Transthoracic Echocardiography in Adult Patients with Ischemic Stroke: A Review of the Diagnostic Yield and Cost Effectiveness

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1 TITLE: Transthoracic Echocardiography in Adult Patients with Ischemic Stroke: A Review of the Diagnostic Yield and Cost Effectiveness DATE: 22 October 2014 CONTEXT AND POLICY ISSUES Ischemic stroke, an interruption of cerebral blood flow leading to death or permanent loss of function, is responsible for significant mortality and disability, particularly in the older population. Transient ischemic attack (TIA), in which there is no tissue infarction and symptoms rapidly resolve, 1 is associated with an elevated risk of subsequent stroke. Investigation of cardiac risk factors and possible sources of emboli of stroke/tia is undertaken to identify modifiable risk factors, and reduce the risk of subsequent stroke. Echocardiography is used to identify potential cardiac sources of emboli, thought to be responsible for 15-30% of stroke. 2 The emboli may originate from abnormalities within the heart itself, or peripheral emboli may reach the cerebral circulation through abnormal right-left shunts within the heart (paradoxical emboli). 2 The major cardiac abnormalities implicated in stroke are left atrial thrombi associated with atrial fibrillation or rheumatic mitral stenosis, left ventricular thrombi associated with wall aneurysms or abnormal wall movements after myocardial infarction, or atherosclerotic emboli from the aortic arch. 3 Tumours or infectious or noninfectious vegetations are less common sources of emboli. The major abnormalities associated with rightleft shunt and paradoxical emboli are patent foramen ovale (PFO) and atrial septal defect (ASD). Thus, depending upon the risk factor, secondary prevention may involve chronic anticoagulation, restoration of normal rhythm, or surgical intervention to close a shunt. 3 Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantoe to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 Transthoracic echocardiography (TTE) involves ultrasound visualization of the heart through the chest wall. Transoesophogeal echocardiography (TOE) involves introducing the probe into the patient s esophagus, which allows better resolution of most of the cardiac structures due to proximity (with the exception of the left ventricle), but is more invasive and less well tolerated, more time-consuming and costly, and potentially less readily available. Both procedures are considered to have low diagnostic yields in identifying cardiac sources of emboli in patients with no other identifiable reason for stroke, but they do enable intervention in patients with positive findings. This report examines the clinical and cost effectiveness of using TTE with clinical evidence to identify cardiac sources of emboli in adult patients with ischemic stroke, alone and compared with TOE. RESEARCH QUESTIONS 1. What is the diagnostic yield and clinical benefit of TTE for identifying cardiac sources of emboli in adult patients with ischemic stroke? 2. What is the comparative diagnostic yield of TTE and TOE for identifying cardiac sources of emboli in adult patients with ischemic stroke? 3. What is the cost effectiveness of TTE for identifying cardiac sources of emboli in adult patients with ischemic stroke? 4. What is the comparative cost effectiveness of TTE and TOE for identifying cardiac sources of emboli in adult patients with ischemic stroke? KEY FINDINGS Transthoracic echocardiography can be used to identify cardiac causes of stroke, in particular left atrial or left ventricular thrombi, or some right to left shunts. It is less invasive, can be more rapidly performed, and requires fewer staff than transoesophageal echocardiography, but is generally less sensitive and somewhat less specific. The more recently developed second harmonic (TTEh) echocardiography is more accurate than the older fundamental harmonic (TTEf). TTE changes management in only a small proportion of patients, and there is no information on its effect in long-term outcomes. METHODS Literature Search Strategy A focused literature search (with the main concepts appearing in title or subject heading) was conducted using key resources including PubMed, The Cochrane Library (2014, Issue 9), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2007 and September 23, TTE in Adult Patients with Ischemic Stroke 2

3 Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Table 1: Selection Criteria Population Adult patients that experienced an ischemic stroke (cerebral ischemia) Intervention Transthoracic echocardiography (TTE) Comparator Q1+Q3: Clinical evidence (medical history, abnormal examination, abnormal chest x-ray, abnormal electrocardiogram) Q2+Q4: Transesophageal echocardiography (TOE) Outcomes Diagnostic yield, clinical benefit (change in management, therapy administered, incidence of stroke) Cost effectiveness Study Designs HTA/ Systematic review/meta-analysis, Randomized controlled trials, Non-randomized studies, Economic evaluations Exclusion Criteria Studies were excluded if they did not satisfy the selection criteria, if they were duplicate publications, or were published prior to Studies were also excluded if they had been included in a selected systematic review, or if they did not report results from TTE separately from those from TOE to allow comparison. Critical Appraisal of Individual Studies Systematic reviews were appraised using AMSTAR, 4 and diagnostic accuracy studies using QUADAS-2. 5 Relevant QUADAS-2 criteria (those pertaining to patient selection and single test administration, but not those that described a comparison) were used to assess the studies of diagnostic yield. Cost-effectiveness studies were appraised according to the 1996 criteria of Drummond et al. 6 The strengths and limitations of individual studies were summarized verbally rather than numerically. SUMMARY OF EVIDENCE Quantity of Research Available A total of 357 citations were identified in the bibliographic database search. Following screening of titles and abstracts, 315 citations were excluded and 42 potentially relevant reports from the electronic search were retrieved for full-text review. Six potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, 36 publications were excluded, while 12 publications met the inclusion criteria and were included in this report. Studies excluded for irrelevant intervention included those in which results for TTE were not reported separately from other interventions so as to permit calculation of diagnostic yield, or where the intervention of interest was TOE with TTE as an adjunct. Appendix 1 presents the PRISMA flowchart of the study selection. TTE in Adult Patients with Ischemic Stroke 3

