Improving reperfusion therapy for acute ischaemic stroke
2011; Elsevier BV; Volume: 9; Linguagem: Inglês
10.1111/j.1538-7836.2011.04371.x
ISSN1538-7933
Autores Tópico(s)Peripheral Artery Disease Management
ResumoSummaryBackground: The first generation of clinical reperfusion treatment, intravenous (IV) fibrinolysis with tissue plasminogen activator (tPA), was a transformative breakthrough in stroke care, but is far from ideal. Objectives: To survey emerging strategies to increase the efficacy and safety of cerebral reperfusion therapy. Methods: Narrative review. Results and Conclusions: Innovative IV pharmacologic reperfusion strategies include: extending IV tPA use to patients with mild deficits; developing novel fibrinolytic agents (tenecteplase, desmetolplase, plasmin); using ultrasound to enhance enzymatic fibrinolysis; combination clot lysis therapies (fibrinolytics with GPIIb/IIIa agents or direct thrombin inhibitors); co‐administration of MMP‐9 inhibitors to deter haemorrhagic transformation; and prehospital neuroprotection to support threatened tissues until reperfusion. Endovascular recanalisation strategies are rapidly evolving, and include intra‐arterial fibrinolysis, mechanical clot retrieval, suction thrombectomy, and primary stenting. Combined approaches appear especially promising, using IV fibrinolysis to rapidly initiate reperfusion, mechanical endovascular treatment to debulk large, proximal thrombi, and intra‐arterial (IA) fibrinolysis to clear residual distal thrombus elements and emboli. Background: The first generation of clinical reperfusion treatment, intravenous (IV) fibrinolysis with tissue plasminogen activator (tPA), was a transformative breakthrough in stroke care, but is far from ideal. Objectives: To survey emerging strategies to increase the efficacy and safety of cerebral reperfusion therapy. Methods: Narrative review. Results and Conclusions: Innovative IV pharmacologic reperfusion strategies include: extending IV tPA use to patients with mild deficits; developing novel fibrinolytic agents (tenecteplase, desmetolplase, plasmin); using ultrasound to enhance enzymatic fibrinolysis; combination clot lysis therapies (fibrinolytics with GPIIb/IIIa agents or direct thrombin inhibitors); co‐administration of MMP‐9 inhibitors to deter haemorrhagic transformation; and prehospital neuroprotection to support threatened tissues until reperfusion. Endovascular recanalisation strategies are rapidly evolving, and include intra‐arterial fibrinolysis, mechanical clot retrieval, suction thrombectomy, and primary stenting. Combined approaches appear especially promising, using IV fibrinolysis to rapidly initiate reperfusion, mechanical endovascular treatment to debulk large, proximal thrombi, and intra‐arterial (IA) fibrinolysis to clear residual distal thrombus elements and emboli. It is true that cerebral reperfusion therapy has been a tremendous success in its first decade and a half of application, since the publication of the two pivotal NINDS‐TPA trials in 1995 [1The National Institute of Neurological Disorders Stroke and rt‐PA Stroke Study GroupTissue plasminogen activator for acute ischemic stroke.NEJM. 1995; 333: 1581-7Crossref Scopus (10124) Google Scholar]. Stroke is the leading combined cause of death and disability worldwide [2Kaste M. Every day is a world stroke day: act now, be a stroke champion and a torchbearer!.Stroke. 2010; 41: 2449-50Crossref PubMed Scopus (5) Google Scholar]. Each year, more than 15 million people suffer a stroke. IV fibrinolysis is now an accepted staple of acute stroke care throughout the world. Treatment within the first 3 h of onset improves outcome in c.290 of every 1000 patients treated, and treatment between 3 and 4.5 h improves outcome in c.140 of every 1000 patients treated [3Saver J.L. 