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REVIEW The great ESCAPE – a clinical pharmacologist’s journey in stroke research Correspondence Professor David Williams, BSc(Pharmacy) MB, BAO, BCh, PhD, FRCPI, FRCPE, FBPhS, FBHS, RCSI, Department of Geriatric and Stroke Medicine, Royal College of Surgeons in Ireland and Beaumont Hospital. Tel.: +353 1797 4791; Fax: +353 1797 4792; E-mail: [email protected] This lecture was delivered as the GSK prize lecture at the annual meeting of the British Pharmacological Society in December 2015. A recording of the lecture can be found at https://www.youtube.com/watch?v=85zJl8uLLlY&index=1&list=PLxoEwD0mB8KqTqBs4QeRUMIRbyQrPCWt_
Received 2 March 2016; revised 4 April 2016; accepted 4 April 2016
David J. P. Williams Royal College of Surgeons in Ireland (RCSI) and Beaumont Hospital Dublin, Dublin, Ireland
Keywords endovascular therapy, pharmacoepidemiology, platelets, secondary prevention, stroke
Stroke is a major cause of death and disability, and the commonest form of acquired major physical disability in adult life, with up to one in six people suffering a stroke in their lifetime. The great ESCAPE – a clinical pharmacologist’s journey in stroke research outlines how clinical pharmacology, and stroke in particular, provides an example of the translational medicine continuum from bench to bedside to community to public policy. Clinical pharmacology is well positioned to have an ever-increasing role in the shaping of future health policies, particularly in the field of patient safety. Endovascular therapy will become the standard of care for treating ischaemic stroke with large vessel occlusion, although the provision of this therapy to all eligible patients will present a challenge to healthcare providers in the future.
Introduction Stroke is a major cause of death and disability, and is one of the most common forms of acquired physical disability in adulthood [1], with up to one in six people suffering a stroke in their lifetime. Stroke is defined as ‘a clinical syndrome characterized by rapidly developing clinical symptoms and/ or signs of focal, and at times global (applied to patients in deep coma and those with subarachnoid haemorrhage), loss of cerebral function, with symptoms lasting more than 24 h or leading to death, with no apparent cause other than that of vascular cause’ [2]. Up to 80% of strokes are ischaemic in origin [3]. While the incidence of stroke is declining, its prevalence will continue to rise as a result of an ever-increasing DOI:10.1111/bcp.12966
ageing population. The management of stroke has often been referred to as the ‘stroke chain of survival’, which begins with the rapid detection of stroke early warning signs and symptoms, followed by rapid paramedical prehospital care, rapid transport and prealert to a comprehensive stroke centre, rapid hospital diagnosis and treatment and, finally, where necessary, rehabilitation, surgical intervention and ongoing tertiary referral [4]. However, one of the principal obstacles to the immediate treatment of stroke is a lack of awareness of its signs and symptoms. A number of research studies have sought to identify these barriers to thrombolysis use, with patient delay in seeking medical attention being highlighted as the main prehospital factor accounting for the underuse of thrombolysis. Media campaigns have been used to promote the identification of the signs and symptoms of stroke as they have the ability to reach a large population and there is a substantial amount of evidence to support the role of a mass media campaign in influencing health services use. In 2010, the Irish Heart Foundation (IHF) funded the Act F.A.S.T. (Face, Arm, Speech, Time) stroke awareness campaign – the first of its kind in Ireland. We employed an interrupted time series design to identify behaviour change related to presentations of suspected stroke in two emergency departments (EDs), serving a population of 580 000, following the introduction of the F.A.S.T campaign. We identified a significant change in ED attendance of patients with reported stroke symptoms after the introduction of the media campaign, although this behaviour was not sustained. Furthermore, ED presentation within 3.5 h (the time window for which thrombolysis was recommended at the time of the study) was associated with © 2016 The British Pharmacological Society
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an increase in emergency medical services (EMS) activation [odds ratio (OR) = 3.1, P < 0.001] and in self-referral to the ED (OR = 2.67, P < 0.001) [5].
Advances in stroke care There have been a number of significant advances in stroke care over the past few decades. Beginning in the early 1990s, evidence for the benefits of stroke units [6], carotid endarterectomy [7] and the use of aspirin [8] to prevent early recurrent stroke appeared in the literature. In 2003, Alteplase was licensed for the treatment of acute ischaemic stroke [9]. This was followed by the development of outpatient stroke/ transient ischaemic attack (TIA) services, which facilitated the rapid assessment of patients presenting with a TIA or minor stroke [10]. This was followed by the development of early supported discharge services, which enabled the timely discharge of patients to the community [11]. Finally, hemicraniectomy for malignant middle cerebral artery (MCA) infarction [12] and the introduction of newer anticoagulants for the prevention of stroke in patients with atrial fibrillation led to further advances in stroke care [13]. Adjusted-dose warfarin is effective in the prevention of stroke in patients with nonvalvular atrial fibrillation [14]. The introduction of the novel oral anticoagulants (NOACs), which act as direct inhibitors of either thrombin or factor Xa, offer potential advantages to patients, including an immediate onset of action, with the potential for eliminating the need for initial treatment or ‘bridging’ of patients at high risk of thrombosis with a parenteral anticoagulant. The relative lack of food interactions, the wide therapeutic index, the limited hepatic metabolism and fewer drug interactions enable fixed dosing of these oral anticoagulants in adults, without the need for specific laboratory monitoring. These agents may also provide greater convenience for patients and healthcare providers, leading to the potential for greater use in comparison with warfarin, particularly in those with atrial fibrillation. They may also prove to be more costeffective than warfarin due to the need for less routine monitoring and fewer serious events requiring hospitalization. However, their renal elimination contraindicates their use or necessitates dose reduction in patients with renal dysfunction. The limited availability of assays for measuring drug levels and the absence of valid and reliable monitoring strategies prevent dose titration and the determination of treatment failure as opposed to poor compliance. There may also be a potential for overuse and they incur a higher acquisition cost in comparison with warfarin. Finally, their shorter half-life results in a rapid decline in anticoagulant/antithrombotic effect if doses are missed and, except for dabigatran, no specific antidote exists in the case of major bleeding.