4 Eleven studies measured the diagnostic yield of TTE, and two of these compared the diagnostic yield of TTE and TOE. One HTA compared the diagnostic accuracy of TTE and TOE, and included a cost-effectiveness analysis of TTE compared with TOE in the UK health services context. No studies reported on the cost-effectiveness of TTE within the Canadian context. Summary of Study Characteristics What is the diagnostic yield and clinical benefit of transthoracic echocardiography for identifying cardiac sources of emboli in adult patients with ischemic stroke? The characteristics of the eleven individual studies of diagnostic yield are summarized in Appendix 2. With the exception of one study, 7 all included studies were retrospective cohort studies or chart reviews. Studies were conducted in Australia, 8 Saudi Arabia, 9 Turkey, 10 Canada, 11,12 Germany, 13 Karachi, 14 Uganda, 15 Thailand, 16 Spain, 17 and Iran. 7 The majority of studies included patients admitted to stroke centres or neurological units, and the majority of patients were elderly (mean age 54.7 to 75.3 years). Four studies explicitly recruited patients with TIA, 8,9,12,13 one explicitly excluded them, 10 and the remainder only specified patients with ischemic stroke. Two studies restricted enrollment to patients with ischemic stroke who had concurrent atrial fibrillation (AF). 11,13 The mode of TTE (fundamental versus harmonic) was not indicated for any of the studies. There was no independent confirmation of abnormalities by surgery, pathology or another imaging modality. Abnormalities considered potentially clinically significant varied across studies: Most studies aimed to identify and classify correctly etiologies of stroke/sources of embolism, 7-11,13-15,17 while two restricted themselves to abnormalities that would potentially influence clinical management (e.g., lead to initiation of anticoagulation). 12,16 All studies sought evidence of left atrial (LA)/LA appendage thrombus and left ventricle (LV) thrombus. Other abnormalities included: mitral stenosis (including rheumatic or with LA dilitation), 7-11, studies; patent foramen ovale (with or without atrial septal defect), 7-11,13,16,17 8 studies; congestive heart failure (including poor LV function or low ejection fraction), 7-9,11-13,15 cardiomyopathy, 7,8,10,12,14-16 atrial myxoma, 7,8,10,12,14-16 and prosthetic valve (mechanical or unspecified, and with or without thrombosis), 7-10,14,15,17 7 studies each; left ventricular wall motion abnormalities, 7,9,10,14,15,17 6 studies; atrial septal aneurysm, 7,9,10,16,17 5 studies; and endocarditis, 7,8,13,16 spontaneous echo contrast, 7,10,11,13 mitral valve prolapse, 9,10,13,17 aortic arch atheroma, 7-9,13 and vegetation, 9,11,12,17 4 studies each. Classification of atrial fibrillation varied; AF being itself a risk factor for intracardiac thrombus and therefore stroke, but one generally diagnosed via electrocardiogram rather than echocardiogram. What is the comparative diagnostic yield of transthoracic echocardiography and transoesophageal echocardiography for identifying cardiac sources of emboli in adult patients with ischemic stroke? A 2014 health technology assessment with systematic review and diagnostic meta-analysis 18 compared echocardiography with other diagnostic imaging methods (including TOE) for the detection of a cardiac risk factors for TIA or stroke. The reviewers searched MEDLINE, EMBASE, PsychINFO, Web of Science, the Cochrane Library, and CINAHL using terms related to stroke and TTE. There were no date and language restrictions in the search, but non-english language studies were excluded at screening. The search was current to September TTE in Adult Patients with Ischemic Stroke 4

