Telemedicine for acute ischaemic stroke (Protocol) - Wiley Online Library

Cochrane Database of Systematic Reviews

Telemedicine for acute ischaemic stroke (Protocol) Arba F, Piccardi B, Baldereschi M, Ricci S, Inzitari D

Arba F, Piccardi B, Baldereschi M, Ricci S, Inzitari D. Telemedicine for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2016, Issue 2. Art. No.: CD012070. DOI: 10.1002/14651858.CD012070.

www.cochranelibrary.com

Telemedicine for acute ischaemic stroke (Protocol) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . ABSTRACT . . . . . . . . . BACKGROUND . . . . . . . OBJECTIVES . . . . . . . . METHODS . . . . . . . . . ACKNOWLEDGEMENTS . . . REFERENCES . . . . . . . . APPENDICES . . . . . . . . CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST . SOURCES OF SUPPORT . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .


. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

1 1 1 2 2 4 4 6 7 7 7

i

[Intervention Protocol]

Telemedicine for acute ischaemic stroke Francesco Arba1 , Benedetta Piccardi1 , Marzia Baldereschi2 , Stefano Ricci3 , Domenico Inzitari1 1 Neurofarba,

University of Florence, Florence, Italy. 2 Institute of Neuroscience, Italian National Research Council, University of Florence, Sesto Fiorentino, Italy. 3 UO Neurologia, ASL 1 dell’ Umbria, Città di Castello, Italy Contact address: Francesco Arba, Neurofarba, University of Florence, Largo Brambilla, 3, Florence, Tuscany, 50134, Italy. [email protected]. Editorial group: Cochrane Stroke Group. Publication status and date: New, published in Issue 2, 2016. Citation: Arba F, Piccardi B, Baldereschi M, Ricci S, Inzitari D. Telemedicine for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2016, Issue 2. Art. No.: CD012070. DOI: 10.1002/14651858.CD012070. Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the efficacy and safety of telemedicine versus conventional clinical assessment and treatment for people with acute ischaemic stroke.

BACKGROUND

Description of the condition Stroke is a major cause of disability and mortality worldwide (Feigin 2014), and interventions aimed to reduce stroke burden are pivotal. Ischaemic stroke, which is caused by a blood clot that occludes a brain vessel, is by far the most frequent subtype of stroke (Wardlaw 2014). Reperfusion of the salvageable tissue, through timely clot lysis of the occluded vessel with a thrombolytic drug, is the key factor to reduce brain damage. The only approved thrombolytic drug is recombinant tissue plasminogen activator (rt-PA) (Wardlaw 2014: meta-analysis, level of evidence I), and guidelines recommend rt-PA delivery within 4.5 hours from stroke onset (Ringleb 2008). Recently, intra-arterial thrombectomy after rt-PA treatment has proved effective in selected patients with proximal occlusions of the middle cerebral artery, and provides a further therapeutic option (Campbell 2015; Goyal 2015: clinical trials, level of evidence II). However, efficacy of both systemic and endovascular treatments is strictly time-dependent (Emberson

2014: meta-analysis, level of evidence I): guidelines encourage administration of rt-PA within 60 minutes of arrival at the hospital emergency department to maximize treatment efficacy (Jauch 2013). Therefore, prompt and guideline-based stroke evaluation and treatment are crucial for the limited therapeutic time window. Unfortunately, geographical barriers and the unavailability of stroke expertise in many places limits the widespread use of effective acute stroke care.

Description of the intervention Telemedicine is the use of any telecommunication technology for medical diagnosis and health care (Scannell 1995). With the introduction of the Internet and other informatics and electronic technologies into everyday life, the concept of telemedicine has evolved (Flodgren 2015). Internet-based telemedicine has the potential to deliver ’live’ real-time high-resolution video and audio to any standard browser window for remote visual examination and evaluation. Regarding stroke care, a relatively new approach consists of a two-way videoconferencing system between a physi-


1

cian based in a peripheral (’spoke’) hospital and another expert stroke physician in a comprehensive (hub) centre hospital (Levine 1999). This approach is known as telestroke, which includes patient assessment, CT scan evaluation, diagnosis, therapy, and management of stroke. Telestroke merges existing videoconferencing, teleradiology, and Internet technologies and enables many physicians to collaboratively examine patients in real-time.