Acute management of stroke Thrombolysis is a cost-effective treatment for patients suffering an acute ischaemic stroke [15]. However, its effectiveness reduces with time, with no significant benefit after 4.5 h from symptom onset [16]. The proportion of patients with good clinical outcomes [a modified Rankin scale (mRS) of 0–1] following thrombolysis treatment varies from approximately a third overall, based on the time to treatment, and 7–69%, based on the severity of the presenting stroke [17]. While over
a quarter of all stroke patients may be eligible for thrombolytic treatment, international data suggest that significantly fewer stroke patients receive it [18] and that obstacles to the timely management of stroke exist. The implementation of hospital protocols for the rapid identification and treatment of stroke patients have improved the rates of thrombolysis [19]. International guidelines recommend that hospitals complete the clinical and imaging evaluation of stroke patients and initiate thrombolysis within 60 min of a patient’s arrival to hospital in those patients who do not have contraindications to thrombolysis [20]. Every 15-min reduction in door-to-needle time is associated with a one in 20 lower odds of risk-adjusted in-hospital mortality. The American Heart Association(AHA) ‘Get With The Guidelines – Stroke’ program found that only a quarter of patients with acute ischaemic stroke thrombolysed within 3 h of symptom onset had door-to-needle times within 60 min; the reported median door-to-needle time for the entire group was 78 min [20]. The Safe Implementation of Thrombolysis in Stroke – Monitoring Study (SITS-MOST) reported a mean door-to-needle time of 68 min [21]. However, a number of factors contribute to delays in the delivery of thrombolysis, including factors outside (e.g. patient/public awareness) and inside [e.g. delay in transfer to the computed tomography (CT) scanner] the hospital [18]. Acute stroke treatment (thrombolysis and thrombectomy) is complex, from an organizational perspective. The effective notification and response of EMS involves communication between the public, the relevant EMS providers and hospital EDs [22]. Furthermore, successful change in the organization of stroke services requires a coordinated and multidimensional approach to the individual processes of care and is most effective when it includes clear and explicit targets; a patient-focused culture within the organization; collaborative, interdisciplinary teams; and engaged clinical leaders and senior management within the organization. All of these factors are important in improving the functioning of stroke units, quality of care and clinical outcomes [23]. Successful measures to hasten door-to-needle times in acute ischaemic stroke include prearrival notification by EMS staff, hospital protocols for acute triage and patient flow, a single call system to alert all of the hospital stroke team members, rapid CT brain imaging for an incoming patient, location of the CT scanner in the ED and the development of treatment pathways among members of the stroke team [24]. Furthermore, it has been demonstrated that treatment by a mobile stroke unit in a specialized ambulance (equipped with a CT scanner, point-of-care laboratory and telemedicine connection) can significantly reduce the median time from the emergency call for stroke to the time when the decision is made to commence treatment [25]. Pharmacological thrombolysis is limited by a brief time window of up to 4.5 h following symptom onset and a recanalization rate of less than 50% [26].While newer thrombolytic agents offer the promise of higher reperfusion rates [27], large-vessel occlusions in the distal internal carotid artery or the first segment of the middle cerebral artery respond less well to thrombolysis. Transvascular revascularization (thrombectomy) provides an alternative or additional option to thrombolysis for those with severe strokes associated with a large-vessel occlusion. Br J Clin Pharmacol (2016) 82 334–339
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Patients who have suffered a stroke caused by large-artery occlusions, including those affecting the terminal parts of the internal carotid artery and the main stem of the middle cerebral artery, have a poor clinical outcome even with optimum medical care, with up to a quarter dying and approximately a half being left with permanent disability, despite the use of intravenous (IV) thrombolysis [28]. However, the need for better treatment for this group of patients with ischaemic stroke was addressed in 2015 by a series of landmark clinical trials which will shape the future of acute stroke management. In the past, endovascular devices for blood clot retrieval were initially used by interventional neuroradiologists for treating intracranial aneurysms or arteriovenous malformations. They were then increasingly used in the setting of acute ischaemic stroke following decisions by funding agencies to pay for their use, despite their absence of clinical benefit. In 2013, a series of clinical trials [Interventional Management of Stroke III (IMS-3), Mechanical Retrieval and Revascularization of Stroke Clots Using Embolectomy (MR RESCUE) and Synthesis Expansion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in the Local versus Systemic Thrombolysis for Acute Ischaemic Stroke (SYNTHESIS Expansion) trial found no significant benefit for thrombectomy in the management of acute stroke, although concerns were raised regarding the design of these studies, late treatment decisions in a number of cases, the predominant use of older and less refined endovascular devices with higher complication rates, and the variation in the use of advanced imaging for patient selection. The Multicentre Randomized Clinical Trial of Endovascular Treatment of Acute Ischaemic Stroke in the Netherlands (MR CLEAN) study reported an absolute improvement of 13.5 percentage points in the rate of functional independence in patients who were treated with thrombectomy, with no significant differences in mortality or symptomatic haemorrhage between the treatment groups [29]. Most other prespecified clinical endpoints favoured thrombectomy treatment. These results led to the initial suspension of a similar study, Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times (ESCAPE). ESCAPE aimed to evaluate rapid endovascular therapy in addition to standard care in those patients who presented with an acute ischaemic stroke associated with a small core infarct, a proximal intracranial arterial occlusion and moderate-to-good collateral circulation. A total of 316 participants were assigned randomly to receive standard medical care (control group) or standard medical care plus endovascular treatment with the use of available thrombectomy devices (intervention group) [30]. Patients with a proximal intracranial occlusion in the anterior cerebral circulation were included up to 12 h following symptom onset. Those with a large core infarct or poor collateral circulation on head CT and CT angiography were excluded from the study. The median time from study CT of the head to first reperfusion was reported to be 84 min, indicating rapid assessment of patients in this study. The rate of functional independence (defined as a 90-day mRS score of 0–2) increased in the intervention group, from 29.3% to 53% (P < 0.001). The primary outcome analysis favoured the intervention group (common odds ratio 2.6; 95% confidence interval (CI) 336
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1.7, 3.8; P < 0.001), with the intervention being associated with a reduced mortality (10.4% vs. 19.0% in the control group; P = 0.04) [30]. This was the first study of its kind to report an improvement in mortality. Further studies were, in turn, halted as a result of the overwhelming benefit which thrombectomy demonstrated in further interim analyses [30–33]. All of these trials included patients with occlusions of the internal carotid artery or middle cerebral artery, with over 85% of participants being treated with IV thrombolysis initiated soon after symptom onset, and with imaging techniques demonstrating only small areas of irreversibly damaged brain tissue. The majority of patients achieved complete or near-complete tissue reperfusion with thrombectomy, predominantly with stent retrievers, with the majority of patients being treated within 6 h of symptom onset. The significant benefits for participants in these trials translated into numbers needed to treat of between four and eight for recovery to independence. Endovascular therapy is now recognized as a proven standard of care in the management of acute ischaemic stroke. It has provided a significant leap forward in the management of stroke, although it has created challenges to the reorganization of stroke services in order to provide this treatment to all eligible patients.