5 Studies were included if they assessed the diagnostic accuracy of TTE in patients with with cardiac conditions identified as potential sources of stroke or TIA, 18 and provided data for TTE against a established reference standard test (e.g., TOE for patent foramen ovale) or, in the absence of an established diagnostic standard, another test or investigation. Studies quality was assessed by a single reviewer using QUADAS. Fifty-one studies compared echocardiography to other diagnostic modalities. The earliest study was published in 1982 and the latest in Although the subject of the review was stroke, the review included diagnostic studies in any indication, leading to the inclusion of studies in patients who underwent investigation for stroke, stroke/tia, atrial fibrillation, congenital heart defects, PFO, atrial septal defect (ASD), mitral valve prolapse or stenosis, aortic valve stenosis, atrial masses, cardiomyopathy, aneurysm, and infectious and non-infectious endocarditis. Thirteen studies recruited only patients with stroke/tia, while six included stroke/tia with other indications, and the remainder recruited patients under investigation for other indications. Provided that consistent diagnostic criteria were applied across studies, pooling across indications should not be expected to affect the comparative measures of specificity and sensitivity. Prevalence would, however, affect positive and negative predictive value, which were not calculated. Mean sensitivity and specificity were calculated across studies pooled by comparator diagnostic method and individual cardiac abnormality (e.g., LA thrombosis, LA appendage thrombosis, LV thrombosis, PFO). The analytic method was a Bayesian diagnostic meta-analysis that accounted for the correlation between sensitivity and specificity. The analysts distinguished TTE in fundamental imaging mode (TTEf) from the more recently-developed and more sensitive TTE in second harmonic imaging mode (TTEh). Data were available for LA thrombus (TTEf 3 studies, TTEh 3 studies), LA appendage thrombus (TTEf 8 studies, TTEh 1 study), atrial septal aneurysm (TTEf 4 studies, TTEh 1 study), atrial myxoma (TTEf 1 study), cardiac vegetations (TTEf 1 study, TTEh 2 studies), mitral valve regurgitation (TTEf 2 studies, TTEh 1 study), stenosis (TTEf 1 study) or prolapse (TTEh 3 studies), PFO (TTEf 13 studies, TTEh 11 studies), ASD (TTEf 4 studies, TTEh 2 studies), and spontaneous echo contrast (TTEf 7 studies, TTEh 1 study). Patient numbers for each comparison are provided in Appendix 4. No studies compared TTE with TOE for detecting ventricular abnormalities (thrombus, aneurysm, wall motion abnormalities), as TOE is acnowledged to be insensitive for ventricular pathology. The characteristics of the two individual studies published since 2007 that compared diagnostic yield of TTE with TOE are summarized in Appendix 2. One was carried out in Turkey (Cokar et al, 2008) 10 and the other in Iran (Yaghoubi et al., 2011); 7 one was a retrospective study and the other a prospective study. Both included predominately older patients (mean 54.7 years and 65.4 years) presenting with ischemic stroke. Neither study gave details of the intervention or comparator, beyond identifying them as TTE and TOE. In common, they considered the following abnormalities: Valvular heart disease (with and without AF), LA/LA atrial appendage thrombus, LV thrombus, prosthetic valve, atrial myxoma, akinetic LV segment (wall motion abnormality), cardiomyopathy, LA spontaneous echo contrast, ASA, mitral valve prolapse, mitral annulus calcification, mitral stenosis, and PFO. What is the cost effectiveness of transthoracic echocardiography for identifying cardiac sources of emboli in adult patients with ischemic stroke? No studies reported on the cost effectiveness for TTE in patients with ischemic stroke. TTE in Adult Patients with Ischemic Stroke 5

6 What is the comparative cost effectiveness of transthoracic echocardiography for identifying cardiac sources of emboli in adult patients with ischemic stroke? The 2014 Health Technology Assessment by Holmes et al. 18 included a systematic review of economic studies and a cost-effectiveness analysis of TTE after a first episode of stroke/tia in secondary care, from the perspective of the UK National Health service. The systematic review involved a search of the bibliographic databases MEDLINE, EMBASE, PsychINFO, Web of Science, DARE, NHS EED, and CINAHL, using terms related to stroke, and filtering the results for economic and cost-related studies. There were no date and language restrictions in the search. The search was current to March Studies were included if they reported cost effectiveness for TTE in first episode stroke/tia patients as life-years gained or as quality-adjusted life-years. In the associated cost-effectiveness analysis, the chosen intervention was TTEh, which according to their survey of practice had been adopted by most UK hospitals in preference to TTEf. They restricted their analysis to diagnoses for which they had diagnostic accuracy data, and that, if made, could change patient management. The only diagnosis that met these criteria was LA thrombus, for which TTEh had a sensitivity of 79% based on three studies, and for which the usual intervention was anticoagulation. The reviewers noted that there was little evidence associating LA thrombus and stroke, but there was support from expert opinion for intervening with anticoagulation. Five diagnostic strategies were compared: No test, TTEh only, TOE only, TTEh followed by TOE in patients with a positive test, and TTEh followed by TOE in patients with a negative test. In this analysis, the diagnostic accuracy of TOE was also derived from the literature, and the diagnostic accuracy of TTE was adjusted to take account of its imperfection as a standard. Patients entered the model with an initial stroke or TIA. All patients with positive findings of LA thrombus were treated with warfarin in addition to standard care (aspirin). Subsequently patients could experience a stroke from which they could emerge independent of care, a stroke from which they could emerge dependent on care, a fatal stroke, or death from other causes. Patients receiving warfarin were at risk of gastrointestinal hemorrhage, which was assumed to require care temporarily, and intracranial hemorrhage (ICH), with possibility of permanent effects of disability or death. The model included initial treatment costs for patients with TIA and dependent and independent stroke, long term costs for patients with dependent and independent stroke, costs of warfarin treatment, treatment costs for GI hemorrhage, initial treatment costs for ICH, and long term costs for ICH leading to disability. Estimates of outcomes were supported by systematic reviews of the literature. The analysis was conducted for patients at 45, 55, and 65 years of age, with a lifetime horizon. Summary of Critical Appraisal Summaries of critical appraisal of individual studies are presented in Appendix 3. The non-comparative studies of diagnostic yield all had similar limitation. As with many diagnostic reviews, the studies examining diagnostic yield were heterogeneous. The studies are retrospective chart reviews conducted at academic and specialty centres, and represent the patients and practice at those centres. However, they offered minimal description of the patient TTE in Adult Patients with Ischemic Stroke 6