How the intervention might work In an acute stroke setting, one of the most promising applications of telemedicine is the delivery of time-dependent acute stroke therapies (e.g. intravenous thrombolysis) in hospitals where stroke expertise is not available. It has been previously reported that in non-urban hospital emergency departments acute stroke care differs substantially from current guidelines or trial results (Burgin 2001; Leira 2007). Telemedicine may overcome geographical and resource barriers and has proven to be an effective way to remotely perform acute consulting, deliver neurological assessment, and direct the treatment of stroke patients (Johansson 2010; Nelson 2011). For instance, the American Heart Association Policy Statement recommended telestroke deployment whenever local or on-site stroke expertise or resources are insufficient to provide around-the-clock coverage of acute stroke care (Schwamm 2009). Telemedicine has therefore the potential to overcome geographical limits and expand expert specialised stroke care.

Why it is important to do this review Telemedicine is an evolving technology that has the potential to deliver specialised assistance and care in real-time to any user (e.g. patients, physicians) in any environment (e.g. home, hospital). Telemedicine has been evaluated extensively in a wide range of fields by previous Cochrane review authors, from asthma (McLean 2010) to ophthalmology (Bittner 2015). The use of telemedicine in stroke care has been already evaluated for implementation of rehabilitation programmes (Laver 2013). Telemedicine for acute ischaemic stroke is a developing strategy to improve stroke care, and its implementation in routine practice is increasing in many parts of the world. Prospective observational studies have shown safety and effectiveness of telemedicine procedures (Audebert 2005; Demaerschalk 2012). However, effect sizes of telemedicine for acute stroke have not been yet systematically reviewed.

OBJECTIVES To assess the efficacy and safety of telemedicine versus conventional clinical assessment and treatment for people with acute ischaemic stroke.

METHODS

Criteria for considering studies for this review

Types of studies We will include individually randomised controlled trials (RCTs) that compared telestroke-assisted acute ischaemic stroke care with either conventional care or telephone-assisted care. Should no RCTs be available, we will include clinical trials that use a quasirandomised method of allocation (quasi-RCTs), including cluster-RCTs. When the study does not state the method of group allocation, we will include it as a controlled clinical trial (CCT).

Types of participants We will include trials of participants with clinical symptoms and radiological features (computerised tomography (CT) or magnetic resonance imaging (MRI)) consistent with the diagnosis of firstever acute ischaemic stroke.

Types of interventions We will include studies that compare two-way video conferencing (telestroke) with either on-site physician (conventional) assistance or other telemedicine systems (e.g. telephone calls). The rationale of telestroke is to deliver expert stroke care provided by a stroke physician from a comprehensive stroke centre hospital to a physician in another hospital. Each telestroke intervention is, by definition, personalised according to patient demographical, clinical, and radiological characteristics. Characteristics of technology: Internet-based two-way video conferencing using personal computers, laptops, tablets, or smart phones.

Types of outcome measures

Primary outcomes

The primary outcome of interest will be the functional outcome as measured with the modified Rankin Score (mRS) (Wolfe 1991). The mRS measures the level of a person’s disability in terms of dependency in activities of daily living. The ’Excellent’ outcome (mRS = 0 to 1) describes asymptomatic participants who have symptoms that do not interfere with their daily living (no disability). The ’Good’ outcome (mRS = 0 to 2) describes participants who have a slight disability but full independence regarding their activities of daily living. We will also include trials that evaluated functional outcome using the Oxford Handicap Scale (OHS) (Bamford 1989). The target outcome timing will be three months


2

after the index stroke. To allow flexibility in outcome timing assessment, we will also include trials with shorter (two months) or longer (up to six months) follow-up evaluation.

Secondary outcomes

• Rates of symptomatic intracerebral haemorrhagic transformation (sICH) within 24 hours after recombinant tissue plasminogen activator (rt-PA) treatment (safety outcome). • Mortality rates (mRS = 6) at three months after the index stroke (safety outcome). • Time from stroke onset to treatment with rt-PA time (efficacy outcome).

Searching other resources In an effort to identify further published, unpublished and ongoing studies we will perform the following tasks. • Screen the reference lists of relevant studies. • Use Science Citation Index Cited Reference Search for forward tracking of relevant articles. • Contact trialists and researchers in the area and international telemedicine organisations. • Search the UK Telemedicine and E-health Information Service (www.teis.port.ac.uk/). • Search Google Scholar (http://scholar.google.com).

Data collection and analysis Search methods for identification of studies See the ’Specialized register’ section in the Cochrane Stroke Group module. We will search for trials in all languages and arrange for the translation of relevant articles when necessary.

