Appendix A: Clinical question and search strategies

Transcription

1 APPENDICES

2 Appendix A: Clinical quetion and earch trategie Study type Quetion ID Quetion wording filter ued Databae and year PHAR2a What i the afety and efficacy of apirin veru Sytematic review, Medline other antiplatelet agent for the treatment of patient RCT Embae with acute ichaemic troke? Cinahl PHAR2b What i the afety and efficacy of antiplatelet agent Sytematic review, Medline veru placebo for the treatment of patient with RCT Embae acute ichaemic troke? Cinahl PHAR2c What i the afety and efficacy of anticoagulant Sytematic review, Medline veru placebo for the treatment of patient with RCT Embae acute ichaemic troke? Cinahl PHAR2d What i the afety and efficacy of antiplatelet agent Sytematic review, Medline veru anticoagulant for the treatment of patient RCT Embae with acute ichaemic troke? Cinahl PHAR3 What i the afety and efficacy of anticoagulant Sytematic review, Medline veru placebo or treatment a uual for the RCT Embae treatment of patient with acute venou troke? Cinahl PHAR4 What i the afety and efficacy of anticoagulant Sytematic review, Medline veru antiplatelet agent for the treatment of RCT, obervational Embae patient with acute arterial diection? tudie Cinahl PHAR5 For patient with acute warfarin aociated All tudy type Medline haemorrhagic troke, what i the afety and efficacy Embae of i) vitamin K, ii) freh frozen plama, iii) prothrombin Cinahl complex conjugate? PHAR6 What i the afety and efficacy of anticoagulant Sytematic review, Medline veru antiplatelet agent or placebo for patient RCT, obervational Embae with acute troke who may require anticoagulation tudie Cinahl for comorbiditie (e.g. atrial fibrillation, prothetic heart valve (mitral/aortic), deep vein thromboi or pulmonary embolim)? What i the afety and efficacy of caval filter for deep vein thromboi or pulmonary embolim? PHAR7 What i the afety and efficacy of anticoagulant All tudy type Medline veru antiplatelet agent for the treatment of Embae antiphopholipid yndrome in patient with acute Cinahl ichaemic troke? continued 1

3 Study type Quetion ID Quetion wording filter ued Databae and year STAT1 a) For patient with acute troke (including Sytematic review, Medline haemorrhagic troke), what i the afety and RCT, obervational Embae efficacy of i) initiating tatin therapy, ii) continuing tudie Cinahl tatin therapy? b) Do patient on tatin, and who ubequently have a troke, have reduced mortality and morbidity? ADM1 In patient with upected troke, what are the Sytematic review, Medline benefit of being admitted to pecialit care veru a RCT, obervational Embae non-pecialied unit in term of recovery time, tudie Cinahl morbidity and mortality? ADM2 Doe rapid admiion to an acute unit reduce Sytematic review, Medline mortality, morbidity and length of hopital tay? RCT, obervational Embae tudie Cinahl ASM1 What i the accuracy of a pre-hopital health Sytematic review, Medline profeional aement tool/checklit for identifying RCT, obervational Embae ign and ymptom of upected troke/tia? tudie Cinahl ASM2 How accurately do coring ytem predict which Sytematic review, Medline patient with upected TIA need to be referred RCT, obervational Embae urgently for pecialit aement? tudie Cinahl ASM3 In patient with a upected minor troke/tia, doe Sytematic review, Medline early veru late expert aement reduce mortality RCT, obervational Embae or morbidity? tudie Cinahl IMAG1 After TIA, which modality (MRI or CT) hould be Sytematic review, Medline ued? RCT, obervational Embae tudie Cinahl IMAG2 Which patient with upected TIA hould be Sytematic review, Medline referred for urgent brain imaging? RCT, obervational Embae tudie Cinahl IMAG3 How quickly hould brain imaging be performed Sytematic review, Medline following an acute troke? RCT, obervational Embae tudie Cinahl IMAG4 Which patient with upected troke/tia hould be Sytematic review, Medline referred for urgent carotid imaging? RCT, obervational Embae tudie Cinahl NUTRI1 In patient with acute troke a) what i the accuracy Sytematic review, Medline of i) bedide wallowing aement, RCT, obervational Embae ii) videofluorocopy, iii) fibreoptic endocopic tudie Cinahl evaluation of wallowing, and b) how do the reult of thee aement affect clinical outcome? continued 2

4 Appendix A: Clinical quetion and earch trategie Study type Quetion ID Quetion wording filter ued Databae and year NUTRI2 In patient with acute troke who can take adequate Sytematic review, Medline fluid orally, doe oral nutritional upplementation RCT, obervational Embae reduce mortality and morbidity? tudie Cinahl NUTRI2b In patient with acute troke, doe fluid therapy Sytematic review, Medline reduce mortality and morbidity? RCT, obervational Embae tudie Cinahl NUTRI3 In patient with acute troke who are unable to Sytematic review, Medline take adequate fluid orally, doe a) early veru late RCT, obervational Embae initiation of tube feeding, or b) naogatric (NG) tudie Cinahl (including naal bridle) veru percutaneou endocopically guided gatrotomy (PEG) (including radiologically inerted gatronomy tube (RIG)) reduce mortality and morbidity? PREV1 Doe withdrawal or modification of oral intake Sytematic review, Medline prevent apiration pneumonia after troke? RCT, obervational Embae tudie Cinahl HYP1 What i the afety and efficacy of the intervention Sytematic review, Medline to control hyperglycaemia veru treatment a uual RCT, obervational Embae in patient with acute troke? tudie Cinahl BP1 What i the afety and efficacy of meaure to Sytematic review, Medline manipulate blood preure veru treatment a uual RCT Embae in patient with acute troke? Cinahl OXY1 What i the afety and efficacy of upplemental Sytematic review, Medline oxygen therapy veru treatment a uual in patient RCT, obervational Embae with acute troke? tudie Cinahl MOBIL1 Doe early mobiliation veru treatment a uual Sytematic review, Medline reduce mortality and morbidity in patient with RCT, obervational Embae acute troke? tudie Cinahl MOBIL2 Doe placing patient with acute troke in pecific Sytematic review, Medline poition reduce mortality and morbidity? RCT, obervational Embae tudie Cinahl REF1 Which patient with primary intracerebral Sytematic review, Medline haemorrhage hould be referred for urgery? RCT Embae Cinahl REF2 Which patient hould be referred for Sytematic review, Medline decompreive hemicraniectomy? RCT Embae Cinahl REF3 Which patient with ymptomatic carotid tenoi Sytematic review, Medline hould be referred for urgent carotid interventional RCT Embae procedure (carotid endarterectomy and tenting)? Cinahl NOTE: The final cut-off date for all earche wa 31 October