The translational medicine continuum Translational medicine aims to develop new therapies and insights, leading to the improvement of health in the wider population [34]. Clinical pharmacology, and stroke medicine in particular, provides an example of the translational medicine continuum which starts at bench to bedside, through to bedside to community and, finally, community to overall health policy. Bench to bedside. Platelets play an important part in the pathogenesis of ischaemic stroke, through their involvement in the development of atherosclerosis, arterial thrombosis or arterial embolism. The International Stroke Trial (IST) demonstrated for the first time that aspirin therapy produced a small but real reduction by approximately ten deaths or recurrent strokes per hundred patients during the initial few weeks following a suspected ischaemic stroke, and specifically recommended that aspirin be started as soon as possible following an ischaemic stroke [8]. There has been significant debate in the literature concerning the phenomenon of aspirin ‘failure’ and stroke recurrence, with a number of studies demonstrating a link between future cardiovascular events and aspirin resistance [35, 36]. More recently, it has been demonstrated that carriage of the PIA2 polymorphism of glycoprotein IIIa is a potential risk factor for ischaemic stroke, specifically in stroke of cardioembolic and large-vessel origin [37]. Aspirin ‘failure’ may result from a number of factors, including inadequate dose, reduced bioavailability of aspirin, genetic factors, interactions with other medications, nonplatelet factors (including inherent disease factors) and nonadherence to aspirin therapy. In order to examine the prevalence and nature of aspirin failure in the context of stroke, we studied 51 patients admitted to a stroke unit with a suspected ischaemic stroke who had already been prescribed aspirin. Within 48 h of onset, blood and urine
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samples were taken to assess platelet aggregation, activation and aspirin response by a range of different assay methods. All tests were repeated on a second sample taken 24 h after the witnessed administration of 75 mg or 150 mg aspirin. Incomplete response to aspirin, measured using arachidonic acid (AA)-stimulated platelet aggregation, was found in 43% of patients. Following in-hospital aspirin administration, there was a significant reduction in AA-aggregation, which suggested poor adherence to therapy prior to hospital admission, although residual platelet aggregation (10–15%) persisted in 11 subjects [36]. More recently, a number of studies have highlighted an increased morbidity and mortality following the planned discontinuation of the antiplatelet agent clopidogrel [38, 39]. We therefore investigated whether a ‘rebound’ phenomenon existed by conducting a randomized controlled trial of platelet activity before and after the (Is cessation of clopidogrel therapy associated with rebound of platelet activity in stable vascular disease patients (CLASP)) study. A total of 171 patients receiving aspirin therapy were randomly assigned to either placebo or clopidogrel therapy for 28 days. Platelet function was assessed at pretreatment baseline, on treatment just before discontinuation of the study drug, and on days 7, 14 and 28 after discontinuation. Adenosine diphosphate-stimulated platelet fibrinogen binding, P-selectin expression and platelet aggregation were found to be significantly lower on clopidogrel treatment compared with baseline (P < 0.0001) but returned to baseline levels by 7 days after discontinuation of clopidogrel. A mixedmodel analysis excluding the on-treatment timepoint showed no overall differences between the clopidogrel and placebo groups (P > 0.05), with no evidence of an interaction between platelet inhibition over time and treatment allocation. We therefore found no evidence for a rebound of platelet activity to above baseline after stopping clopidogrel in patients with stable coronary artery disease or peripheral artery disease [40]. Secondary prevention of stroke – bedside to community. Approximately a third of strokes occur in those who have suffered a previous stroke, with approximately half occurring in those with a history of prior vascular events of any kind. These relatively high recurrence rates therefore emphasize the importance of implementing effective secondary preventive strategies. A number of large population-based studies which identified strong associations between cardiovascular risk factors and future stroke risk have helped inform the development of evidence-based guidelines on stroke prevention, aimed at improving future stroke outcomes. However, information on the adequacy of secondary prevention after ischaemic stroke is lacking, despite the evidence that appropriate secondary prevention improves long-term patient outcomes. The Action on Secondary Prevention Interventions and Rehabilitation in Stroke (ASPIRE-S) study prospectively assessed secondary prevention measures in patients 6 months after an ischaemic stroke. A total of 302 patients were recruited over a 1-year period and underwent a comprehensive assessment of ongoing risk factors for stroke at 6 months, modelled on the EUROASPIRE (European Action on Secondary Prevention through Intervention to Reduce Events). protocol for the evaluation
of secondary prevention measures in patients with a history of established cardiac disease. At follow-up, approximately two-thirds of patients had a body mass index greater than 25 kg m–2, and 16.4% were still smoking. Almost two-thirds had a clinic blood pressure greater than 140/90 mmHg and approximately a fifth had a low-density lipoprotein level greater than 2.5 mmol L–1. A quarter of diabetic patients had a glycosylated haemoglobin greater than or equal to 7%. The majority (97%) of patients were receiving antiplatelet and/or anticoagulant therapy. Of those with a diagnosis of atrial fibrillation, 82% were on anticoagulant therapy. The majority (95%) were receiving lipid-lowering therapy, with three-quarters receiving antihypertensive therapy. This study therefore demonstrated a high prevalence of remaining modifiable risk factors at 6 months poststroke. These results provide an opportunity to improve secondary preventive measures following ischaemic stroke by incorporating evidence-based guidelines into future quality assurance cycles in stroke care [41]. Inequalities in the management of coronary heart disease (CHD) and stroke have been widely reported in the literature [42, 43]. CHD is a leading cause of death in women and has a mortality rate higher than for all neoplastic diseases combined [42]. While women suffer chest pain as their chief symptom of cardiac disease more often than men, women are referred less frequently for invasive and non-invasive tests for CHD and are less likely to undergo interventional management of CHD, including percutaneous transluminal coronary angioplasty or coronary artery bypass grafting [44]. Women with ischaemic heart disease are also prescribed beta-blockers and aspirin less frequently and have a poorer long-term prognosis following myocardial infarction. This phenomenon has been referred to as the ‘Yentl syndrome’ (Yentl was the 19th century heroine of Isaac Bashevis Singer’s story, who had to disguise herself as a man to attend school and study the Talmud), whereby a woman has to assume the characteristics of a man to receive equal treatment [45]. Using a large prescription database, our research group therefore wished to determine whether the ‘Yentl syndrome’ existed in Irish primary care. Nitrate prescribing has been shown to be a useful surrogate for diagnosing CHD. We found that women with presumed CHD were less likely to be prescribed a beta-blocker, calcium channel antagonist, statin therapy, aspirin or warfarin compared with their male counterparts. Furthermore, women with presumed CHD were more likely to be prescribed an antidepressant, benzodiazepine or nonsteroidal anti-inflammatory agent [46]. Similar patterns in the management of CHD and stroke have been demonstrated in Scottish primary care [47, 48]. However, the introduction of a new general practice contract based on financial incentives was shown to improve the documentation of quality indicators for the management of stroke. Large increases in the documentation of cardiovascular quality indicators were found among the oldest (>75 years) and most affluent patient groups, although women with stroke were still less likely to have their smoking habits recorded or receive antiplatelet/anticoagulant therapy [49]. Community to policy. It is likely that 2015 will be remembered in the field of stroke as the year when endovascular therapy came of age. However, the provision Br J Clin Pharmacol (2016) 82 334–339
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of this evidence-based treatment to eligible patients will present challenges to healthcare providers. Guidelines for the management of stroke are currently being updated to include the use of endovascular therapy for the acute treatment of stroke. Furthermore, the British Pharmacological Society has recently identified five priorities to help to deliver the future ambitions of clinical pharmacology [50]. These include patient safety, productivity and efficiency, patientcentred care, innovation, and improving access to medicines, and workforce. Clinical pharmacology therefore has an important role to play in the field of patient safety. The Irish National Adverse Events Study (INAES) has recently published its main findings. The prevalence of adverse events (defined as an injury caused by healthcare management resulting in prolonged hospitalization, disability on discharge or death) in 1574 admissions was reported as 12.2% (95% CI 9.5%, 15.5%), with an incidence of 10.3 events per 100 admissions (95% CI 7.5%, 13.1%). Over 70% of these adverse events were deemed preventable. Two-thirds were rated as having a mild-to-moderate impact on the patient, 9.9% causing permanent impairment and 6.7% contributing to death. This was the first study of adverse events to be reported in Ireland and has demonstrated similar rates of adverse events to those in other countries and will provide important baseline data on the adverse event burden for the Irish healthcare system [51].
Conclusion Clinical pharmacology, and stroke medicine in particular, provides an example of the translational medicine continuum from bench to bedside to community to public health policy. Clinical pharmacology is therefore well positioned to have an ever-increasing role in the shaping of future health policies, particularly in the field of patient safety. Endovascular therapy will become the standard of care for treating ischaemic stroke with large-vessel occlusion, although the provision of this therapy will present a challenge to healthcare providers in the future.
Competing Interest Professor Williams has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares that he has served on advisory boards for Bayer, Boehringer Ingelheim, Daiichi Sankyo and Bristol Myers Squibb. He has received a speaker’s fee from Boehringer Ingelheim. I would like to acknowledge all of my collaborators who have contributed to my research over many years.
References 1 Lopez A, Mathers C, Ezzati M, Jamison D, Murray C. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 1747–57.