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Also, reperfusion must occur early to be beneficial. Every minute that goes by without reperfusion, more tissue in the ischaemic zone progresses from ailing but salvageable penumbral tissue to irreversibly infarcted core. In the first 3 h after a vascular occlusion, virtually every patient still harbours at least some salvageable penumbral tissue. Thereafter, a steadily increasing proportion of patients will have fully completed their initial infarct. By 12–24 h, virtually no patient still has tissue at risk that has not already progressed to infarction. Techniques to identify the subset of late‐arriving patients who still harbour salvageable tissues and will benefit from delayed recanalisation remain incompletely validated. Fortunately, several strategies to improve cerebral reperfusion therapy are progressing in preclinical studies and human clinical trials. This review will highlight several advances that presage another coming paradigm shift, from an era of moderately effective to an era of highly effective reperfusion treatment for acute ischaemic stroke. Systematic studies have shown that it takes an average of 17 years for new knowledge generated by randomised controlled trials to be incorporated into practice, and even then the application is highly uneven [14Institute of MedicineCrossing the Quality Chasm: A New Health System for the 21st Century. National Academies Press, 2001Google Scholar]. IV fibrinolysis for acute cerebral ischaemia, which will reach the 17‐year translation milestone in 2012, well illustrates the challenges to rapid dissemination of a novel, efficacious therapy. When thrombolytic stroke therapy was introduced in the 1990s, it was a disruptive medical innovation that could not easily be incorporated into existing patterns of care. Neurologists resisted the changes in practice that lytic therapy required, including the need to respond emergently to the Emergency Department [15Horowitz S.H. Thrombolytic therapy in acute stroke: neurologists, get off your hands!.Arch Neurol. 1998; 55: 155-7Crossref PubMed Scopus (21) Google Scholar]. Radiologists resisted reading CT or MR scans emergently, rather than the following morning during routine reading sessions [16Burton T. Doctors push for more scans in stroke cases.Wall St J. 2009; 21: Sect. D1Google Scholar]. Emergency Physicians resisted having to give a therapy with risks as well as benefits, for a complex brain disease, if they were not supported by neurologist, radiologist, and institutional backing [17American College of Emergency Physicians. Use of intravenous tPA for the management of acute stroke in the Emergency Department. http://www.acep.org/content.aspx?id=29834 2002. Accessed 8 June 2011.Google Scholar]. 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Attitudes and beliefs of Michigan emergency physicians toward tissue plasminogen activator use in stroke: baseline survey results from the INcreasing Stroke Treatment through INteractive behavioral Change Tactic (INSTINCT) Trial Hospitals.Stroke. 2010; 41: 2026-32Crossref PubMed Scopus (33) Google Scholar]; hospital‐level commitments to create stroke units and stroke centres [21Alberts M.J. Hademenos G. Latchaw R.E. Jagoda A. Marler J.R. Mayberg M.R. Starke R.D. Todd H.W. Viste K.M. Girgus M. Shephard T. Emr M. Shwayder P. Walker M.D. Recommendations for the establishment of primary stroke centers. Brain Attack Coalition.JAMA. 2000; 283: 3102-9Crossref PubMed Scopus (593) Google Scholar]; development of regional and national certifying authorities to designate and regulate stroke centres [22Schwamm L.H. Pancioli A. Acker III, J.E. Goldstein L.B. Zorowitz R.D. Shephard T.J. Moyer P. Gorman M. Johnston S.C. Duncan P.W. Gorelick P. Frank J. Stranne S.K. Smith R. Federspiel W. Horton K.B. 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Timeliness of tissue‐type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door‐to‐needle times within 60 minutes.Circulation. 2011; 123: 750-8Crossref PubMed Scopus (450) Google Scholar]; and studies indicating safety and benefit across race‐ethnic groups with distinctive stroke aetiologies and haemorrhage propensities (including Asians and Blacks) [28Nakagawara J. Minematsu K. Okada Y. Tanahashi N. Nagahiro S. Mori E. Shinohara Y. Yamaguchi T. Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice: the Japan post‐Marketing Alteplase Registration Study (J‐MARS).Stroke. 2010; 41: 1984-9Crossref PubMed Scopus (137) Google Scholar, 29Chao A.C. Hsu H.Y. Chung C.P. Liu C.H. Chen C.H. Teng M.M. Peng G.S. Sheng W.Y. Hu H.H. 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In a regional system, prehospital Emergency Medical Services providers preferentially route most acute stroke patients directly to Primary Stroke Centres capable of delivering IV fibrinolytic therapy reliably and safely, and select acute stroke patients directly or by interfacility transfer to Comprehensive Stroke Centres capable of endovascular recanalisation interventions, more sophisticated, multimodal imaging, and neurocritical care [31Acker III, J.E. Pancioli A.M. Crocco T.J. Eckstein M.K. Jauch E.C. Larrabee H. Meltzer N.M. Mergendahl W.C. Munn J.W. Prentiss S.M. Sand C. Saver J.L. Eigel B. Gilpin B.R. Schoeberl M. Solis P. Bailey J.R. Horton K.B. Stranne S.K. Implementation strategies for emergency medical services within stroke systems of care: a policy statement from the American Heart Association/American Stroke Association Expert Panel on Emergency Medical Services Systems and the Stroke Council.Stroke. 2007; 38: 3097-115Crossref PubMed Scopus (167) Google Scholar]. These systems to date have achieved wide, but uneven distribution. In the United States, at the end of 2010, 53% of the population lived in a state or a county with a regional acute stroke care system, but 47% did not [8Song S. Saver J. Growth of regional stroke systems of care in the United States in the first decade of the 21st century.Stroke. 2011; 42: e340Google Scholar]. In Europe, penetration of regional acute stroke systems varies markedly across countries. In much of Asia, individual hospitals are well‐organised, but rationalised ambulance routing is fragmentary. In low and middle income nations of the world, access to recanalisation therapy is limited [5Hachinski V. Donnan G.A. Gorelick P.B. Hacke W. Cramer S.C. Kaste M. Fisher M. Brainin M. Buchan A.M. Lo E.H. Skolnick B.E. Furie K.L. Hankey G.J. Kivipelto M. Morris J. Rothwell P.M. Sacco R.L. Smith Jr, S.C. Wang Y. Bryer A. et al.Stroke: working toward a prioritized world agenda.Stroke. 2010; 41: 1084-99Crossref PubMed Scopus (88) Google Scholar]. Fortunately, with increasing recognition that acute stroke systems pay for themselves by reducing long‐term health system costs associated with post stroke disability, more and more national healthcare systems are devoting appropriate resources to build out of regional systems of care. The demonstration that telemedicine can cost‐effectively extend imaging interpretation and bedside stroke specialist expertise to remote sites is accelerating the geographic development of stroke‐ready hospitals [32Switzer J.A. Hall C. Gross H. Waller J. Nichols F.T. Wang S. Adams R.J. Hess D.C. A web‐based telestroke system facilitates rapid treatment of acute ischemic stroke patients in rural emergency departments.J Emerg Med. 2009; 36: 12-8Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. Within established stroke centres, further improvements in outcome from standard IV fibrinolysis can be achieved by systematic efforts to reduce the time interval from patient arrival to start of drug infusion – the door to needle (DTN) time. The therapeutic benefit of tPA is greatest when given early after ischaemic stroke onset and declines exponentially with time, to no significant benefit after 4.5 h [24Lees K.R. Bluhmki E. von Kummer R. Brott T.G. Toni D. Grotta J.C. Albers G.W. Kaste M. Marler J.R. Hamilton S.A. Tilley B.C. Davis S.M. Donnan G.A. Hacke W. Allen K. Mau J. Meier D. del Zoppo G. De Silva D.A. Butcher K.S. et al.Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.Lancet. 