5 Appendix B: Scope of the guideline and referral from the Department of Health SCOPE 1 Guideline title : national clinical guideline for diagnoi and initial management of acute troke and tranient ichaemic attack (TIA). 1.1 Short title. 2 Background a) The National Intitute for Health and Clinical Excellence ( NICE or the Intitute ) ha commiioned the National Collaborating Centre for Chronic Condition (NCC-CC) to develop a clinical guideline on acute troke and TIA for ue in the NHS in England and Wale. Thi follow referral of the topic by the Department of Health (DH). The guideline will provide recommendation for good practice that are baed on the bet available evidence of clinical and cot effectivene. b) The Intitute clinical guideline will upport the implementation of National Service Framework (NSF) in thoe apect of care where a Framework ha been publihed. The tatement in each NSF reflect the evidence that wa ued at the time the Framework wa prepared. The clinical guideline and technology appraial publihed by the Intitute after an NSF ha been iued will have the effect of updating the Framework. c) In parallel to the development of the Intitute acute troke and TIA clinical guideline, the Royal College of Phyician Intercollegiate Working Party will alo be updating their guideline to focu on longer-term management and rehabilitation. The developer will work cloely with the Intercollegiate Working Party to enure continuity and to avoid any overlapping or gap. d) The DH ha developed a National Strategy which wa publihed in Thi addree many of the iue regarding ervice model, tructure and taffing. Where poible, thi guideline will work cloely with the Strategy Project Executive. e) NICE clinical guideline upport the role of healthcare profeional in providing care in partnerhip with patient, taking account of their individual need and preference, and enuring that patient (and their carer and familie, where appropriate) can make informed deciion about their care and treatment. 4

6 Appendix B: Scope of the guideline and referral from the Department of Health 3 Clinical need for the guideline a) i the third mot common caue of death in the UK, and one of the mot important caue of ignificant adult diability. Each year in the UK, approximately 120,000 people have a firt troke, 30% of whom die within a month. In addition, about 30,000 recurrent troke occur. The rik of having a troke before the age of 85 year i one in four for men, and one in five for women. b) i a medical emergency and brain damage can be reduced if troke i identified early enough. c) and tranient ichaemic attack (TIA) are very imilar, the only difference being that the ymptom of TIA reolve completely within 24 hour, and troke ymptom and ign perit. With refined enitive imaging technique, it ha been clearly hown that many people who have experienced a TIA have utained ignificant permanent cerebral damage. TIA i not, therefore, a benign condition. and TIA management depend upon accurate diagnoi of the underlying pathology and aetiology. d) The rik of troke within the firt month after a TIA can be a high a 32% for ome patient group. With effective diagnoi, invetigation and treatment, many troke could be prevented. e) The recent National Audit Office report Reducing brain damage: fater acce to better troke care identified major problem with the conitent delivery of high-quality troke care to all patient in England. Evidence clearly demontrating that troke i both a preventable and treatable dieae ha accumulated rapidly over recent year, but health ervice have been low to reflect thi. f) The National Sentinel Audit in 2006 covering all hopital in England, Wale and Northern Ireland howed that 78% of hopital have a neurovacular clinic where only 35% of patient are een within 7 day. Few hopital had protocol agreed between the ambulance ervice and the acute Trut to enure rapid tranfer of patient with troke to caualty, and acce to brain can remain difficult for ome, particularly outide normal working hour. g) The cot of troke care i high, with an etimate in the National Audit Office report of 7 billion per year. Much of thi i pent on providing longer-term healthcare, ocial ervice and financial upport to people with reidual diability. More effective acute treatment would ave live and money. 4 The guideline a) The guideline development proce i decribed in detail in two publication which are available from the NICE webite (ee Further information ). The guideline development proce: an overview for takeholder, the public and the NHS decribe how organiation can become involved in the development of a guideline. The guideline manual provide advice on the technical apect of guideline development. b) Thi document i the cope. It define exactly what thi guideline will (and will not) examine, and what the guideline developer will conider. The cope i baed on the referral from the DH. c) The area that will be addreed by the guideline are decribed in the following ection. 5