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2 Hatano S. Experience from a multicentre stroke register: a preliminary report. Bull World Health Organ 1976; 54: 541–53. 3 Sudlow CLM, Wardlow CP. For the International Incidence Collaboration. Comparable studies on the incidence of stroke and its pathological types: results from an international collaboration. Stroke 1997; 28: 491–9. 4 Jauch EC, Cucchiara B, Adeoye O, Meurer W, Brice J, Chan YY, et al. Part 11: adult stroke: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122 (18 Suppl. 3): S818–28. 5 Mellon L, Hickey A, Doyle F, Dolan E, Williams D. Can a media campaign change health service use in a population with stroke symptoms? Examination of the first Irish stroke awareness campaign. Emerg Med J 2014; 31: 536–40. 6 Stroke Unit Trialists Collaboration. A collaborative systematic review of the randomised trials of organised inpatient (stroke unit) care after stroke. Br Med J 1997; 314: 1151–9. 7 Ferguson GG, Eliasziw M, Barr HW, Clagett GP, Barnes RW, Wallace MC, et al. The North American Symptomatic Carotid Endarterectomy Trial: surgical results in 1415 patients. Stroke 1999; 30: 1751–8. 8 International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569–81. 9 National Institute for Health and Care Excellence (NICE). Alteplase for treating acute ischaemic stroke. NICE Technology Appraisal Guidance (TA 264). September 2012 [online[. Available at: https://www.nice.org.uk/guidance/ta264 (last accessed 9 March 2016). 10 Paul NL, Koton S, Simoni M, Geraghty OC, Luengo-Fernandez R, Rothwell PM. Feasibility, safety and cost of outpatient management of acute minor ischaemic stroke: a populationbased study. J Neurol Neurosurg Psychiatry 2013; 84: 356–61. 11 Langhorne P, Jepsen BG, Larsen T. Early home-supported discharge after stroke: a brief report on the practical implementation. Int J Rehabil Res 2014; 37: 192–4. 12 Heiss WD, Malignant MCA. Infarction: pathophysiology and imaging for early diagnosis and management decisions. Cerebrovasc Dis 2016; 41: 1–7. 13 Boos CJ, Brown L. Anticoagulation in atrial fibrillation and chronic heart failure: the risk and drug of choice. Curr Opin Cardiol 2016; 31: 229–34. 14 Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131: 492–501. 15 Fagan SC, Morgenstern LB, Petitta A, Ward R, Tilley B, Marler J, et al. Cost-effectiveness of tissue plasminogen activator for acute ischaemic stroke. NINDS rt–PA Stroke Study Group. Neurology 1998; 50: 883–90. 16 Bluhmki E, Chamorro A, Davalos A, Machnig T, Sauce C, Wahlgren N, et al. Implementation of thrombolysis for ischaemic stroke. Lancet Neurol 2013; 12: 120–1. 17 Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Stroke Thrombolysis Trialists’ Collaborative Group. Lancet 2014; 384: 1929–35.
Clinical pharmacology and stroke medicine 18 van Wijngaarden J, Dirks M, Dippel D, Minkman M, Niessen L. Towards effective and efficient care pathways: thrombolysis in acute ischaemic stroke. Q J Med 2006; 99: 267–72.
35 Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin ‘resistance’ and risk of cardiovascular mortality: a systematic review and meta-analysis. BMJ 2008; 336: 195–8.
19 Dirks M, Dippel D. Implementation of thrombolysis for ischaemic stroke. Lancet Neurol 2013; 12: 120–1.
36 Halawani SH, Williams DJ, Adefurin A, Webster J, Greaves M, Ford I. Aspirin failure in patients presenting with acute cerebrovascular ischaemia. Thromb Haemost 2011; 106: 240–7.
20 Fonarow G, Smith E, Saver JL, Reeves M, Hernandez A, Peterson E, et al. Improving door-to-needle times in acute ischaemic stroke: the design and rationale for the American Heart association/ American Stroke Association’s target: stroke initiative. Stroke 2011; 42: 2983–9. 21 Walhgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke–Monitoring Study (SITS—MOST): an observational study. Lancet 2007; 369: 275–82. 22 Sulch D, Kalra L. Integrated care pathways in stroke management. Age Ageing 2012; 29: 349–52. 23 Kwan J, Hand P, Sandercock PA. Systematic review of barriers to delivery of thrombolysis for acute stroke. Age Ageing 2004; 33: 116–21. 24 Schwamm L, Pabcioli A, Acker J, Goldstein LB, Zorowitz R, Shephard T, et al. Recommendations for the establishment of stroke systems of care: recommendations from the American Stroke Association’s Task Force. Stroke 2005; 36: 690–703.
37 Floyd CN, Ellis BH, Ferro A. The PIA1/A2 polymorphism of glycoprotein IIIa as a risk factor for stroke: a systematic review and meta-analysis. PLoS One 2014; 9: .e100239 38 Bonvini R, Baumgartner I, Do DD, Alerci M, Segatto JM, Tutta P, et al. Late acute thrombotic occlusion after endovascular brachytherapy and stenting of femoropopliteal arteries. J Am Coll Cardiol 2003; 41: 409–12. 39 Collet J, Montalescot G, Blanchet B, Tanguy ML, Golmard JL, Choussat R, et al. Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 2004; 110: 2361–7. 40 Ford I, Scott NW, Herd V, Mitchell LR, Williams DJ, Brittenden J. A randomised controlled trial of platelet activity before and after cessation of clopidogrel therapy in patients with stable cardiovascular disease. J Am Coll Cardiol 2014; 63: 233–9. 41 Brewer L, Mellon L, Hall P, Dolan E, Horgan F, Shelley E, et al. Secondary prevention after ischaemic stroke: the ASPIRE-S study. BMJ Neurology 2015; 15: 216.
25 Walter S, Kostopoulos P, Haass A, Keller I, Lesmeister M, Schlechtriemen T, et al. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. Lancet Neurol 2012; 11: 397–404.
42 Steingart R, Packer M, Hamm P, Coglianese ME, Gersh B, Geltman EM, et al. Sex differences in the management of coronary artery disease. Survival and Ventricular Enlargement Investigators. N Engl J Med 1991; 325: 226–30.
26 Wardlaw J, Hacke W. Stroke treatment with alteplase given 3.0–4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol 2009; 8: 1095–102.
43 Holroyd-Leduc JM, Kapral MK, Austin PC, Tu JV. Sex differences and similarities in the management and outcome of stroke patients. Stroke 2000; 31: 1833–7.
27 Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomised trial of tenecteplase versus alteplase for acute ischaemic stroke. N Engl J Med 2012; 366: 1099–107. 28 Muir KM. Stroke in 2015: the year of endovascular treatment. Lancet Neurol 2016; 15: 2–3. 29 Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372: 11–20. 30 Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372: 1019–30. 31 Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372: 1009–18. 32 Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015; 372: 2285–95. 33 Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015; 372: 2296–306. 34 Sarker I. Biomedical informatics and translational medicine. J Transl Med 2010; 8: 22.
