of basilar artery and small infarct. Fig. 6 e Left PCA blocked. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 1 1 e2 1 6214
2. Conclusion IV thrombolysis remains the only proven effective treatment for acute ischemic stroke. Streamlining of treatment criteria might substantially increase the number of patients selected for treatment. It is imperative that this important aspect of IV thrombolytic treatment be addressed and efforts made to deﬁne common eligibility criteria for treatment with rtPA. Only in this way we can safely and effectively increase the use of throm- bolysis and achieve the ultimate goal of improved patient care. Conﬂicts of interest All authors have none to declare. r e f e r e n c e s 1. Tissue plasminogen activator for acute ischemic stroke: the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581e1587. 2. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999;282:2003e2011. 3. Adams H, Adams R, Del Zoppo G, Goldstein LB. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update e a scientiﬁc statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke. 2005;36:916e923. 4. Adams Jr HP, Adams RJ, Brott T, et al. Guidelines for the early management of patients with ischemic stroke: a scientiﬁc statement from the Stroke Council of the American Stroke Association. Stroke. 2003;34:1056e1083. 5. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl 3):483Se512S. 6. Clark WM, Albers GW, Madden KP, Hamilton S. Thromblytic therapy in acute ischemic stroke study investigators. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study. Stroke. 2000;31:811e816. 7. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352:1245e1251. 8. Meretoja A, Putaala J, Tatlisumak T, et al. Off-label thrombolysis is not associated with poor outcome in patients with stroke. Stroke. 2010;41:1450e1458. 9. Rubiera M, Ribo M, Santamarina E, et al. Is it time to reassess the SITS-MOST criteria for thrombolysis? A comparison of patients with and without SITS-MOST exclusion criteria. Stroke. 2009;40:2568e2571. 10. Norris JW, Buchan A, Cote R, et al. Canadian guidelines for intravenous thrombolytic treatment in acute stroke: a consensus statement of the Canadian Stroke Consortium. Can J Neurol Sci. 1998;25:257e259. 11. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999;282:2019e2026. 12. Sylaja PN, Cote R, Buchan AM, Hill MD, on behalf of Canadian Alteplase for Stroke Effectiveness Study (CASES) Investigators. Thrombolysis in patients older than 80 years with acute ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study. J Neurol Neurosurg Psychiatry. 2006;77:826e829. 13. Engelter ST, Bonati LH, Lyrer PA. Intravenous thrombolysis in stroke patients of 80 versus <80 years of age e a systematic review across cohort studies. Age Ageing. 2006;35:572e580. 14. Carlson MD, Leber S, Deveikis J, Silverstein FS. Successful use of rt-PA in pediatric stroke. Neurology. 2001;57:157e158. 15. Demchuk AM, Morgenstern LB, Krieger DW, et al. Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke. Stroke. 1999;30:34e39. 16. Tanne D, Kasner SE, Demchuk AM, et al. Markers of increased risk of intracerebral hemorrhage after intravenous Fig. 8 e Inferior branch of left MCA blocked with left ICA aneurysm. Fig. 7 e Post rtPA PCA opened. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 1 1 e2 1 6 215
recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: the Multicenter rt-PA Stroke Survey. Circulation. 2002;105:1679e1685. 17. Kase CS, Furlan AJ, Wechsler LR, et al. Cerebral hemorrhage after intra-arterial thrombolysis for ischemic stroke: the PROACT II trial. Neurology. 2001;57:1603e1610. f u r t h e r r e a d i n g 18. Larrue V, von Kummer R, Muller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II). Stroke. 2001;32:438e441. 19. Smith EE, Abdullah AR, Petkovska I, Rosenthal E, Koroshetz WJ, Schwamm LH. Poor outcomes in patients who do not receive intravenous tissue plasminogen activator because of mild or improving ischemic stroke. Stroke. 2005;36:2497e2499. 20. Barber PA, Zhang J, Demchuk AM, Hill MD, Buchan AM. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology. 2001;56:1015e1020. 21. Kane I, Sandercock P, Thomas B. Can patients with unruptured intracranial aneurysms be treated with thrombolysis? Cerebrovasc Dis. 2005;20:51e52. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 1 1 e2 1 6216
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Review Article Stroke IV thrombolysis beyond limitations; case series and review of literature Mukesh Sharmaa,*, Mudgerikar Suchetaa, Andani Nareshb
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