7 4.1 Population Group that will be covered: Patient with tranient ichaemic attack (TIA) or completed troke, that i, an acute neurological event preumed to be vacular in origin and cauing cerebral ichaemia, cerebral infarction or cerebral haemorrhage. Thi include: firt and recurrent event thrombotic and embolic event primary intracerebral haemorrhage of any caue, including venou thromboi Group that will not be covered: a) Specific iue relating to the general management of underlying condition will not be conidered, but the immediate management to reduce the extent of brain damage will be included. b) Subarachnoid haemorrhage. c) Children (16 and under). 4.2 Healthcare etting Primary and econdary NHS healthcare etting, including referral to tertiary care. Pre-hopital emergency care etting, including ambulance ervice. 4.3 Clinical management The purpoe of the guideline i to decribe the initial and early management (without pecifying a fixed time) aimed at reducing the ichaemic brain damage, and in the cae of TIA, preventing ubequent troke. Thi include: a) the rapid recognition of ymptom and diagnoi b) initial and early management of troke and TIA c) diagnotic procedure aimed to delineate the nature and location of the pathology d) treatment intervention that aim to minimie the pathology e) management and maintenance of homeotai (including fluid, nutrition and oxygen therapy) f) initial and early pharmacotherapie including thrombolyi (note that guideline recommendation will normally fall within licened indication; exceptionally, and only where clearly upported by evidence, ue outide a licened indication may be recommended. The guideline will aume that precriber will ue the Summary of product characteritic to inform their deciion for individual patient). g) management of complication where thee are likely to affect the area of brain damage (for example, the early ue of anticoagulant for venou thromboembolim in acute troke) h) non-pharmacological management, including the role of early mobiliation and poitioning 6

8 Appendix B: Scope of the guideline and referral from the Department of Health i) indication for referral for pecific intervention (for example, carotid angioplaty, carotid endarterectomy) j) identification of people who need continuing or early anticoagulation. 4.4 Statu Scope Thi i the final verion of the cope. It ha been out for conultation, modified in repone to comment received and igned off by one of NICE independent Guideline Review Panel. Related NICE guidance: Clopidogrel and modified-releae dipyridamole in the prevention of occluive vacular event. NICE technology appraial guidance no. 90 (2005). Available from: Ichaemic troke (acute) alteplae. NICE technology appraial guidance no. 122 (2007). Available from: Development of guideline recommendation The development of the guideline recommendation began in November Further information Information on the guideline development proce i provided in: The guideline development proce: an overview for takeholder, the public and the NHS The guideline manual. Thee booklet are available a PDF file from the NICE webite: Referral from the Department of Health The Department of Health (DH) aked the Intitute: To prepare a clinical guideline on the diagnoi and acute management of troke and tranient ichaemic attack, concentrating on initial treatment. 7

9 Appendix C: Model to determine the cot effectivene of immediate pecialit aement in a troke unit compared to pecialit aement at a weekly clinic or no pecialit aement Quetion: ASM 1 What i the accuracy of a pre-hopital health profeional aement tool/checklit for identifying ign and ymptom of upected troke/tia? ASM 2 How accurately do coring ytem predict which patient with upected TIA need to be referred urgently to a pecialit aement? ASM 3 In patient with a upected minor troke/tia, doe early veru late expert aement reduce mortality or morbidity? ADM 2 Doe rapid admiion to a hyperacute troke unit reduce mortality, morbidity and length of hopital tay? Background: The rik of developing a troke after hemipheric TIA can be a high a 30% within the firt month, with the greatet rik being within the firt 72 hour.* It i conidered that effective management of patient with TIA or minor troke require identification of individual at the highet rik and then appropriate early intervention. 195 The ABCD 2 core aim to identify individual at high rik of troke and who may require emergency intervention. The core i baed on known clinical predictor of troke: Age <60 year=0 60=1 BP ytolic 140 mmhg and/or diatolic 90 mmhg=0 ytolic >140 mmhg and/or diatolic >90 mmhg =1 clinical feature unilateral weakne=2 peech diturbance without weakne=1 other ymptom=0 * National Pre-hopital Guideline Group. The recognition and emergency management of upected troke and TIA: guideline upplement. London: RCP,

10 Appendix C: Model to determine cot effectivene duration of ymptom <10 min=0 10 to 59 min=1 60 min=2 Preence of diabete=1 The ubgroup of patient with carotid tenoi account for the highet proportion of early recurrent troke. Carotid endarterectomy reduce the rik of troke in patient with recently ymptomatic tenoi. For neurologically table patient with TIA and minor troke, benefit from endarterectomy i greatet if performed within 2 week of the event and fall rapidly with increaing delay. 196 Aim: Population: patient with a TIA or minor troke identified by a general practitioner (GP), in the accident and emergency (A&E) department or by an ambulance crew. To evaluate the relative cot effectivene of aeing TIA or minor troke patient: immediately at a pecialit troke unit, or within 7 day at a weekly pecialit troke unit clinic, or by the patient GP. We ae cot effectivene of each trategy not only for all minor troke/tia patient but alo broken down by ABCD 2 core group. General method: The cot effectivene of the different trategie wa etimated uing a imple deciion analyi. The NICE reference cae wa followed: Cot are meaured from the perpective of the NHS and peronal ocial ervice (PSS) perpective including the long-term care cot for troke patient. Health outcome i meaured from the perpective of the patient (not carer or family member). Health outcome i meaured in term of quality adjuted life year (QALY), where one QALY i equal to one year of full health (or two year at half health etc.). A 3.5% dicount rate wa applied to both cot and effect. The dicount rate reflect that people prefer to receive a benefit earlier and to incur a cot later, even in a world with zero inflation and no bank interet. 197 Where appropriate, we have ued data and aumption from the HTA report on the effectivene and cot effectivene of carotid artery aement by Wardlaw et al. 27 The model: A deciion tree i ued to repreent the model (ee Figure C1, C2 and C3). The deciion model eek to capture the following effect: Patient een at a pecialit clinic are more likely to be given appropriate medication and therefore will have troke averted (in the firt 90 day). 9