44 Ayanian JZ, Epstein AM. Differences in the use of procedure between women and men hospitalised for coronary artery disease. N Engl J Med 1991; 325: 221–5. 45 Healy B. The Yentl syndrome. N Engl J Med 1991; 325: 274–6. 46 Williams D, Bennett K, Feely J. Evidence for an age and gender bias in the secondary prevention of ischaemic heart disease in primary care. Br J Clin Pharmacol 2003; 55: 604–8. 47 Simpson C, Hannaford P, Williams D. Evidence for Inequalities in the management of coronary heart disease in Scotland. Heart 2005; 5: 630–4. 48 Simpson C, Wilson C, Hannaford P, Williams D. Evidence for age and sex differences in the secondary prevention of stroke in Scottish primary care. Stroke 2005; 36: 1771–5. 49 Simpson C, Wilson C, Hannaford P, Lefevre K, Williams D. The effect of the UK incentive-based contract on the management of patients with stroke in primary care. Stroke 2006; 37: 2354–60. 50 British Pharmacological Society. Five Year Strategy: 2012–17 [online]. Available at: https://www.bps.ac.uk/about/what-we-do/ our-strategic-approach (last accessed 9 March 2016). 51 Rafter N, Hickey A, Comroy RM, Condell S, O′Connoe P, Vaughan D, et al. The Irish National Adverse Events Study (INAES): the frequency and nature of adverse events in Irish hospitals – a retrospective record review study. BMJ Qual Saf 2016. doi: 10.1136/bmjqs-2015-004828. [Epub ahead of print]
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REVIEW The great ESCAPE – a clinical pharmacologist’s journey in stroke research Correspondence Professor David Williams, BSc(Pharmacy) MB, BAO, BCh, PhD, FRCPI, FRCPE, FBPhS, FBHS, RCSI, Department of Geriatric and Stroke Medicine, Royal College of Surgeons in Ireland and Beaumont Hospital. Tel.: +353 1797 4791; Fax: +353 1797 4792; E-mail: [email protected] This lecture was delivered as the GSK prize lecture at the annual meeting of the British Pharmacological Society in December 2015. A recording of the lecture can be found at https://www.youtube.com/watch?v=85zJl8uLLlY&index=1&list=PLxoEwD0mB8KqTqBs4QeRUMIRbyQrPCWt_
Received 2 March 2016; revised 4 April 2016; accepted 4 April 2016
David J. P. Williams Royal College of Surgeons in Ireland (RCSI) and Beaumont Hospital Dublin, Dublin, Ireland
Keywords endovascular therapy, pharmacoepidemiology, platelets, secondary prevention, stroke
Stroke is a major cause of death and disability, and the commonest form of acquired major physical disability in adult life, with up to one in six people suffering a stroke in their lifetime. The great ESCAPE – a clinical pharmacologist’s journey in stroke research outlines how clinical pharmacology, and stroke in particular, provides an example of the translational medicine continuum from bench to bedside to community to public policy. Clinical pharmacology is well positioned to have an ever-increasing role in the shaping of future health policies, particularly in the field of patient safety. Endovascular therapy will become the standard of care for treating ischaemic stroke with large vessel occlusion, although the provision of this therapy to all eligible patients will present a challenge to healthcare providers in the future.
Introduction Stroke is a major cause of death and disability, and is one of the most common forms of acquired physical disability in adulthood [1], with up to one in six people suffering a stroke in their lifetime. Stroke is defined as ‘a clinical syndrome characterized by rapidly developing clinical symptoms and/ or signs of focal, and at times global (applied to patients in deep coma and those with subarachnoid haemorrhage), loss of cerebral function, with symptoms lasting more than 24 h or leading to death, with no apparent cause other than that of vascular cause’ [2]. Up to 80% of strokes are ischaemic in origin [3]. While the incidence of stroke is declining, its prevalence will continue to rise as a result of an ever-increasing DOI:10.1111/bcp.12966
ageing population. The management of stroke has often been referred to as the ‘stroke chain of survival’, which begins with the rapid detection of stroke early warning signs and symptoms, followed by rapid paramedical prehospital care, rapid transport and prealert to a comprehensive stroke centre, rapid hospital diagnosis and treatment and, finally, where necessary, rehabilitation, surgical intervention and ongoing tertiary referral [4]. However, one of the principal obstacles to the immediate treatment of stroke is a lack of awareness of its signs and symptoms. A number of research studies have sought to identify these barriers to thrombolysis use, with patient delay in seeking medical attention being highlighted as the main prehospital factor accounting for the underuse of thrombolysis. Media campaigns have been used to promote the identification of the signs and symptoms of stroke as they have the ability to reach a large population and there is a substantial amount of evidence to support the role of a mass media campaign in influencing health services use. In 2010, the Irish Heart Foundation (IHF) funded the Act F.A.S.T. (Face, Arm, Speech, Time) stroke awareness campaign – the first of its kind in Ireland. We employed an interrupted time series design to identify behaviour change related to presentations of suspected stroke in two emergency departments (EDs), serving a population of 580 000, following the introduction of the F.A.S.T campaign. We identified a significant change in ED attendance of patients with reported stroke symptoms after the introduction of the media campaign, although this behaviour was not sustained. Furthermore, ED presentation within 3.5 h (the time window for which thrombolysis was recommended at the time of the study) was associated with © 2016 The British Pharmacological Society
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an increase in emergency medical services (EMS) activation [odds ratio (OR) = 3.1, P < 0.001] and in self-referral to the ED (OR = 2.67, P < 0.001) [5].
Advances in stroke care There have been a number of significant advances in stroke care over the past few decades. Beginning in the early 1990s, evidence for the benefits of stroke units [6], carotid endarterectomy [7] and the use of aspirin [8] to prevent early recurrent stroke appeared in the literature. In 2003, Alteplase was licensed for the treatment of acute ischaemic stroke [9]. This was followed by the development of outpatient stroke/ transient ischaemic attack (TIA) services, which facilitated the rapid assessment of patients presenting with a TIA or minor stroke [10]. This was followed by the development of early supported discharge services, which enabled the timely discharge of patients to the community [11]. Finally, hemicraniectomy for malignant middle cerebral artery (MCA) infarction [12] and the introduction of newer anticoagulants for the prevention of stroke in patients with atrial fibrillation led to further advances in stroke care [13]. Adjusted-dose warfarin is effective in the prevention of stroke in patients with nonvalvular atrial fibrillation [14]. The introduction of the novel oral anticoagulants (NOACs), which act as direct inhibitors of either thrombin or factor Xa, offer potential advantages to patients, including an immediate onset of action, with the potential for eliminating the need for initial treatment or ‘bridging’ of patients at high risk of thrombosis with a parenteral anticoagulant. The relative lack of food interactions, the wide therapeutic index, the limited hepatic metabolism and fewer drug interactions enable fixed dosing of these oral anticoagulants in adults, without the need for specific laboratory monitoring. These agents may also provide greater convenience for patients and healthcare providers, leading to the potential for greater use in comparison with warfarin, particularly in those with atrial fibrillation. They may also prove to be more costeffective than warfarin due to the need for less routine monitoring and fewer serious events requiring hospitalization. However, their renal elimination contraindicates their use or necessitates dose reduction in patients with renal dysfunction. The limited availability of assays for measuring drug levels and the absence of valid and reliable monitoring strategies prevent dose titration and the determination of treatment failure as opposed to poor compliance. There may also be a potential for overuse and they incur a higher acquisition cost in comparison with warfarin. Finally, their shorter half-life results in a rapid decline in anticoagulant/antithrombotic effect if doses are missed and, except for dabigatran, no specific antidote exists in the case of major bleeding.