2010; 375: 1695-703Abstract Full Text Full Text PDF PubMed Scopus (1656) Google Scholar, 33Saver J.L. Time is brain – quantified.Stroke. 2006; 37: 263-6Crossref PubMed Scopus (1212) Google Scholar]. With every 10 min delay in the start of thrombolytic infusion within the 1–4.5 h treatment time period, one fewer patient out of 100 patients has an improved disability outcome [34Lansberg M. Bluhmki E. Saver J. Number needed to treat estimates for tPA per 90‐minute time interval.Stroke. 2008; 39: 560Google Scholar]. Because of the importance of rapid treatment, treatment guidelines recommend that hospitals complete the clinical and imaging evaluation of acute ischaemic stroke patients and initiate IV tPA therapy within 60 min of patient arrival in those without contraindications [35Marler J.R. Winters Jones P. Emr M. The National Institute of Neurological Disorders and Stroke: Proceedings of National Symposium on Rapid Identification and Treatment of Acute Stroke. National Institute of Neurological Disorders and Stroke, 1997Google Scholar, 36Summers D. Leonard A. Wentworth D. Saver J.L. Simpson J. Spilker J.A. Hock N. Miller E. Mitchell P.H. Comprehensive overview of nursing and interdisciplinary care of the acute ischemic stroke patient: a scientific statement from the American Heart Association.Stroke. 2009; 40: 2911-44Crossref PubMed Scopus (188) Google Scholar]. However, this target is more often missed than achieved. In the United States, among over 25 500 tPA treated patients in the national Get With The Guidelines – Stroke registry, only a little over one quarter had DTN times within 60 min and the overall median DTN time was 78 min [27Fonarow G.C. Smith E.E. Saver J.L. Reeves M.J. Bhatt D.L. Grau‐Sepulveda M.V. Olson D.M. Hernandez A.F. Peterson E.D. Schwamm L.H. Timeliness of tissue‐type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door‐to‐needle times within 60 minutes.Circulation. 2011; 123: 750-8Crossref PubMed Scopus (450) Google Scholar]. In Europe, among nearly 24 000 tPA patients in the SITS‐ISTR registry, fewer than half had DTN times under 60 min, and median DTN time was 65 min for those treated within 3 h of onset and 77 min for those treated between 3 and 4.5 h [37Ahmed N. Wahlgren N. Grond M. Hennerici M. Lees K.R. Mikulik R. Parsons M. Roine R.O. Toni D. Ringleb P. Implementation and outcome of thrombolysis with alteplase 3–4.5 h after an acute stroke: an updated analysis from SITS‐ISTR.Lancet Neurol. 2010; 9: 866-74Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar]. To improve DTN times in the United States, the American Heart Association/American Stroke Association in 2010 launched the Target: Stroke campaign, disseminating to stroke centre hospitals key best practice strategies that are associated with achieving faster DTN times in acute ischaemic stroke. Among the 10 key strategies chosen by Target: Stroke are: Emergency Medical Service prearrival‐notification, activating the stroke team with a single call, rapid acquisition and interpretation of brain imaging, use of specific protocols and tools, pre‐mixing tPA, a team‐based approach, and rapid data feedback. With build out of regional stroke systems of care and acceleration of in hospital treatment delivery processes, it should be possible to deliver standard IV fibrinolytic therapy effectively to 8–15% of all patients with ischaemic stroke in any geographic region, including 30–50% of all patients with moderate to severe ischaemic strokes [38Majersik J.J. Smith M.A. Zahuranec D.B. Sanchez B.N. Morgenstern L.B. Population‐based analysis of the impact of expanding the time window for acute stroke treatment.Stroke. 2007; 38: 3213-7Crossref PubMed Scopus (40) Google Scholar]. It is a little appreciated, but well‐demonstrated, fact that the majority of ischaemic strokes are mild. In one population‐based sample, 67% of all ischaemic stroke patients present with an NIH Stroke Scale score of 5 or less, one common definition of mild deficits [39Khatri P. Khoury J.C. Alwell K. Moomaw J.C. Kissela B.M. Woo D. Flaherty M.L. Adeoye O. Ferioli S. Kleindorfer D.O. The public health impact of an effective acute treatment for mild ischemic strokes (abstract).Stroke. 