11 Patient een immediately will receive thi medication ooner and therefore will have more troke averted than thoe een at weekly clinic. Patient een at a pecialit clinic will receive carotid artery ultraound imaging (and ubequent carotid endarterectomy if tenoi >=50%), which will reduce the incidence of troke (over 5 year). Wherea patient followed up by their GP do not receive imaging or urgery. Patient een at a pecialit clinic immediately will be more likely to receive endarterectomy within 2 week, when it i more effective, compared with patient who are een at a weekly clinic. Furthermore, more patient will have a troke before they have urgery. Carotid artery imaging i not perfectly accurate. Endarterectomy confer a rik of death in the hort term. Specialit clinic are more cotly than GP aement. Cot of drug over the lifetime will be increaed. But thee cot will be at leat partly offet by cot aving from reduced troke treatment over the lifetime. The effect of different treatment trategie i firt modelled in term of effect on troke incidence. Patient are then divided into whether or not the troke wa fatal and whether or not it left them dependent. Long-term quality adjuted life expectancy i etimated for each group and for the patient who do not experience a troke. Similarly, lifetime healthcare cot are meaured for each troke outcome. Patient in lower ABCD 2 core group have a lower baeline rik of troke and therefore have fewer troke averted compared with patient in higher ABCD 2 core group. 10

12 Appendix C: Model to determine cot effectivene No pecialit aement medical treatment No troke alive Dependent troke Dead Independent troke Figure C1: Deciion tree arm for no pecialit aement No troke alive Poitive U/S endarterectomy Dead Dependent troke Dead Independent troke Specialit aement at weekly clinic before receiving pecialit treatment Dependent troke Dead Independent troke Negative U/S No troke alive Dependent troke Dead Independent troke Figure C2: Deciion tree arm for pecialit aement at a weekly clinic (the poitive and negative can reult include true and fale reult) No troke alive Poitive U/S endarterectomy Dead Dependent troke Immediate pecialit aement Dead Independent troke No troke alive, bet medical treatment Negative U/S Dependent troke Dead Independent troke Figure C3: Deciion tree arm for immediate pecialit aement (the poitive and negative can reult include true and fale reult) 11

13 Age/ex ditribution of TIA and troke mimic The incidence of TIA and minor troke in a population of 500,000 people wa reported in Wardlaw et al. 27 which ued data from the Oxford Vacular Study (OXVASC). Table C1 Wardlaw et al. 27 Expected number of TIA and minor troke per annum in a tandard population of 500,000 people Age (year) Total Male 22.5 (5%) 66.3 (14%) 63.4 (13%) 25.7 (5%) (36%) Female 30.1 (6%) 65.3 (13%) (27%) 86 (18%) (64%) All 52.3 (11%) (27%) (40%) (23%) 490 The bae cae for thi model aume that all patient have a TIA or a minor troke. The GDG felt thi wa unlikely to be the ituation in practice a a high proportion of patient upected a having a TIA would be dicharged when found to have a TIA mimic. TIA mimic include epilepy, migraine and brain tumour. Rate will vary according to the referral criteria of different centre. The TIA mimic rate ha been etimated to be 50% uing OXVASC data. 28 Although a fairly recent BMJ editorial uggeted a TIA mimic rate of 30%. 198 We have added thee reult to the text. The impact of thee additional patient will be explored by doubling the cot of initial aement in each trategy to reflect a ratio of 1:1 of patient with actual TIA or minor troke to thoe with troke mimic who are dicharged without further treatment for troke prevention. Incidence of troke after TIA Johnton et al. (2007) reported the incidence of troke up to 90 day after a TIA, by ABCD 2 core (Table C2). They had reviewed the evidence from ix cohort of patient from England and USA totalling 4,799 patient. The overall troke rate were very imilar for the UK and USA. The pooling wa neceary to give greater preciion to the etimate of troke rik for the individual ABCD 2 group. Taking the aggregate figure acro all ix cohort, we etimated troke rate (Table C2) for each ABCD 2 core group uing the following formula: m=( 1/t)ln(S/S 0 ) Where t i the number of day of follow-up ince the TIA, S i the number of patient who urvived the follow-up period without a troke, and S 0 i the total number of patient in the group. To calculate the rate from 3 7 day the denominator, S0, i the number of patient who didn t have an event in the firt 2 day. Similarly, to calculate the rate from 8 90 day the denominator, S0, i the number of patient who didn t have an event in the firt 7 day. 12

14 Appendix C: Model to determine cot effectivene Table C2 incidence after TIA, by ABCD 2 core Patient Patient Patient with with with rate rate rate ABCD 2 All troke troke troke day 1 2 day 3 7 day 8 90 core patient by day 2 by day 7 by day 90 (%) (%) (%) , All 4, Accuracy of carotid ultraound can It wa aumed that all patient aeed at a pecialit troke unit will have a carotid ultraound can (U/S). If the can i poitive (carotid tenoi 50%), patient will have urgery (endarterectomy) in addition to medical treatment. If the carotid can i negative (carotid tenoi <50%), patient will be treated with medical treatment alone. Wardlaw et al. 27 reported that 10% of all patient with TIA had a carotid tenoi level of 50 99% (uing NASCET criteria) which hould be treated with urgery. Table C3 Wardlaw et al. 27 Ditribution of patient with TIA and minor troke between tenoi band Stenoi level % of all TIA 70 99% % %, 100% 90 The enitivitie and pecificitie of U/S for detecting carotid tenoi were alo reported by Wardlaw et al. 27 Surgery i recommended for patient with a tenoi level of 50%. Wardlaw et al. alo reported the ditribution of midiagnoi by band, which i hown in Table C5. 13