7 population, without detail of the criteria used for establishing the diagnosis of stroke/tia, and the investigations supporting it. The definition of stroke is less likely to have changed over the period of the studies, but the criteria for diagnosis of TIA has been evolving, which may influence the diagnostic yield of the procedures used. 1 The intervention was poorly described; in particular, studies did not indicate whether the less sensitive TTEf or the more sensitive TTEh mode was used. The sequence and time relationship between interventions in the two studies that compared diagnostic yields were poorly described and variable. The abnormalities of interest varied across the studies, which would have affected the diagnostic yield, although the pathologies of principal concern (intracardiac thrombus and right-left shunts) were included in most if not all the studies. All but one study was retrospective, and there were long intervals between data collection and study publication (9 years, in one case). This is of particular concern given the ongoing innovation in both equipment and software. The systematic review 18 was well-conducted and reported by an independent team, with clear questions, a comprehensive search across six bibliographic databases, and selection and dataextraction by two independent reviewers. Grey literature was not included. The quality of studies was assessed, with the most consistently noted deficit being a lack of detail about the tests, including the blinding status, and the availability of clinical information while the tests were being evaluated. Bayesian diagnostic meta-analysis was used in the pooling of studies, with correlation between sensitivity and specificity; this is a standard method, and appropriate, although the analysis assumed perfection in the reference standard. The reviewers noted the study heterogeneity and moderate quality, and qualified their findings. Publication bias was not assessed. The economic analysis 18 was well conducted and reported by an independent team. The questions were clearly stated, the models were described and justified and their limitations were assessed. The outcome data that entered the models was presented and supported by literature review, and the cost data and its source was provided. Summary of Findings What is the diagnostic yield and clinical benefit of transthoracic echocardiography for identifying cardiac sources of emboli in adult patients with ischemic stroke? The results of the eleven individual studies of diagnostic yield are summarized in Appendix 4. The diagnostic yield of TTE in identifying cardiac sources of emboli in adult patients with ischemic stroke ranged from 6.5% 10 to 25%. 16 In the former study, the investigation was for sources of embolic stroke, and in the latter, it was for indications for management change; other than that, it is difficult to account for the broad range of values observed. For patients with stroke/tia diagnostic yield was around 6.5%, and for those with stroke and AF, it was 6.4% for all sources in one study 11 and 8.2% for major sources of stroke in the other. 13 A smaller proportion of patients had a change in clinical management. In the five studies that reported the effect on clinical management, this ranged from no change to 5%. No studies reported long term clinical outcomes. What is the comparative diagnostic yield of transthoracic echocardiography and transesophageal echocardiography for identifying cardiac sources of emboli in adult patients with ischemic stroke? TTE in Adult Patients with Ischemic Stroke 7

8 The results for the comparative pooled diagnostic accuracy of transthoracic echocardiography and transoesophageal echocardiography are tabulated in Appendix 5, and the results for the two studies published since 2007 appear in Appendix 6. Compared with TOE, sensitivity of TTE in detecting individual cardiac abnormalities was extremely variable: The pooled sensitivity of TTEf to detect individual cardiovascular anomalies ranged from 0.00 (left atrial spontaneous echo contrast) to 1.00 (mitral valve stenosis), and that of TTEh from 0.57 (mitral valve regurgitation) to 1.00 (left atrial appendage thrombus). Specificities were generally close to 1.0, with a few exceptions. In general, TTEh performed better than TTEf, with the caveat that in many comparisons it was represented by single studies. For left atrial thrombus, TTEf had a pooled sensitivity of 0.34 (95% Credible Interval (CrI) 0.07 to 0.71) and specificity of 1.00 (95% CrI 0.97 to 1.00), across three studies (142 patients). TTEh had a pooled sensitivity of 0.79 (95% CrI 0.47 to 0.94) and specificity of 1.00 (95% CrI 0.99 to 1.00), across three studies (477 patients). For LA appendage thrombus, TTEf had a pooled sensitivity of 0.06 (95% CrI 0.00 to 0.26) and specificity of 1.00 (95% CrI 0.99 to 1.00), over eight studies (554 patients). TTEh had a pooled sensitivity of 1.00 (95% CrI 0.16 to 1.00) and sensitivity of 1.00 (95% CrI 0.97 to 1.00), for one study only (118 patients). For PFO, TTEf had a sensitivity of 0.34 (95% CrI 0.21 to 0.47) and specificity 1.00 (95% CrI 0.99 to 1.00), across 13 studies (905 patients). TTEh had a sensitivity of 0.89 (95% CrI 0.80 to 0.95) and specificity 0.99 (95% CrI 0.97 to 1.00), across 11 studies (1115 patients). In the first of the two studies published since 2007 that directly compared diagnostic yields of TTE with TOE for detecting cardiac abnormalities in the same group of patients, the diagnostic yields were 18.7% and 47.5%, respectively. In the second, the diagnostic yield of TTE was 18.8%, while TOE identified an additional potential embolic source in 26.9%. What is the cost effectiveness of transthoracic echocardiography for identifying cardiac sources of emboli in adult patients with ischemic stroke? No reports of the cost effectiveness of TTE were identified. What is the comparative cost effectiveness of transthoracic echocardiography and transesophageal echocardiography for identifying cardiac sources of emboli in adult patients with ischemic stroke? The systematic review identified two cost-effectiveness analyses from the US health service perspective, one published in 1997 and one in 2007, 19 neither of which found TTE cost-effective in identifying cardioembolic causes of stroke. The analyses did not distinguish between TTEf or TTEh. The more recent of the two 19 used a decision-analytic Markov model in which TTE and/or TOE was used to diagnose intracardiac thrombus in new stroke/tia patients. Diagnosis was followed by warfarin anticoagulation. The model was run for a cohort of white male patients aged 65 years, with 30 year horizon, and a baseline prevalence of cardiac thrombus of 5%. Given these conditions, the estimated incremental cost effectiveness ratio (ICER) of both cardiac TTE and TOE compared with standard therapy was >$83 000, with all alternative strategies dominated. For the cost-effectiveness analysis within the UK health system context, 18 TTEh emerged as the optimal strategy for the diagnosis of LA thrombus in stroke/tia patients in all age groups. In the TTE in Adult Patients with Ischemic Stroke 8