Electronic searches We will search the trials registers of the Cochrane Stroke Group and the Cochrane Effective Practice and Organisation of Care Group (EPOC). We will also search the following electronic databases and trials registers. • Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library). • Database of Reviews of Effects (DARE) (the Cochrane Library). • Health Technology Assessment Database (HTA) (the Cochrane Library). • MEDLINE (Ovid) (from 1946) (Appendix 1). • EMBASE (Ovid) (from 1980). • CINHAL (Ebsco) (from 1982). • ClinicalTrials.gov (http://www.clinicaltrials.gov/). • EU Clinical Trials Register (https:// www.clinicaltrialsregister.eu). • Stroke Trials Registry (www.strokecenter.org/trials/). • ISRCTN Registry (http://www.isrctn.com/), previously Current Controlled Trials (www.controlled-trials.com). • World Health Organization International Clinical Trials Registry Platform (http://www.who.int/ictrp/en/). • Australian New Zeland Clinical Trials Registry ( www.anzctr.org.au/). • UK Clinical Research Network Study Portfolio (http:// public.ukcrn.org.uk/search/). We developed the MEDLINE search strategy with the help of the Cochrane Stroke Group Trials Search Co-ordinator and will adapt it for the other databases as necessary (Appendix 1).

Selection of studies Two review authors (FA and BP) will independently screen titles and abstracts of the references we obtain as a result of the literature search activities and will exclude obviously irrelevant reports. We will retrieve the full-text articles of the remaining references and the two review authors (FA and BP) will independently screen the full-text articles and identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreements through discussion or, if required, we will consult another review author (SR). We will collate multiple reports of the same study so that each study, not each reference, is the unit of interest in the Cochrane review. If necessary, we will email primary study authors or principal investigators of the studies for clarification. We will record the selection process and complete a PRISMA flow diagram. Data extraction and management From the list of titles we identify by the electronic search strategy, one review author (FA) will exclude irrelevant studies based on title and abstract. Three review authors (FA, BP and MB) will independently determine from the titles and abstracts which remaining studies meet the inclusion criteria. We will resolve any disagreements by discussion, and will consult another review author (SR) for final judgment when there is uncertainty. Three review authors will extract data from the included studies. We will use a form to collect details from the included studies. The data extraction form will include relevant information on the type of the study, patient population, randomisation, patient allocation, duration and methods of follow-up, and relevant outcomes. Assessment of risk of bias in included studies Two review authors (FA and BP) will independently assess the risk of bias for each included study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions


3

(Higgins 2011). We will resolve any disagreements by discussion or by involving a third review author (SR). We will assess the risk of bias according to the following domains. • Random sequence generation. • Allocation concealment. • Blinding of participants and personnel. • Blinding of outcome assessment. • Incomplete outcome data. • Selective outcome reporting. • Other bias. We will grade the risk of bias for each domain as either high, low, or unclear and provide information from the study report together with a justification for our judgment in the ’Risk of bias’ tables.

Dealing with missing data During data extraction, we will record the amount of missing data for outcome variables. If necessary, we will email the primary study authors or principal study investigators from all included studies to request information on primary outcomes. If the missing data are unavailable, we will consider these data as the “worst scenario” for the primary endpoint of the study. Assessment of heterogeneity We will use the I² statistic to measure heterogeneity among the trials in each analysis. We will define significant heterogeneity as an I² statistic value of greater than 50%. Assessment of reporting biases We will use funnel plots to assess the presence of publication bias.

Measures of treatment effect We will use the risk ratio (RR) with 95% confidence interval (CI) to measure treatment effects for dichotomous data. We will use the standardised mean difference (SMD) for continuous data. We will calculate the 95% CIs as well as the precise P values for all comparisons, where possible. Where we cannot include studies in a meta-analysis, we will present a descriptive synthesis of these studies using a narrative summary with extracted data in tables and figures. We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (http://www.gradeworkinggroup.org/) and construct ’Summary of findings’ tables using the GRADEpro Guideline Development Tool (www.gradepro.org).

Data synthesis Where we consider included studies to be sufficiently similar, we will conduct a meta-analysis by pooling the appropriate data using Review Manager (RevMan) (RevMan 2014). We will consider a random-effects approach to better estimate the effect size of the different studies with small sample sizes. Subgroup analysis and investigation of heterogeneity We have not planned to perform any subgroup analyses. Sensitivity analysis

Unit of analysis issues

We have not planned to perform any sensitivity analyses.

For studies with unit of analysis errors, we will make appropriate corrections by contacting primary study authors or principal study investigators to obtain missing information. If the data are unavailable within the correct unit of analysis, we will reassess the results and will estimate the P value. If we cannot obtain the appropriate data, we will report the effect size without a P value.