15 Table C4 Senitivity and pecificity of ultraound by tenoi level 27 Stenoi Senitivity (95%CI) Specificity (95%CI) 70 99% 0.89 (0.85 to 0.92) 0.84 (0.77 to 0.89) 50 69% 0.36 (0.25 to 0.49) 0.91 (0.87 to 0.94) 0 49% 0.83 (0.73 to 0.90) 0.84 (0.62 to 0.95) Table C5 Midiagnoi ditribution for ultraound by tenoi level 27 Actual tenoi band Midiagnoed tenoi band 0 49% 50 69% 70 99% 0 49% N/A % 0.36 N/A % N/A The aociation between the ABCD 2 core and preence of carotid tenoi 50% were tudied by Koton and Rothwell, but no clear relationhip wa found. 199 Wardlaw et al. reported a 0.53% relative rik of troke in patient with tenoi level <70% compared to 70%. 27 By uing thi relative rik and keeping the proportion of patient with 70% tenoi contant in each group (6%), we were able to etimate troke rik by both ABCD 2 core and tenoi level a follow: Table C6 Baeline troke rik, by ABCD 2 core and level of tenoi All (ee Table C2) Stenoi >=70 Stenoi <70 rate rate rate rate rate rate rate rate rate ABCD 2 day day day day day day day day day Score 1 2 (%) 3 7 (%) 8 90 (%) 1 2 (%) 3 7 (%) 8 90 (%) 1 2 (%) 3 7 (%) 8 90 (%) All

16 Appendix C: Model to determine cot effectivene Effectivene of carotid endarterectomy Table C7 below give the abolute rik reduction in troke or death for patient having urgery compared to medical treatment by time to urgery and tenoi level. Table C7 Abolute rik reduction per 100 patient with urgery in 5-year actuarial rik of ipilateral carotid ichaemic troke and any troke or death within 30 day after trial urgery from the pooled analyi of the RCT 45 Factor 50 to 69% tenoi 70% tenoi Surgical v medical Surgical v medical Time ince lat event (week) (ARR; 95%CI) (ARR; 95%CI) <2 17/158 v 34/150 23/167 v 54/149 (14.8; 6.2 to 23.4) (23.0; 13.6 to 32.4) 2 to 4 week 21/135 v 20/110 10/133 v 24/105 (3.3; 6.3 to 13.0) (15.9; 6.6 to 25.2) In the bae cae analyi, it wa aumed that 80% of patient who were aeed immediately and had a tenoi level of 50% would have urgery within 2 week of their TIA. For patient having pecialit aement at a weekly clinic, only 25% were aumed to have urgery within 2 week. All other patient with a tenoi level of 50% would have urgery from 2 to 4 week after their TIA. Thee were teted in a enitivity analyi. For immediate aement, 50% to 100% of urgery would take place within 2 week of TIA. For aement at a weekly clinic, 0 to 50% of urgery would take place within 2 week of TIA. Effectivene of medical treatment The following data wa baed on the QRESEARCH databae that wa upplied for a modelling project being carried out in Birmingham. Thi data wa drawn from 463 practice which ue the EMIS clinical ytem (mot common (>50%) primary care computer ytem). 200 * It how that mot patient are precribed apirin but only a mall proportion of patient are precribed appropriate combination medication pot-tia. * QRESEARCH relie on GP Read code and o i repreentative of people thought to have had a TIA in primary care roughly half referred to pecialit clinic with upected TIA (OXVASC) are ubequently thought to have had a TIA. 15

17 Table C8 Precription given by a GP at 1 month following a TIA (3,366 people were coded a uffering a TIA) Drug (precribed or over the counter) N (%) Antiplatelet/anticoagulant Apirin 2,144 (64%) Warfarin 171 (5%) Statin 1,244 (37%) Antihypertenive Thiazide 585 (17%) Angiotenin-converting enzyme (ACEI) 672 (20%) Angiotenin II receptor blocker (ARB) 174 (5%) Combination Antiplatelet agent/warfarin + tatin + ACEI + thiazide 153 (5%) Antiplatelet agent/warfarin + tatin + any hypertenive 742 (22%) gold tandard Wardlaw et al. 27 included relative rik reduction aociated with variou drug given a treatment for TIA or minor troke (Table C9). We aumed that all three group would benefit from apirin, but our baeline rik data (Table C2 and C6) almot certainly already account for apirin ue. Our treatment effect i therefore a 15% reduction in the 90-day troke rik for patient being aeed by pecialit due to precribing of modified releae dipyridamole. Patient going immediately to the pecialit clinic get thi benefit from day 1, wherea patient being ent to the weekly clinic are aumed to get thi effect from day 4. Table C9 Wardlaw et al. 27 Rik of troke in medically-treated patient by time after TIA or minor troke and tenoi band Time ince initiation of Reduction in medical therapy troke rik (%) Drug aumed to affecting rik <3 month 15 Modified releae dipyridamole <3 month 33 Apirin and modified releae dipyridamole 3 6 month 25 Apirin and modified releae dipyridamole 6 12 month 47 Apirin, modified releae dipyridamole and blood preure-lowering drug 1 year and beyond 55 Apirin, modified releae dipyridamole, blood preure-lowering drug and lipid-lowering drug 16