9 deterministic analysis, compared with no test, TTEh had ICERs of 17,541 to 22,362 for the three age groups, while the other strategies were either extendedly dominated, or had ICERs of greater than 44,492. In the probabilistic analysis, the estimates were similar: TTEh had ICERs of 18,526 to 24,648, while the other diagnostic strategies were either dominated/extendedly dominated, or had ICERs of greater than 65,490. TTEh was the only strategy that met the usual willingness-to-pay threshold of 30,000. Limitations The studies of diagnostic yield were heterogeneous in patient intake and in the list of abnormalities thought clinically significant. Although all studies recruited stroke patients, the criteria used for establishing the diagnosis of stroke/tia, and the investigations supporting it were not specified. There was insufficient detail on the interventions to determine the type of TTE used (TTEf or TTEh), which would lead to an underestimate of the diagnostic yield if the less sensitive TTEf was used. Better understanding of patient selection and use of modern methods would likely increase measured diagnostic yield. Reporting quality was moderate and for some studies there was a marked delay in publication between data collection and publication. The systematic review and diagnostic meta-analysis of studies comparing TTE to TOE could not produce a single measure across all potential cardiac causes of stroke, but was able to estimate sensitivity and specificity for several of the more important potential causes. However, the evidence-base is clinically heterogeneous, with studies conducted across three decades and in multiple clinical indications for the same abnormality. Given such a span, there would likely have been background changes in the technologies and the criteria used to evaluate the abnormality. Reporting quality was moderate, with most of the deficits in the description of the interventions. In addition, as the authors note, the wide uncertainty in some estimates also arises from the small number of contributing studies and the low prevalence rates for abnormalities in some of the studies. The meta-analysis method assumed that TOE was a perfect reference standard, and therefore may have produced a biased estimate of the performance of TTE. None of the studies reported adverse event data, so no risk-benefit assessment was possible for the procedure itself. Both methods are generally regarded as safe. For the economic analysis, the results depended both on the model and the data, some of which was scant. The authors indicated its results should be treated with some caution since it modeled only a single abnormality, LA thrombus, and the rate of stroke recurrence was based only on one small study. The only treatment included in the model was warfarin. Inclusion of the new, non-warfarin anticoagulants would increase the cost of routine treatment, with a possibly altered risk profile. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING Notwithstanding the limitations of the evidence, TTE is consistently less sensitive than TOE in detecting potential cardiac sources of embolism. The more recently developed TTEh improves on TTEf sensitivity in detecting LA thrombus and LV thrombus, at the cost of a decrease in specificity, but the number of studies explicitly reporting these methods is small. TTE is expected to be more useful in detecting disorders of the LV apex. In studies that describe management, TTE results (and ultrasound results in general) influenced management in only a minority of patients. This was in part because the management had already been determined by TTE in Adult Patients with Ischemic Stroke 9

10 patient history (anticoagulation for a prosthetic valve) or the results of other tests (anticoagulation for atrial fibrillation detected by ECG). There were no studies reporting clinical outcomes from diagnostic studies, and optimal management for other abnormalities (eg, closure of PFO) is uncertain. Thus, further diagnostic studies using current study design and reporting standards, further investigation of the relationship between cardiac abnormalities and risk of stroke, and further investigation into treatment of abnormalities is warranted. Prepared by: Canadian Agency for Drugs and Technologies in Health Tel: TTE in Adult Patients with Ischemic Stroke 10

11 REFERENCES 1. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke Jun;40(6): Pepi M, Evangelista A, Nihoyannopoulos P, Flachskampf FA, Athanassopoulos G, Colonna P, et al. Recommendations for echocardiography use in the diagnosis and management of cardiac sources of embolism: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur J Echocardiogr [Internet] Jul [cited 2014 Sep 25];11(6): Available from: 3. Manning WJ. Echocardiography in detection of intracardiac sources of embolism [cited 2014 Sep 25]. In: UpToDate [Internet]. Waltham (MA): UpToDate; c Available from: Subscription required. 4. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet] [cited 2014 Oct 20];7:10. Available from: 5. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med Oct 18;155(8): Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers of economic submissions to the BMJ. The BMJ Economic Evaluation Working Party. BMJ Aug 3;313(7052): Available from: 7. Yaghoubi E, Nemati R, Aghasadeghi K, Borhani HA. The diagnostic efficiency of transesophageal compared to transthoracic echocardiographic findings from 405 patients with ischemic stroke. J Clin Neurosci Nov;18(11): Ahmad O, Ahmad KE, Dear KB, Harvey I, Hughes A, Lueck CJ. Echocardiography in the detection of cardioembolism in a stroke population. J Clin Neurosci May;17(5): Al-Faleh HF, Al-Qadi AO, Hersi AS. Diagnostic yield and therapeutic impact of transthoracic echocardiography in patients with potential cardiac sources of cerebral embolism. Saudi Med J Jun;31(6): Cokar O, Ozturk O, Aydemir T, Tiras R, Ozer F, Hakyemez HA. Transoesophageal echocardiographic findings in patients with ischemic lacunar and nonlacunar stroke. J Clin Neurosci Mar;15(3): TTE in Adult Patients with Ischemic Stroke 11