ACKNOWLEDGEMENTS We thank Brenda Thomas for her invaluable help in developing the search strategy.

REFERENCES

Additional references

Audebert 2005 Audebert HJ, Kukla C, Clarmann von Claranau S, Kühn J, Vatankhah B, Schenkel J, et al. TEMPiS Group. Telemedicine for safe and extended use of thrombolysis in stroke: the Telemedic Pilot Project for Integrative Stroke Care (TEMPiS) in Bavaria. Stroke 2005;36(2):287–91.

Bamford 1989 Bamford JM, Sandercock PA, Warlow CP, Slattery J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1989;20(6):828. Bittner 2015 Bittner AK, Wykstra SL, Yoshinaga PD, Li T. Telerehabilitation for people with low vision. Cochrane Database of Systematic Reviews 2015, Issue 8. [DOI: 10.1002/14651858.CD011019.pub2]


4

Burgin 2001 Burgin WS, Staub L, Chan W, Wein TH, Felberg RA, Grotta JC, et al. Acute stroke care in non-urban emergency departments. Neurology 2001;57(11):2006–12. Campbell 2015 Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusionimaging selection. New England Journal of Medicine 2015; 372(11):1009–18. Demaerschalk 2012 Demaerschalk BM, Raman R, Ernstrom K, Meyer BC. Efficacy of telemedicine for stroke: pooled analysis of the Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC) and STRokE DOC Arizona telestroke trials. Telemedicine Journal and e-Health 2012;18(3):230–7. Emberson 2014 Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Stroke Thrombolysis Trialists’ Collaborative Group. 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. Lancet 2014;384(9958):1929–35. Feigin 2014 Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, et al. Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) and the GBD Stroke Experts Group. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 2014;383 (9913):245–54. Flodgren 2015 Flodgren G, Rachas A, Farmer AJ, Inzitari M, Shepperd S. Interactive telemedicine: effects on professional practice and health care outcomes. Cochrane Database of Systematic Reviews 2015, Issue 9. [DOI: 10.1002/ 14651858.CD002098.pub2] Goyal 2015 Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. New England Journal of Medicine 2015;372(11): 1019–30. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Jauch 2013 Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, et al. American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Peripheral Vascular Disease, Council on Clinical

Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American HeartAssociation/ American Stroke Association. Stroke 2013;44(3):870–947. Johansson 2010 Johansson T, Wild C. Telemedicine in acute stroke management: systematic review. International Journal of Technology Assessment in Health Care 2010;26(2):149–55. Laver 2013 Laver KE, Schoene D, Crotty M, George S, Lannin NA, Sherrington C. Telerehabilitation services for stroke. Cochrane Database of Systematic Reviews 2013, Issue 12. [DOI: 10.1002/14651858.CD010255.pub2] Leira 2007 Leira EC, Pary JK, Davis PH, Grimsman KJ, Adams HP Jr. Slow progressive acceptance of intravenous thrombolysis for patients with stroke by rural primary care physicians. Archives of Neurology 2007;64(4):518–21. Levine 1999 Levine SR, Gorman M. “Telestroke” : the application of telemedicine for stroke. Stroke 1999;30(2):464–9. McLean 2010 McLean S, Chandler D, Nurmatov U, Liu JLY, Pagliari C, Car J, et al. Telehealthcare for asthma. Cochrane Database of Systematic Reviews 2010, Issue 10. [DOI: 10.1002/ 14651858.CD007717.pub2] Nelson 2011 Nelson RE, Saltzman GM, Skalabrin EJ, Demaerschalk BM, Majersik JJ. The cost-effectiveness of telestroke in the treatment of acute ischemic stroke. Neurology 2011;77(17): 1590–8. RevMan 2014 [Computer program] The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. Ringleb 2008 Ringleb PA, Bousser MG, Ford G, Bath P, Brainin M, Caso V, et al. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovascular Diseases 2008;25(5):457–507. Scannell 1995 Scannell K, Douglas A, Perednia DA, Kissman H. Telemedicine: past, present, future. Current Bibliographies in Medicine. Maryland: National Library of Medicine, 1995. Schwamm 2009 Schwamm LH, Holloway RG, Amarenco P, Audebert HJ, Bakas T, Chumbler NR, et al. American Heart Association Stroke Council, Interdisciplinary Council on Peripheral Vascular Disease. A review of the evidence for the use of telemedicine within stroke systems of care: a scientific statement from the American Heart Association/American Stroke Association. Stroke 2009;40(7):2616–34.