18 Appendix C: Model to determine cot effectivene -related health tatu The outcome of a troke occurring le than 90 day after a firt TIA (Table C10) wa taken from the Expre tudy (peronal communication from Peter Rothwell). A low Rankin core (0 2) wa conidered an independent health tate. A higher core (3 5) wa conidered a dependent tate requiring long-term nuring care. Table C10 Outcome of troke within 90 day of firt TIA Dependent after troke 11 (29%) Independent after troke 18 (47% Dead 9 (24%) All 38 (100%) Life Expectancy The life expectancy wa derived from data for the general population in England & Wale from the Office for National Statitic for Baed on the age-ex profile of patient (Table C1), the average life expectancy for a TIA patient who did not have a follow-up troke within 90 day wa etimated to be 10.8 year. It wa aumed that a TIA patient who had a troke which reulted in an independent health tate would have half the life expectancy, 5.4 year. If the troke reulted in a dependent health tate, then their life expectancy would be a third, 3.6 year. Utilitie Utilitie are the name given to generic meaure of (health-related) quality of life meaured on 0 1 cale. Health-related utilitie core are on a cale from 0 to 1, with 0 repreenting death and 1 repreenting perfect health. The utilitie ued in thi model relate to each troke-related health tate and were taken from Wardlaw et al. 27 Table C11 Utility core for each outcome for the model 27 Utility core Dependent after a troke 0.31 Independent after a troke 0.71 Fully recovered after TIA/no troke at 90 day 0.88 Calculation of QALY For each troke-related outcome the utility value wa multiplied by the correponding life expectancy to calculate the number of QALY (Table C12). The QALY were then dicounted by 3.5% per year. Since we did not have data on troke incidence up to 5 year for all patient group, the QALY gained attributable to averting troke due to urgery were calculated eparately but in the ame manner (Table C13). 17

19 Table C12 Calculation of QALY, baed on troke outcome within 90 day of TIA Life Dicounted Health tate at 90 day Utility expectancy QALY QALY Dependent after a troke within 90 day Independent after a troke within 90 day Fully recovered after TIA/no troke at 90 day Fatal troke by 90 day/urgical death Table C13 Calculation of QALY gained from urgery, baed on averting troke up to 5 year Dicounted LE* Utility QALY QALY Type of troke averted LE* no troke LYG** no troke gained gained Dependent after a troke Independent after a troke Fatal troke LE, life expectancy; LYG, life year gained Cot The cot of aement at a troke unit wa taken from cot for a one-top TIA clinic, which include taffing, overhead cot, imaging and lab. 201 A range of cot were collected from variou centre in the UK, to be ued to develop a new unit cot for the DH. The highet cot reported wa ued for immediate aement ( 410) and the mean cot wa ued for a weekly clinic ( 316). Thee cot were varied in the probabilitic enitivity analyi and the cot of immediate aement at a troke unit wa doubled in a one-way enitivity analyi. It wa aumed that a patient who did not receive pecialit aement would have two GP conultation within the firt month, at 25 per 10 minute conultation. 202 Table C14 Cot of one-top TIA clinic in the UK 201 Specialit aement cot Mean Immediate daily clinic 410 Weekly clinic 316 GP clinic 50 18

20 Appendix C: Model to determine cot effectivene Table C15 Cot of urgery and troke care by level of dependency 27 Mean ( ) Low ( ) High ( ) Cot of endarterectomy* 3,442 2,525 4,360 Dependent health tate: troke unit cot per patient for firt year 22,255 16,691 27,819 of treatment** Dependent health tate: cot per patient per year for ubequent 11,292 8,469 14,115 year Independent health tate: troke unit cot per patient for firt year 3,716 2,787 4,645 of treatment Independent health tate: cot per patient per year for ubequent ,095 year*** *cot per inpatient day 407 and average length of tay (LOS) in the hopital i 6 day **mean LOS of 51 day inpatient, rehabilitation cot of 763 and average annual cot of 11,292 baed on 1,854 firt ever troke patient from Scotland ***mean LOS of 14 day inpatient, rehabilitation cot of 40 and average annual cot of long-term care of 876 The mot commonly precribed drug and their doe were taken from the Precription Pricing Authority (PPA). 203 (Table C16) Table C16 Mot commonly cardiovacular precribing taken from the Precription Pricing Authority webite 203 Apirin 75 mg Ye Simvatatin* [40 mg]* Ye Ued in bae cae analyi Atorvatatin 10 mg Modified releae dipyridamole** [2*200 mg]** Ye Clopidogrel 75 mg Liinopril 10 mg Ye Bendrofluazide 2.5 mg Ye loartan Perindopril* 50 mg 20 mg * The doe of Simvatatin wa thought to be too low by the GDG (15mg) and thi wa changed to 40mg. ** The GDG thought it wa more likely that modified releae dipyridamole would be precribed in doe of 200mg, rather than 4 doe of 100mg a day a reported by the PPA. For the bae cae analyi, it wa aumed that patient aeed at the pecialit clinic would be precribed apirin, a tatin, an ace inhibiter and thiazide, all for life, plu modified releae dipyridamole for 2 year. Wherea for the GP-aeed patient, only 14% would get thi combination (minu modified releae dipyridamole) and the ret would get only apirin (baed on the Oxford data ee Table C8 above). Drug price are hown in Table C17. 19