Acute management of stroke Thrombolysis is a cost-effective treatment for patients suffering an acute ischaemic stroke [15]. However, its effectiveness reduces with time, with no significant benefit after 4.5 h from symptom onset [16]. The proportion of patients with good clinical outcomes [a modified Rankin scale (mRS) of 0–1] following thrombolysis treatment varies from approximately a third overall, based on the time to treatment, and 7–69%, based on the severity of the presenting stroke [17]. While over
a quarter of all stroke patients may be eligible for thrombolytic treatment, international data suggest that significantly fewer stroke patients receive it [18] and that obstacles to the timely management of stroke exist. The implementation of hospital protocols for the rapid identification and treatment of stroke patients have improved the rates of thrombolysis [19]. International guidelines recommend that hospitals complete the clinical and imaging evaluation of stroke patients and initiate thrombolysis within 60 min of a patient’s arrival to hospital in those patients who do not have contraindications to thrombolysis [20]. Every 15-min reduction in door-to-needle time is associated with a one in 20 lower odds of risk-adjusted in-hospital mortality. The American Heart Association(AHA) ‘Get With The Guidelines – Stroke’ program found that only a quarter of patients with acute ischaemic stroke thrombolysed within 3 h of symptom onset had door-to-needle times within 60 min; the reported median door-to-needle time for the entire group was 78 min [20]. The Safe Implementation of Thrombolysis in Stroke – Monitoring Study (SITS-MOST) reported a mean door-to-needle time of 68 min [21]. However, a number of factors contribute to delays in the delivery of thrombolysis, including factors outside (e.g. patient/public awareness) and inside [e.g. delay in transfer to the computed tomography (CT) scanner] the hospital [18]. Acute stroke treatment (thrombolysis and thrombectomy) is complex, from an organizational perspective. The effective notification and response of EMS involves communication between the public, the relevant EMS providers and hospital EDs [22]. Furthermore, successful change in the organization of stroke services requires a coordinated and multidimensional approach to the individual processes of care and is most effective when it includes clear and explicit targets; a patient-focused culture within the organization; collaborative, interdisciplinary teams; and engaged clinical leaders and senior management within the organization. All of these factors are important in improving the functioning of stroke units, quality of care and clinical outcomes [23]. Successful measures to hasten door-to-needle times in acute ischaemic stroke include prearrival notification by EMS staff, hospital protocols for acute triage and patient flow, a single call system to alert all of the hospital stroke team members, rapid CT brain imaging for an incoming patient, location of the CT scanner in the ED and the development of treatment pathways among members of the stroke team [24]. Furthermore, it has been demonstrated that treatment by a mobile stroke unit in a specialized ambulance (equipped with a CT scanner, point-of-care laboratory and telemedicine connection) can significantly reduce the median time from the emergency call for stroke to the time when the decision is made to commence treatment [25]. Pharmacological thrombolysis is limited by a brief time window of up to 4.5 h following symptom onset and a recanalization rate of less than 50% [26].While newer thrombolytic agents offer the promise of higher reperfusion rates [27], large-vessel occlusions in the distal internal carotid artery or the first segment of the middle cerebral artery respond less well to thrombolysis. Transvascular revascularization (thrombectomy) provides an alternative or additional option to thrombolysis for those with severe strokes associated with a large-vessel occlusion. Br J Clin Pharmacol (2016) 82 334–339
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Patients who have suffered a stroke caused by large-artery occlusions, including those affecting the terminal parts of the internal carotid artery and the main stem of the middle cerebral artery, have a poor clinical outcome even with optimum medical care, with up to a quarter dying and approximately a half being left with permanent disability, despite the use of intravenous (IV) thrombolysis [28]. However, the need for better treatment for this group of patients with ischaemic stroke was addressed in 2015 by a series of landmark clinical trials which will shape the future of acute stroke management. In the past, endovascular devices for blood clot retrieval were initially used by interventional neuroradiologists for treating intracranial aneurysms or arteriovenous malformations. They were then increasingly used in the setting of acute ischaemic stroke following decisions by funding agencies to pay for their use, despite their absence of clinical benefit. In 2013, a series of clinical trials [Interventional Management of Stroke III (IMS-3), Mechanical Retrieval and Revascularization of Stroke Clots Using Embolectomy (MR RESCUE) and Synthesis Expansion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in the Local versus Systemic Thrombolysis for Acute Ischaemic Stroke (SYNTHESIS Expansion) trial found no significant benefit for thrombectomy in the management of acute stroke, although concerns were raised regarding the design of these studies, late treatment decisions in a number of cases, the predominant use of older and less refined endovascular devices with higher complication rates, and the variation in the use of advanced imaging for patient selection. The Multicentre Randomized Clinical Trial of Endovascular Treatment of Acute Ischaemic Stroke in the Netherlands (MR CLEAN) study reported an absolute improvement of 13.5 percentage points in the rate of functional independence in patients who were treated with thrombectomy, with no significant differences in mortality or symptomatic haemorrhage between the treatment groups [29]. Most other prespecified clinical endpoints favoured thrombectomy treatment. These results led to the initial suspension of a similar study, Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times (ESCAPE). ESCAPE aimed to evaluate rapid endovascular therapy in addition to standard care in those patients who presented with an acute ischaemic stroke associated with a small core infarct, a proximal intracranial arterial occlusion and moderate-to-good collateral circulation. A total of 316 participants were assigned randomly to receive standard medical care (control group) or standard medical care plus endovascular treatment with the use of available thrombectomy devices (intervention group) [30]. Patients with a proximal intracranial occlusion in the anterior cerebral circulation were included up to 12 h following symptom onset. Those with a large core infarct or poor collateral circulation on head CT and CT angiography were excluded from the study. The median time from study CT of the head to first reperfusion was reported to be 84 min, indicating rapid assessment of patients in this study. The rate of functional independence (defined as a 90-day mRS score of 0–2) increased in the intervention group, from 29.3% to 53% (P < 0.001). The primary outcome analysis favoured the intervention group (common odds ratio 2.6; 95% confidence interval (CI) 336
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1.7, 3.8; P < 0.001), with the intervention being associated with a reduced mortality (10.4% vs. 19.0% in the control group; P = 0.04) [30]. This was the first study of its kind to report an improvement in mortality. Further studies were, in turn, halted as a result of the overwhelming benefit which thrombectomy demonstrated in further interim analyses [30–33]. All of these trials included patients with occlusions of the internal carotid artery or middle cerebral artery, with over 85% of participants being treated with IV thrombolysis initiated soon after symptom onset, and with imaging techniques demonstrating only small areas of irreversibly damaged brain tissue. The majority of patients achieved complete or near-complete tissue reperfusion with thrombectomy, predominantly with stent retrievers, with the majority of patients being treated within 6 h of symptom onset. The significant benefits for participants in these trials translated into numbers needed to treat of between four and eight for recovery to independence. Endovascular therapy is now recognized as a proven standard of care in the management of acute ischaemic stroke. It has provided a significant leap forward in the management of stroke, although it has created challenges to the reorganization of stroke services in order to provide this treatment to all eligible patients.