12 11. Douen AG, Sabih M, Pageau N. Thrombus detection by echocardiography in patients with acute ischemic stroke and chronic or new-onset atrial fibrillation. J Stroke Cerebrovasc Dis Jul;17(4): Menon BK, Coulter JI, Bal S, Godzwon C, Weeks S, Hutchison S, et al. Acute ischaemic stroke or transient ischaemic attack and the need for inpatient echocardiography. Postgrad Med J Aug;90(1066): Herm J, Konieczny M, Jungehulsing GJ, Endres M, Villringer A, Malzahn U, et al. Should transesophageal echocardiography be performed in acute stroke patients with atrial fibrillation? J Clin Neurosci Apr;20(4): Khan MA, Khealani B, Hameed B, Kamal A, Wasay M, Syed NA. Diagnostic yield of transthoracic echocardiography for stroke patients in a developing country. J Pak Med Assoc Jul;58(7): Nakibuuka J, Nyakoojo WB, Namale A, Ddumba E, Leontsini E, Nuwaha F. Utility of Transthoracic Echocardiography and Carotid Doppler Ultrasound in Differential Diagnosis and Management of Ischemic Stroke in a Developing Country. J Cardiol Clin Res [Internet] [cited 2014 Sep 24];1(2): Available from: Piriyapong T, Dharmasaroja PA, Muengtaweepongsa S, Piyayotai D, Hutayanon P. Transthoracic echocardiography in Thai patients with acute ischemic stroke. J Med Assoc Thai Jan;95 Suppl 1:S24-S Secades S, Martin M, Corros C, Rodriguez ML, Garcia-Campos A, de la Hera Galarza JM, et al. Diagnostic yield of echocardiography in stroke: should we improve patient selection? Neurologia Jan;28(1): Holmes M, Rathbone J, Littlewood C, Rawdin A, Stevenson M, Stevens J, et al. Routine echocardiography in the management of stroke and transient ischaemic attack: a systematic review and economic evaluation. Health Technol Assess [Internet] Mar [cited 2014 Sep 25];18(16): Available from: data/assets/pdf_file/0017/113246/fullreporthta18160.pdf 19. Meenan RT, Saha S, Chou R, Swarztrauber K, Pyle KK, O'Keeffe-Rosetti MC, et al. Cost-effectiveness of echocardiography to identify intracardiac thrombus among patients with first stroke or transient ischemic attack. Med Decis Making Mar;27(2): TTE in Adult Patients with Ischemic Stroke 12

13 APPENDIX 1: Selection of Included Studies 357 citations identified from electronic literature search and screened 315 citations excluded 42 potentially relevant articles retrieved for scrutiny (full text, if available) 6 potentially relevant reports retrieved from other sources (grey literature, hand search) 48 potentially relevant reports 36 reports excluded: -irrelevant population (4) -irrelevant intervention (17) -other (review articles, editorials)(15) 12 reports included in review TTE in Adult Patients with Ischemic Stroke 13

14 APPENDIX 2: Characteristics of included studies of diagnostic yield in TTE First author, pub. year, country, dates of accrual Menon, 2014, 12 Canada, Study design. Inclusions/exclusions. Retrospective chart review. Patients admitted with a diagnosis of ischemic stroke or TIA with TTE/TOE. Patient characteristics 370 patients with TTE/TOE, mean age 65.7 years, male 56.5%. TTE alone: 307. Diagnostic method/lesions considered clinically significant. TTE, not further described. Dilated cardiomyopathy, LVEF 35%, vegetation, definite/possible LA or LV thrombus, LA or LV myxoma/tumours. Herm, 2013, 13 Germany, Nakibuuka, 2013, 15 Uganda, 2006 Secades, 2013, 17 Spain, 2010 Retrospective cohort study Patients with a discharge diagnosis of AF and stroke or transient ischemic attack, who had undergone echocardiography. Retrospective cohort from prospective CT study. Patients presenting with acute stroke, who had undergone CT and TTE. Retrospective cohort study. Patients admitted with a diagnosis of stroke, referred for echocardiography. Patients with TTE: 110, mean age 75.3, male 54.7%. 66 patients total, mean age 62 years, male 53%. Analyzed. 405 patients, mean age 64.5 years, male 57%. Excluded those not expected to change management. TTE, not further described. Major sources of embolism: endocarditis, LA or LV tumour or thrombus, LV dyskinesia, LVEF<30%. Minor sources: spontaneous echo contrast, mitral valve prolapse, PFO, ventricular aneurysm, aortic plaques, ascending aortic aneurysm. TTE, not further described. TOAST criteria. Severe LV systolic dysfunction, LV thrombus, atrial myxoma, dilated cardiomyopathy, valve prosthesis, LV segmental wall motion abnormalities with MI, LA dilatation with mitral stenosis. (TOAST criteria). ie33 system (Philips, the Netherlands). Saline echo in patients with firm suspicion of embolism or evidence of ASA. TOE if indicated. Findings considered clinically significant (European Echocardiography Association): Major: AF, recent MI, prior MI (LV aneurysm), myocardial diseases, TTE in Adult Patients with Ischemic Stroke 14