21 Table C17 Drug price ued in the model BNF March 2007 ( ) Annual cot ( ) Apirin (non-prop) 75mg 28-tab Bendroflumethiazide (non-prop) 2.5mg 28-tab Liinopril (ACEi) (non-prop) 10mg 28 tab Simvatatin (non-prop) 40mg 28 tab Perantin Retard (modified releae dipyridamole) (Boehringer Ingelheim), 200mg 60-cap Lifetime cot Both drug cot and long-term care cot after troke are calculated over the patient lifetime (Table C18). The total cot differ between the alternative aement trategie not only becaue aement and urgery cot differ but alo becaue troke incidence will differ due to the different treatment given. Table C18 Lifetime treatment cot,* by troke-related health tate Lifetime Dicounted Life expectancy cot lifetime cot Dependent after a troke within 90 day ,614 49,684 Independent after a troke within 90 day 5.4 7,570 7,214 Fully recovered after a TIA/no troke at 90 day (i.e. drug cot only) GP aement pecialit aement ,327 1,152 Fatal troke by 90 day/urgical death * Not including the one-off cot of aement and urgery Senitivity analye One-way enitivity analye were carried out to tet the robutne of the reult to change in the key parameter/aumption. Reult The number of troke, death and QALY reulting from each trategy are preented in Table C19 immediate pecialit aement had the leat number of troke and the mot QALY. GP care had the mot troke and leat QALY. The breakdown of cot i hown in Table C21 weekly pecialit aement wa mot cotly and GP care leat cotly. 20

22 Appendix C: Model to determine cot effectivene Table C19 Bae cae reult: event per 1,000 TIA patient Immediate Weekly pecialit pecialit 90-day outcome aement aement GP care Alive no troke Dependent troke Independent troke death Surgical death All patient 1,000 1,000 1,000 Additional troke averted by urgery beyond 90 day QALY 7,123 7,062 6,920 Table C20 Bae cae reult: cot per 1,000 TIA patient Immediate Weekly pecialit pecialit aement ( ) aement ( ) GP care ( ) Aement 410, ,508 50,000 Surgery 846, ,775 0 Drug 964, , ,797 care (independent) 821, , ,681 care (dependent) 3,336,510 3,474,151 3,876,994 care (troke averted 275, ,662 0 by urgery) Total cot 6,103,988 6,199,458 5,430,472 When all patient were aeed in the ame way regardle of ABCD 2 core, immediate pecialit aement wa the mot cot-effective option. Immediate pecialit aement dominated weekly pecialit aement, it wa more effective and le expenive than weekly pecialit aement. Table C21 Bae cae reult: cot effectivene GP care ,430 Mean Mean ICER ICER QALY Cot ( ) (v GP care) ( ) (v Weekly) Weekly pecialit aement ,199 5,412 Immediate pecialit aement ,104 3,332 Immediate dominate ICER=Incremental cot-effectivene ratio (cot per QALY gained) 21

23 Uing the ABCD 2 core The number of troke averted in the firt 90 day after TIA varied greatly by ABCD 2 core group (Table C1). However, immediate pecialit aement wa till the mot cot-effective trategy for all group except 0 and 1 (Table C23). For group 0 the GP aement wa optimal and for group 1 it wa either immediate aement or GP care depending on whether the 20,000 or 30,000 per QALY threhold wa ued. Table C22 by 90 day per 1,000 patient, by ABCD 2 core group per 1,000 patient Immediate pecialit Weekly pecialit ABCD 2 core aement aement GP care All Table C23 Cot effectivene by ABCD 2 core group Optimal Optimal ABCD 2 ICER ICER trategy at trategy at core ICER (weekly (Immediate (Immediate 20,000 per 30,000 per v GP) v GP) v weekly) QALY gained QALY gained 0 50,625 31,397 1,231 GP GP 1 27,819 20,579 1,231 GP Immediate 2 18,014 11,849 Immediate Immediate Immediate dominate 3 17,286 11,662 Immediate Immediate Immediate dominate 4 6,398 3,989 Immediate Immediate Immediate dominate 5 3,630 2,120 Immediate Immediate Immediate dominate 6 1, Immediate Immediate Immediate dominate Immediate Immediate Immediate dominate All 5,412 3,332 Immediate Immediate Immediate dominate ICER=Incremental cot-effectivene ratio ( per QALY gained) 22

24 Appendix C: Model to determine cot effectivene One-way enitivity analye The reult of the enitivity analye are preented in Table C24 and C25. Table C24 Reult of one-way enitivity analye Immediate pecialit Weekly pecialit aement aement GP care Senitivity Mean cot Mean Mean cot Mean Mean cot Mean analyi ( ) QALY ( ) QALY ( ) QALY Bae cae 6, , , A 6, , , B 6, , , C 5, , , D 6, , , E 7, , , F 2, , G 5, , , Table C25 Reult of one-way enitity analye (continued) Optimal Optimal Reult ICER ICER ICER trategy at trategy at by Senitivity (weekly (Immediate (Immediate 20,000 per 30,000 per ABCD 2 analyi v GP) v GP) v weekly) QALY gained QALY gained core Bae cae 5,412 3,332 Immediate Immediate Immediate See dominate Table C23 A 7,524 5, Immediate Immediate No change B 6,383 4,682 Immediate Immediate Immediate GP care i dominate now optimal for group 2 and 3 C 2,553 1,275 Immediate Immediate Immediate Immediate dominate i now optimal for group 1 D 10,885 7,234 Immediate Immediate Immediate No change dominate E 4,403 1,503 Immediate Immediate Immediate No change dominate F 5,526 3,820 Immediate Immediate Immediate Immediate dominate i now optimal for group 1 G 7,965 5,416 Immediate Immediate Immediate No change dominate ICER=Incremental cot-effectivene ratio ( per QALY gained) 23