The translational medicine continuum Translational medicine aims to develop new therapies and insights, leading to the improvement of health in the wider population [34]. Clinical pharmacology, and stroke medicine in particular, provides an example of the translational medicine continuum which starts at bench to bedside, through to bedside to community and, finally, community to overall health policy. Bench to bedside. Platelets play an important part in the pathogenesis of ischaemic stroke, through their involvement in the development of atherosclerosis, arterial thrombosis or arterial embolism. The International Stroke Trial (IST) demonstrated for the first time that aspirin therapy produced a small but real reduction by approximately ten deaths or recurrent strokes per hundred patients during the initial few weeks following a suspected ischaemic stroke, and specifically recommended that aspirin be started as soon as possible following an ischaemic stroke [8]. There has been significant debate in the literature concerning the phenomenon of aspirin ‘failure’ and stroke recurrence, with a number of studies demonstrating a link between future cardiovascular events and aspirin resistance [35, 36]. More recently, it has been demonstrated that carriage of the PIA2 polymorphism of glycoprotein IIIa is a potential risk factor for ischaemic stroke, specifically in stroke of cardioembolic and large-vessel origin [37]. Aspirin ‘failure’ may result from a number of factors, including inadequate dose, reduced bioavailability of aspirin, genetic factors, interactions with other medications, nonplatelet factors (including inherent disease factors) and nonadherence to aspirin therapy. In order to examine the prevalence and nature of aspirin failure in the context of stroke, we studied 51 patients admitted to a stroke unit with a suspected ischaemic stroke who had already been prescribed aspirin. Within 48 h of onset, blood and urine
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samples were taken to assess platelet aggregation, activation and aspirin response by a range of different assay methods. All tests were repeated on a second sample taken 24 h after the witnessed administration of 75 mg or 150 mg aspirin. Incomplete response to aspirin, measured using arachidonic acid (AA)-stimulated platelet aggregation, was found in 43% of patients. Following in-hospital aspirin administration, there was a significant reduction in AA-aggregation, which suggested poor adherence to therapy prior to hospital admission, although residual platelet aggregation (10–15%) persisted in 11 subjects [36]. More recently, a number of studies have highlighted an increased morbidity and mortality following the planned discontinuation of the antiplatelet agent clopidogrel [38, 39]. We therefore investigated whether a ‘rebound’ phenomenon existed by conducting a randomized controlled trial of platelet activity before and after the (Is cessation of clopidogrel therapy associated with rebound of platelet activity in stable vascular disease patients (CLASP)) study. A total of 171 patients receiving aspirin therapy were randomly assigned to either placebo or clopidogrel therapy for 28 days. Platelet function was assessed at pretreatment baseline, on treatment just before discontinuation of the study drug, and on days 7, 14 and 28 after discontinuation. Adenosine diphosphate-stimulated platelet fibrinogen binding, P-selectin expression and platelet aggregation were found to be significantly lower on clopidogrel treatment compared with baseline (P < 0.0001) but returned to baseline levels by 7 days after discontinuation of clopidogrel. A mixedmodel analysis excluding the on-treatment timepoint showed no overall differences between the clopidogrel and placebo groups (P > 0.05), with no evidence of an interaction between platelet inhibition over time and treatment allocation. We therefore found no evidence for a rebound of platelet activity to above baseline after stopping clopidogrel in patients with stable coronary artery disease or peripheral artery disease [40]. Secondary prevention of stroke – bedside to community. Approximately a third of strokes occur in those who have suffered a previous stroke, with approximately half occurring in those with a history of prior vascular events of any kind. These relatively high recurrence rates therefore emphasize the importance of implementing effective secondary preventive strategies. A number of large population-based studies which identified strong associations between cardiovascular risk factors and future stroke risk have helped inform the development of evidence-based guidelines on stroke prevention, aimed at improving future stroke outcomes. However, information on the adequacy of secondary prevention after ischaemic stroke is lacking, despite the evidence that appropriate secondary prevention improves long-term patient outcomes. The Action on Secondary Prevention Interventions and Rehabilitation in Stroke (ASPIRE-S) study prospectively assessed secondary prevention measures in patients 6 months after an ischaemic stroke. A total of 302 patients were recruited over a 1-year period and underwent a comprehensive assessment of ongoing risk factors for stroke at 6 months, modelled on the EUROASPIRE (European Action on Secondary Prevention through Intervention to Reduce Events). protocol for the evaluation
of secondary prevention measures in patients with a history of established cardiac disease. At follow-up, approximately two-thirds of patients had a body mass index greater than 25 kg m–2, and 16.4% were still smoking. Almost two-thirds had a clinic blood pressure greater than 140/90 mmHg and approximately a fifth had a low-density lipoprotein level greater than 2.5 mmol L–1. A quarter of diabetic patients had a glycosylated haemoglobin greater than or equal to 7%. The majority (97%) of patients were receiving antiplatelet and/or anticoagulant therapy. Of those with a diagnosis of atrial fibrillation, 82% were on anticoagulant therapy. The majority (95%) were receiving lipid-lowering therapy, with three-quarters receiving antihypertensive therapy. This study therefore demonstrated a high prevalence of remaining modifiable risk factors at 6 months poststroke. These results provide an opportunity to improve secondary preventive measures following ischaemic stroke by incorporating evidence-based guidelines into future quality assurance cycles in stroke care [41]. Inequalities in the management of coronary heart disease (CHD) and stroke have been widely reported in the literature [42, 43]. CHD is a leading cause of death in women and has a mortality rate higher than for all neoplastic diseases combined [42]. While women suffer chest pain as their chief symptom of cardiac disease more often than men, women are referred less frequently for invasive and non-invasive tests for CHD and are less likely to undergo interventional management of CHD, including percutaneous transluminal coronary angioplasty or coronary artery bypass grafting [44]. Women with ischaemic heart disease are also prescribed beta-blockers and aspirin less frequently and have a poorer long-term prognosis following myocardial infarction. This phenomenon has been referred to as the ‘Yentl syndrome’ (Yentl was the 19th century heroine of Isaac Bashevis Singer’s story, who had to disguise herself as a man to attend school and study the Talmud), whereby a woman has to assume the characteristics of a man to receive equal treatment [45]. Using a large prescription database, our research group therefore wished to determine whether the ‘Yentl syndrome’ existed in Irish primary care. Nitrate prescribing has been shown to be a useful surrogate for diagnosing CHD. We found that women with presumed CHD were less likely to be prescribed a beta-blocker, calcium channel antagonist, statin therapy, aspirin or warfarin compared with their male counterparts. Furthermore, women with presumed CHD were more likely to be prescribed an antidepressant, benzodiazepine or nonsteroidal anti-inflammatory agent [46]. Similar patterns in the management of CHD and stroke have been demonstrated in Scottish primary care [47, 48]. However, the introduction of a new general practice contract based on financial incentives was shown to improve the documentation of quality indicators for the management of stroke. Large increases in the documentation of cardiovascular quality indicators were found among the oldest (>75 years) and most affluent patient groups, although women with stroke were still less likely to have their smoking habits recorded or receive antiplatelet/anticoagulant therapy [49]. Community to policy. It is likely that 2015 will be remembered in the field of stroke as the year when endovascular therapy came of age. However, the provision Br J Clin Pharmacol (2016) 82 334–339
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of this evidence-based treatment to eligible patients will present challenges to healthcare providers. Guidelines for the management of stroke are currently being updated to include the use of endovascular therapy for the acute treatment of stroke. Furthermore, the British Pharmacological Society has recently identified five priorities to help to deliver the future ambitions of clinical pharmacology [50]. These include patient safety, productivity and efficiency, patientcentred care, innovation, and improving access to medicines, and workforce. Clinical pharmacology therefore has an important role to play in the field of patient safety. The Irish National Adverse Events Study (INAES) has recently published its main findings. The prevalence of adverse events (defined as an injury caused by healthcare management resulting in prolonged hospitalization, disability on discharge or death) in 1574 admissions was reported as 12.2% (95% CI 9.5%, 15.5%), with an incidence of 10.3 events per 100 admissions (95% CI 7.5%, 13.1%). Over 70% of these adverse events were deemed preventable. Two-thirds were rated as having a mild-to-moderate impact on the patient, 9.9% causing permanent impairment and 6.7% contributing to death. This was the first study of adverse events to be reported in Ireland and has demonstrated similar rates of adverse events to those in other countries and will provide important baseline data on the adverse event burden for the Irish healthcare system [51].
Conclusion Clinical pharmacology, and stroke medicine in particular, provides an example of the translational medicine continuum from bench to bedside to community to public health policy. Clinical pharmacology is therefore well positioned to have an ever-increasing role in the shaping of future health policies, particularly in the field of patient safety. Endovascular therapy will become the standard of care for treating ischaemic stroke with large-vessel occlusion, although the provision of this therapy will present a challenge to healthcare providers in the future.
Competing Interest Professor Williams has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares that he has served on advisory boards for Bayer, Boehringer Ingelheim, Daiichi Sankyo and Bristol Myers Squibb. He has received a speaker’s fee from Boehringer Ingelheim. I would like to acknowledge all of my collaborators who have contributed to my research over many years.
References 1 Lopez A, Mathers C, Ezzati M, Jamison D, Murray C. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 1747–57.