15 First author, pub. year, country, dates of accrual Piriyapong, 2012, 16 Thailand, Yaghoubi, 2011, 7 Iran, Study design. Inclusions/exclusions. Retrospective cohort study. Acute ischemic stroke who had echocardiography. Prospective cohort study. Consecutive patients presenting with ischemic stroke within 5 days prior to TTE and TOE. Excluded: hemorrhagic stroke, neoplasm, or other explanation for neurological deficit; outside 5 day window; condition inconsistent with TOE. Ahmad, Retrospective cohort 2010, 8 study. Patient characteristics 207 patients (203 with TTE, 4 with TTE+TOE), mean 62 years, male 61%. 405 patients, mean age 64.5 years, men 52.1%. 428 patients, mean age 69 years, M:F Diagnostic method/lesions considered clinically significant. intracardiac masses, thrombi, tumours, fibroelastoma, vegetations, rheumatic mitral stenosis, mechanical heart valve. Minor: mitral valve prolapse, mitral annular calcification, calcific aortic stenosis, ASA, PFO, Giant Lambl s excrescences TTE, not further described. Classified by need for management change: thrombus, large MI, cardiomyopathy, mitral stenosis, infective endocarditis, atrial myxoma or PFO with ASA. TTE or TOE. Vivid 3 DE Medical Systems, Oslo, Norway Classified according to TOAST and Causitive Classification of Stroke criteria. High-risk: LA thrombus, LA appendage thrombus, LV thrombus, rheumatic heart disease, mechanical heart valve, chronic MI with EF<28%, dilated cardiomyopathy, endocarditis, atrial myxoma, papillary fibroelastoma, PFO with concurrent systemic embolism. Low risk: mitral annular calcification, PFO, ASA, PFO+ASA, LA spontaneous echo contrast, CHF with EF<30%, complex aortic atheroma, wall motion abnormalities, or ASD or VSD. TTE or TOE. Further details not described. TTE in Adult Patients with Ischemic Stroke 15

16 First author, pub. year, country, dates of accrual Study design. Inclusions/exclusions. Australia, Discharge diagnosis of ischemic stroke, transient ischemic attack, intracerebral hemorrhage. Excluded: non-stroke diagnosis, poor documentation. Al-Faleh, 2010, 9 Saudi Arabia, Douen, 2008, 11 Canada, no date. Khan, 2008, 14 Karachi, Retrospective cohort study. Included: Admitted with diagnosis of ischemic stroke or TIA, referred for TTE for investigation of cardiac source of embolism. Excluded: non-stroke diagnosis or inadequate discharge documentation. Retrospective chart review. Included: Patients admitted to regional stroke centre who had TTE during admission. Subset with AF. Retrospective cohort study. Patients with ischemic stroke identified from acute stroke database. Cokar, Retrospective cohort 2007, 10 study. Patient characteristics 1:1.3. Patients undergoing TTE: 246 (86%). 240 patients, mean age 58.5 years, 55.4% male. Not described. 393 patients overall, mean age 60.4 years, 63.6% male. TTE: patients, mean age 54.7 years, Diagnostic method/lesions considered clinically significant. Mechanical heart valve, mitral stenosis, dilated cardiomyopathy, LVEF <35%, infective endocarditis, noninfective endocarditis, definite/possible left atrial/ventricular thrombus, atrial myxoma, aortic arch atheroma, PFO, atrial/ventricular septal defect. HP Sonos 5500 imaging system with 3-4 MHz transducer, for 2-deminsional, M mode, and Doppler. Mitral stenosis, mitral valve prolapse, valve vegetation, LVEF 35%, LV wall motion abnormalities, LV thrombus, LA thrombus, ASD, ASA, PFO, evidence of right-left intracardiac shunting, aortic atheroma, cardiac mass, mechanical valve thrombosis. TTE, not further described. PFO or ASD, LA spontaneous echo contrast, mitral or aortic valve stenosis or vegetation, LA or LV thrombus or mass, poor LV function. TTE, not further described TOAST criteria. Prosthetic valve, LA dilitation with mitral stenosis, LA thrombus, LV thrombus, dilated cardiomyopathy, akinetic LV segment, atrial myxoma TTE or TOE. Further details not given. TTE in Adult Patients with Ischemic Stroke 16