2011; 42: e66Google Scholar]. Among consecutive, hospital‐presenting patients, the median NIH Stroke Scale deficit severity score among consecutive, unselected ischaemic stroke patients is 5–6 [40Weimar C. Mieck T. Buchthal J. Ehrenfeld C.E. Schmid E. Diener H.C. Neurologic worsening during the acute phase of ischemic stroke.Arch Neurol. 2005; 62: 393-7Crossref PubMed Scopus (171) Google Scholar, 41Sato S. Toyoda K. Uehara T. Toratani N. Yokota C. Moriwaki H. Naritomi H. Minematsu K. Baseline NIH Stroke Scale Score predicting outcome in anterior and posterior circulation strokes.Neurology. 2008; 70: 2371-7Crossref PubMed Scopus (181) Google Scholar]. Mild or rapidly improving initial stroke deficits are a frequent reason for non‐use of tPA treatment. Patients with nondisabling deficits at presentation were excluded from the pivotal trials because mild impairments were felt insufficient to justify exposure to the risk of haemorrhagic side effects. However, multiple studies have now shown that 25–40% of patients in whom IV tPA is withheld due to mild initial deficits have poor final functional outcomes [42Barber P.A. Zhang J. Demchuk A.M. Hill M.D. Buchan A.M. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility.Neurology. 2001; 56: 1015-20Crossref PubMed Scopus (625) Google Scholar, 43Fischer U. Baumgartner A. Arnold M. Nedeltchev K. Gralla J. Marco De Marchis G. Kappeler L. Mono M.‐.L. Brekenfeld C. Schroth G. Mattle H.P. What is a minor stroke?.Stroke. 2010; 41: 661-6Crossref PubMed Scopus (238) Google Scholar, 44Rajajee V. Kidwell C. Starkman S. Ovbiagele B. Alger J.R. Villablanca P. Vinuela F. Duckwiler G. Jahan R. Fredieu A. Suzuki S. Saver J.L. Early MRI and outcomes of untreated patients with mild or improving ischemic stroke.Neurology. 2006; 67: 980-4Crossref PubMed Scopus (162) Google Scholar]. Frequently, these patients have flow through collateral routes that is adequate to support the neural parenchyma during the first few hours after onset, but fails over the next day or two. A persisting large artery occlusion is a strong predictor of delayed deterioration among mild deficit patients [44Rajajee V. Kidwell C. Starkman S. Ovbiagele B. Alger J.R. Villablanca P. Vinuela F. Duckwiler G. Jahan R. Fredieu A. Suzuki S. Saver J.L. Early MRI and outcomes of untreated patients with mild or improving ischemic stroke.Neurology. 2006; 67: 980-4Crossref PubMed Scopus (162) Google Scholar]. When these patients deteriorate beyond the 3–4.5 h window, the opportunity to use thrombolytic therapy has been lost. The risks of thrombolytic therapy in patients with mild or rapidly improving deficits are likely substantially lower than in moderate to severe deficit patients. Haemorrhagic transformation risk is directly related to the volume of irreversibly infarcted tissue present at the time of fibrinolytic exposure [45Singer O.C. Humpich M.C. Fiehler J. Albers G.W. Lansberg M.G. Kastrup A. Rovira A. Liebeskind D.S. Gass A. Rosso C. Derex L. Kim J.S. Neumann‐Haefelin T. Risk for symptomatic intracerebral hemorrhage after thrombolysis assessed by diffusion‐weighted magnetic resonance imaging.Ann Neurol. 2008; 63: 52-60Crossref PubMed Scopus (170) Google Scholar, 46Lee S.J. Saver J.L. Liebeskind D.S. Ali L. Ovbiagele B. Kim D. Vespa P. Froehler M. Tenser M. Gadhia J. Starkman S. Safety of intravenous fibrinolysis in imaging‐confirmed single penetrator artery infarcts.Stroke. 2010; 41: 2587-91Crossref PubMed Scopus (17) Google Scholar]. Since established infarct cores are quite small in patients with mild stroke deficits, haemorrhagic risk should also be much reduced. However, the degree to which thrombolytic therapy may improve outcome in mild stroke patients is uncertain. Since many of these patients do well without re
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