25 Senitivity analyi A The GDG commented that for every upected TIA patient who ha had a TIA or minor troke, one patient will have had a TIA mimic. 200 It i difficult to etimate the conequence for thee patient. To reflect thi, the cot of pecialit aement were doubled auming that for each patient treated for a TIA, the cot of another patient would be incurred who wa dicharged after aement. Thi i a very conervative aumption ince the model doe not etimate the health gain (and poibly cot aving) attained by thee patient from getting an improved diagnoi. Immediate pecialit aement remain the mot cot-effective trategy for ABCD 2 core 2 7 and overall. Similarly, the addition of the cot of brain can would alo not affect which trategy i mot cot effective. Senitivity analyi B In the bae cae analyi, it wa aumed that the proportion of patient with tenoi wa contant acro the ABCD 2 core group and that the abolute rik reduction from urgery wa contant acro the ABCD 2 core group. However, it i poible that the rik reduction i maller for patient in the lower ABCD 2 core group. For thi enitivity analyi, we etimated the health gain uing relative rik intead of abolute rik reduction (etimated from the ame data Table C7). The relative rik reduction (e.g. 65%RRR for tenoi >=70%) were applied to the 90-day troke rate. The benefit of endarterectomy in the bae cae analyi are baed on 5-year follow-up of troke rik. However, the ABCD core indicate only the rik in the hort-term. The enitivity analyi uing relative rik reduction i baed only on the 90-day troke rik, and therefore underetimate the longer-term benefit. Hence, we believe that the enitivity analyi i le plauible than the bae cae aumption. Senitivity analyi C In the bae cae analyi, patient undergoing pecialit aement are aumed to be precribed a number of drug and yet only the health effect of apirin and dipyridamole are modelled. The model had a time horizon of 90 day for key event (troke); unlike apirin and dipyridamole, the other drug are unlikely to influence troke rate in the hort term. Given our time contraint, we were unable to model the longer term health effect. However, for the key comparion of immediate veru weekly clinic, the health impact i not important ince both et of patient will receive the long-term benefit. In enitivity analyi C, we calculate only the cot of apirin and modified releae dipyridamole for 90 day, a with the bae cae but the other drug cot are removed. The reult of the model were largely unchanged. Senitivity analyi D In the bae cae, only patient receiving pecialit aement receive modified releae dipyridamole. In thi enitivity analyi, we aume that 50% of patient receiving GP care are precribed modified releae dipyridamole. The cot-effectivene reult were largely unchanged. Senitivity analyi E We changed the life expectancy of a dependent troke patient from 1/3 of normal to 2/3, and then the life expectancy of an independent troke patient wa changed from 1/2 of normal to 3/4. The cot-effectivene reult were largely unchanged. 24

26 Appendix C: Model to determine cot effectivene Senitivity analyi F We changed the life expectancy of a dependent troke patient from 1/3 of normal to 1/6, and then the life expectancy of an independent troke patient wa changed from 1/2 of normal to 1/4. The cot-effectivene reult were largely unchanged. Senitivity analyi G We changed the probability of death after a firt troke to the lower confidence interval 11%. Similarly we changed the probability of dependency after a firt troke to the lower confidence limit 15%. The cot-effectivene reult were largely unchanged. Dicuion The mot cot-effective trategy overall appear to be immediate pecialit aement. Thi trategy wa optimal for all ABCD 2 core group apart from 0 and 1, and the reult appear to be robut to change in key parameter. Although the model include cot for long-term nuring care for dependent troke patient, informal care cot were not included ince thee are not within the NHS perpective. If they had been included, then immediate pecialit aement would appear even more cot effective. The main driver for the cot effectivene of immediate aement appear to be getting patient on effective medication fater, which improve their outcome. The model i a imple repreentation, looking at only 90 day after the TIA for the effect of medical treatment and extrapolating from thi to get long-term outcome, and o caution hould be applied when uing thee reult. However, the reult of thi analyi reinforce the concluion of other tudie. The Wardlaw et al. NHS HTA report 27 indicated that the net benefit of troke prevention clinic wa dependent on the peed with which patient could be invetigated or treated. A the rik of troke for TIA patient i high in the firt month, treatment trategie which allow patient to be treated within thi period appear to be cot effective. The EXPRESS tudy, which wa publihed after the development of thi model, ugget that the impact of early pecialit aement on troke rik might be greater till. Thi before and after cohort tudy found a relative reduction in troke rik of about 80% for immediate pecialit aement compared to an appointment-baed clinic. Finally, a forthcoming report for the National Co-ordinating Centre for NHS Service Delivery and Organiation R&D ha contructed a imilar cot-effective model comparing different aement trategie. 28 It too found that ame day clinic are cot effective compared with weekly clinic for every ABCD 2 core group. In concluion, referral of upected TIA patient for immediate pecialit aement appear to be cot effective for all but the lowet rik patient becaue it upport timely precribing of effective drug and election of patient for effective urgery. 25

27 Appendix D: GDG member declaration of interet Name and date of ignature on declaration of Peronal pecuniary Peronal family Non-peronal Peronal noninteret form interet interet pecuniary interet pecuniary interet ALLISON Rhoda None None None None BARKER Julie None Huband work for None None Xana-SBS who contract out financial function of ome NHS Trut BOWMASTER Alan None None None None DAY Diana None None None None FORD Gary Honoraria from Family ownerhip of Reearch grant to Director UK Boehringer Ingelheim, GlaxoSmithKline intitution or/and Reearch Network Atra Zeneca for hare unretricted educational activitie educational grant and adviory board. from Boehringer Ingelheim, Lundbeck, and Atra Zeneca HATTON Steve None None Company director at None BPA/College of Paramedic KORNER Joeph None None None None (Form igned on 15 November 2007) LAMONT Peter None None None None McMANUS Richard None None In the lat 5 year, None Dr McManu ha participated in reearch funded by: Pfizer, Sanofi Aventi and A. Menarini Pharma and received funding to attend a reearch conference from MSD. MORSE Mariane None None None None POTTER John Received lecture and None None None reearch funding from variou pharma companie more directly related to thi GDG RUDD Anthony None None None None TYRRELL Pippa None None None None 26