5

Wardlaw 2014 Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2014, Issue 7. [DOI: 10.1002/ 14651858.CD000213.pub3] Wolfe 1991 Wolfe CD, Taub NA, Woodrow EJ, Burney PG. Assessment of scales of disability and handicap for stroke patients. Stroke 1991;22(10):1242–4. ∗ Indicates the major publication for the study

APPENDICES Appendix 1. MEDLINE search strategy MEDLINE (Ovid) search strategy (from 1946) 1. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or brain ischemia/ or exp brain infarction/ or hypoxia-ischemia, brain/ or carotid artery diseases/ or carotid artery thrombosis/ or carotid artery, internal, dissection/ or intracranial arterial diseases/ or cerebral arterial diseases/ or infarction, anterior cerebral artery/ or infarction, middle cerebral artery/ or infarction, posterior cerebral artery/ or exp “intracranial embolism and thrombosis”/ or exp stroke/ or vertebral artery dissection/ 2. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw. 3. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation or basilar artery or vertebral artery) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw. 4. 1 or 2 or 3 5. telemedicine/ or telemetry/ or exp videoconferencing/ or telecommunications/ or computer communication networks/ or remote consultation/ or remote sensing technology/ or exp telephone/ or electronic mail/ or internet/ or wireless technology/ or teleradiology/ 6. (telestroke or tele-stroke or telemedicine or tele-medicine or telemedical or tele-medical or telemetry or telecommunication$ or telecommunication$ or videoconferenc$ or video-conferenc$ or videoconsultation or video-consultation or Stroke Doc or teleconferenc$ or tele-conferenc$ or teleconsultation or tele-consultation or e-consultation$ or teleradiology or tele-radiology).tw. 7. ((remote$ or distanc$ or distant or audio or audio-visual or audiovisual or telephone$ or phone$ or video$ or internet$ or computer$ or sensor$ or modem or webcam or website$ or electronic or smartphone$ or email or e-mail) adj5 (consult$ or communicat$ or assess$ or examin$ or evaluat$ or diagnos$ or specialist$ or neurologist$)).tw. 8. 5 or 6 or 7 9. 4 and 8 10. Randomized Controlled Trials as Topic/ 11. random allocation/ 12. Controlled Clinical Trials as Topic/ 13. control groups/ 14. clinical trials as topic/ or clinical trials, phase i as topic/ or clinical trials, phase ii as topic/ or clinical trials, phase iii as topic/ or clinical trials, phase iv as topic/ 15. double-blind method/ 16. single-blind method/ 17. randomized controlled trial.pt. 18. controlled clinical trial.pt. 19. (clinical trial or clinical trial phase i or clinical trial phase ii or clinical trial phase iii or clinical trial phase iv).pt. 20. (random$ or RCT or RCTs).tw. 21. (controlled adj5 (trial$ or stud$)).tw. 22. (clinical$ adj5 trial$).tw. Telemedicine for acute ischaemic stroke (Protocol) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

6

23. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw. 24. (quasi-random$ or quasi random$ or pseudo-random$ or pseudo random$).tw. 25. ((control or experiment$ or conservative) adj5 (treatment or therapy or procedure or manage$)).tw. 26. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw. 27. trial.ti. 28. (assign$ or allocat$).tw. 29. controls.tw. 30. or/10-29 31. 9 and 30 32. exp animals/ not humans/ 33. 31 not 32

CONTRIBUTIONS OF AUTHORS Francesco Arba wrote and edited the protocol draft. Benedetta Piccardi, Stefano Ricci, Marzia Baldereschi and Domenico Inzitari edited the draft.

DECLARATIONS OF INTEREST Francesco Arba received a grant from Fondazione Cassa di Risparmio di Firenze to conduct a systematic review of literature on telestroke. Benedetta Piccardi has no known conflicts of interest. Stefano Ricci has no known conflicts of interest. Marzia Baldereschi has no known conflicts of interest. Domenico Inzitari received a research grant from Fondazione Ente Cassa di Risparmio di Firenze for the project “Stroke: Communication & Innovation”, and is the chairman of the steering committee of Evidence-based Gestional Processes in Stroke, Italian Stroke Organisation.

SOURCES OF SUPPORT

Internal sources • No sources of support supplied

External sources • Ente Cassa di Risparmio di Firenze. Project:“Ictus: Comunicazione&Innovazione”, Italy. The funding source had no role in planning any part of this Cochrane protocol.


7