338
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2 Hatano S. Experience from a multicentre stroke register: a preliminary report. Bull World Health Organ 1976; 54: 541–53. 3 Sudlow CLM, Wardlow CP. For the International Incidence Collaboration. Comparable studies on the incidence of stroke and its pathological types: results from an international collaboration. Stroke 1997; 28: 491–9. 4 Jauch EC, Cucchiara B, Adeoye O, Meurer W, Brice J, Chan YY, et al. Part 11: adult stroke: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122 (18 Suppl. 3): S818–28. 5 Mellon L, Hickey A, Doyle F, Dolan E, Williams D. Can a media campaign change health service use in a population with stroke symptoms? Examination of the first Irish stroke awareness campaign. Emerg Med J 2014; 31: 536–40. 6 Stroke Unit Trialists Collaboration. A collaborative systematic review of the randomised trials of organised inpatient (stroke unit) care after stroke. Br Med J 1997; 314: 1151–9. 7 Ferguson GG, Eliasziw M, Barr HW, Clagett GP, Barnes RW, Wallace MC, et al. The North American Symptomatic Carotid Endarterectomy Trial: surgical results in 1415 patients. Stroke 1999; 30: 1751–8. 8 International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569–81. 9 National Institute for Health and Care Excellence (NICE). Alteplase for treating acute ischaemic stroke. NICE Technology Appraisal Guidance (TA 264). September 2012 [online[. Available at: https://www.nice.org.uk/guidance/ta264 (last accessed 9 March 2016). 10 Paul NL, Koton S, Simoni M, Geraghty OC, Luengo-Fernandez R, Rothwell PM. Feasibility, safety and cost of outpatient management of acute minor ischaemic stroke: a populationbased study. J Neurol Neurosurg Psychiatry 2013; 84: 356–61. 11 Langhorne P, Jepsen BG, Larsen T. Early home-supported discharge after stroke: a brief report on the practical implementation. Int J Rehabil Res 2014; 37: 192–4. 12 Heiss WD, Malignant MCA. Infarction: pathophysiology and imaging for early diagnosis and management decisions. Cerebrovasc Dis 2016; 41: 1–7. 13 Boos CJ, Brown L. Anticoagulation in atrial fibrillation and chronic heart failure: the risk and drug of choice. Curr Opin Cardiol 2016; 31: 229–34. 14 Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131: 492–501. 15 Fagan SC, Morgenstern LB, Petitta A, Ward R, Tilley B, Marler J, et al. Cost-effectiveness of tissue plasminogen activator for acute ischaemic stroke. NINDS rt–PA Stroke Study Group. Neurology 1998; 50: 883–90. 16 Bluhmki E, Chamorro A, Davalos A, Machnig T, Sauce C, Wahlgren N, et al. Implementation of thrombolysis for ischaemic stroke. Lancet Neurol 2013; 12: 120–1. 17 Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Stroke Thrombolysis Trialists’ Collaborative Group. Lancet 2014; 384: 1929–35.
Clinical pharmacology and stroke medicine 18 van Wijngaarden J, Dirks M, Dippel D, Minkman M, Niessen L. Towards effective and efficient care pathways: thrombolysis in acute ischaemic stroke. Q J Med 2006; 99: 267–72.
35 Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin ‘resistance’ and risk of cardiovascular mortality: a systematic review and meta-analysis. BMJ 2008; 336: 195–8.
19 Dirks M, Dippel D. Implementation of thrombolysis for ischaemic stroke. Lancet Neurol 2013; 12: 120–1.
36 Halawani SH, Williams DJ, Adefurin A, Webster J, Greaves M, Ford I. Aspirin failure in patients presenting with acute cerebrovascular ischaemia. Thromb Haemost 2011; 106: 240–7.
20 Fonarow G, Smith E, Saver JL, Reeves M, Hernandez A, Peterson E, et al. Improving door-to-needle times in acute ischaemic stroke: the design and rationale for the American Heart association/ American Stroke Association’s target: stroke initiative. Stroke 2011; 42: 2983–9. 21 Walhgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke–Monitoring Study (SITS—MOST): an observational study. Lancet 2007; 369: 275–82. 22 Sulch D, Kalra L. Integrated care pathways in stroke management. Age Ageing 2012; 29: 349–52. 23 Kwan J, Hand P, Sandercock PA. Systematic review of barriers to delivery of thrombolysis for acute stroke. Age Ageing 2004; 33: 116–21. 24 Schwamm L, Pabcioli A, Acker J, Goldstein LB, Zorowitz R, Shephard T, et al. Recommendations for the establishment of stroke systems of care: recommendations from the American Stroke Association’s Task Force. Stroke 2005; 36: 690–703.
37 Floyd CN, Ellis BH, Ferro A. The PIA1/A2 polymorphism of glycoprotein IIIa as a risk factor for stroke: a systematic review and meta-analysis. PLoS One 2014; 9: .e100239 38 Bonvini R, Baumgartner I, Do DD, Alerci M, Segatto JM, Tutta P, et al. Late acute thrombotic occlusion after endovascular brachytherapy and stenting of femoropopliteal arteries. J Am Coll Cardiol 2003; 41: 409–12. 39 Collet J, Montalescot G, Blanchet B, Tanguy ML, Golmard JL, Choussat R, et al. Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 2004; 110: 2361–7. 40 Ford I, Scott NW, Herd V, Mitchell LR, Williams DJ, Brittenden J. A randomised controlled trial of platelet activity before and after cessation of clopidogrel therapy in patients with stable cardiovascular disease. J Am Coll Cardiol 2014; 63: 233–9. 41 Brewer L, Mellon L, Hall P, Dolan E, Horgan F, Shelley E, et al. Secondary prevention after ischaemic stroke: the ASPIRE-S study. BMJ Neurology 2015; 15: 216.
25 Walter S, Kostopoulos P, Haass A, Keller I, Lesmeister M, Schlechtriemen T, et al. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. Lancet Neurol 2012; 11: 397–404.
42 Steingart R, Packer M, Hamm P, Coglianese ME, Gersh B, Geltman EM, et al. Sex differences in the management of coronary artery disease. Survival and Ventricular Enlargement Investigators. N Engl J Med 1991; 325: 226–30.
26 Wardlaw J, Hacke W. Stroke treatment with alteplase given 3.0–4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol 2009; 8: 1095–102.
43 Holroyd-Leduc JM, Kapral MK, Austin PC, Tu JV. Sex differences and similarities in the management and outcome of stroke patients. Stroke 2000; 31: 1833–7.
27 Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomised trial of tenecteplase versus alteplase for acute ischaemic stroke. N Engl J Med 2012; 366: 1099–107. 28 Muir KM. Stroke in 2015: the year of endovascular treatment. Lancet Neurol 2016; 15: 2–3. 29 Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372: 11–20. 30 Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372: 1019–30. 31 Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372: 1009–18. 32 Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015; 372: 2285–95. 33 Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015; 372: 2296–306. 34 Sarker I. Biomedical informatics and translational medicine. J Transl Med 2010; 8: 22.
44 Ayanian JZ, Epstein AM. Differences in the use of procedure between women and men hospitalised for coronary artery disease. N Engl J Med 1991; 325: 221–5. 45 Healy B. The Yentl syndrome. N Engl J Med 1991; 325: 274–6. 46 Williams D, Bennett K, Feely J. Evidence for an age and gender bias in the secondary prevention of ischaemic heart disease in primary care. Br J Clin Pharmacol 2003; 55: 604–8. 47 Simpson C, Hannaford P, Williams D. Evidence for Inequalities in the management of coronary heart disease in Scotland. Heart 2005; 5: 630–4. 48 Simpson C, Wilson C, Hannaford P, Williams D. Evidence for age and sex differences in the secondary prevention of stroke in Scottish primary care. Stroke 2005; 36: 1771–5. 49 Simpson C, Wilson C, Hannaford P, Lefevre K, Williams D. The effect of the UK incentive-based contract on the management of patients with stroke in primary care. Stroke 2006; 37: 2354–60. 50 British Pharmacological Society. Five Year Strategy: 2012–17 [online]. Available at: https://www.bps.ac.uk/about/what-we-do/ our-strategic-approach (last accessed 9 March 2016). 51 Rafter N, Hickey A, Comroy RM, Condell S, O′Connoe P, Vaughan D, et al. The Irish National Adverse Events Study (INAES): the frequency and nature of adverse events in Irish hospitals – a retrospective record review study. BMJ Qual Saf 2016. doi: 10.1136/bmjqs-2015-004828. [Epub ahead of print]
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