17 First author, pub. year, country, dates of accrual Study design. Inclusions/exclusions. Turkey, Included: first episode ischemic stroke, underwent both TTE and TOE. Excluded: TIA, recurrent stroke, initial coma, rare causes of stroke (vasculitis, arterial dissection, hematologic disorders, collagen disease) Patient characteristics males 53.2% Diagnostic method/lesions considered clinically significant. TOAST criteria. High risk: AF ± valvular heart disease, LA/atrial appendage thrombus, LV thrombus, prosthetic valve, atrial myxoma, akinetic LV segment, cardiomyopathy. Considered medium risk: LA spontaneous echo contrast, ASA, mitral valve prolapse, mitral annulus calcification, mitral stenosis, PFO. ASA, atrial septal aneurysm; ASD, atrial septal defect; CHF, congestive heart failure; LA, left atrium; EF, ejection fraction; LV, left ventricle; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PFO, patent foramen ovale; TOAST, Trial of Org in Acute Stroke Treatment. TTE in Adult Patients with Ischemic Stroke 17

18 APPENDIX 3: Summaries of critical appraisal for included studies Summary of critical appraisal of systematic review of diagnostic studies by Holmes et al, 2014, 18 by AMSTAR criteria Was an a priori design provided? Yes 2. Was there duplicate study selection and data Yes extraction? 3. Was a comprehensive literature search performed Yes 4. Was the status of publication (ie, grey literature) used as an inclusion criterion? Yes. Search was conducted on six bibliographic databases augmented by a citation search. 5. Was a list of studies (included and excluded) provided? Yes 6. Were the characteristics of the included studies Yes provided? 7. Was the scientific quality of the included studies Yes assessed and documented? 8. Was the scientific quality of the included studies used Yes appropriately in formulating conclusions? 9. Were the methods used to combine the findings of Yes studies appropriate? 10. Was the likelihood of publication bias assessed? No 11. Was the conflict of interest stated? Yes Summary of critical appraisal of comparative studies of diagnostic yield by QUADAS-2 criteria. 5 Cokar et al., 2008 Yaghoubi et al, Risk of bias: patient selection No No 2. Risk of bias: index test Unclear Unclear 3. Risk of bias: reference standard Unclear Unclear 4. Risk of bias: flow and timing Unclear No 5. Applicability concerns: patient selection No No 6. Applicability concerns: index test Unclear Unclear 7. Applicability concerns: reference standard Unclear Unclear Signalling questions 1. Was a consecutive or random sample of patients enrolled? Was a case-controlled design avoided? Did the study avoid inappropriate exclusions? 2. Were the index test results interpreted without knowledge of results of the reference standard? 3. Is the reference standard likely to correctly classify the correct condition? Were the reference standard results interpreted without knowledge of the results of the index test? TTE in Adult Patients with Ischemic Stroke 18

19 4. Was there an appropriate interval between index tests and reference standard? Did all patients receive the same reference standard? Were all patients included in the analysis? Could the patient flow have introduced bias? 5. Are there concerns that the included patients do not match the review question? 6. Are their concerns that the index test, its conduct, or its interpretation, differ from the review question? 7. Are there concerns that the target condition as defined by the reference standard does not match the review question? Summary of critical appraisal of economic analysis comparing transthoracic echocardiography with transoesophageal echocardiography by Holmes et al, 2014, 18 by the criteria of Drummond et al, The research question is stated. Yes 2. The economic importance of the research question is Yes stated. 3. The viewpoint(s) of the analysis are clearly stated and Yes justified. 4. The rationale for choosing alternative programmes or Yes interventions compared is stated. 5. The alternatives being compared are clearly described. Yes 6. The form of economic evaluation used is stated. Yes 7. The choice of form of economic evaluation is justified in Yes relation to the questions addressed. Data collection 8. The source(s) of effectiveness estimates used are Yes stated. 9. Details of the design and results of effectiveness study Yes are given (if based on a single study). 10. Details of the methods of synthesis or meta-analysis Yes of estimates are given (if based on a synthesis of a number of effectiveness studies). 11. The primary outcome measure(s) for the economic Yes evaluation are clearly stated. 12. Methods to value benefits are stated. Yes 13. Details of the subjects from whom valuations were Yes obtained were given. 14. Productivity changes (if included) are reported Not applicable separately. 15. The relevance of productivity changes to the study Not applicable question is discussed. 16. Quantities of resource use are reported separately Not clear from their unit costs. 17. Methods for the estimation of quantities and unit costs Yes are described. TTE in Adult Patients with Ischemic Stroke 19

20 18. Currency and price data are recorded. Yes 19. Details of currency of price adjustments for inflation or Yes currency conversion are given. 20. Details of any model used are given. Yes 21. The choice of model used and the key parameters on Yes which it is based are justified. Analysis and interpretation of results 22. Time horizon of costs and benefits is stated. Yes 23. The discount rate(s) is stated. Yes 24. The choice of discount rate(s) is justified. Yes 25. An explanation is given if costs and benefits are not Not applicable discounted. 26. Details of statistical tests and confidence intervals are Yes given for stochastic data. 27. The approach to sensitivity analysis is given. Yes 28. The choice of variables for sensitivity analysis is Yes justified. 29. The ranges over which the variables are varied are Yes justified. 30. Relevant alternatives are compared. Yes 31. Incremental analysis is reported. Yes 32. Major outcomes are presented in a disaggregated as Yes well as aggregated form. 33. The answer to the study question is given. Yes 34. Conclusions follow from the data reported. Yes 35. Conclusions are accompanied by the appropriate Yes caveats. TTE in Adult Patients with Ischemic Stroke 20