Evidence Report/Technology Assessment: Number 49
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Overview / Reporting the Evidence / Methods / Findings / Future Research / Availability of Full Report
Each year, 600,000 Americans have strokes: of these, 500,000 are first attacks. In 1997, stroke directly accounted for about one of every 14.5 deaths (160,000 total) in the United States. Stroke was the third leading cause of death behind non-stroke-related heart disease and cancer, and was an underlying or contributing cause of 280,000 deaths. There are currently 4.4 million stroke survivors in the United States, many of whom experience serious, long-term disability; 15 to 30 percent of stroke survivors are permanently disabled.
The economic costs of stroke are also substantial—$51.3 billion in 1999, about 16 percent of the total economic burden of all cardiovascular diseases. This includes $30.6 billion in direct health expenditures and $21.7 billion in lost productivity from morbidity and mortality. This estimate excludes the losses of quality of life experienced by the stroke patient and his or her family.
About 85 percent, or 510,000, of all strokes in a given year (including most recurrent strokes) are ischemic in nature. Identification of a particular stroke mechanism guides clinical decisionmaking about therapy. The purpose of imaging procedures such as transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), and carotid ultrasound (CUS) is to detect cardiac and carotid sources of cerebral emboli. However, the most effective and cost-effective policies for implementing these technologies and the patient subgroups for which they provide greatest benefit are unclear.
Although a 1997 cost-effectiveness analysis concluded that TEE should be performed on all new-onset stroke patients, other studies have not supported this strategy. Cardiogenic embolism accounts for 15 to 30 percent of ischemic strokes, which suggests that a broad range of patients with stroke (50,000 to 150,000) may be candidates for echocardiography in the United States annually.
Yet, many patients with cardiogenic emboli also have other conditions, such as atrial fibrillation (AF), that warrant anticoagulant therapy, obviating the need for echocardiography in therapeutic decisionmaking. In addition, for many cardiac lesions that are potentially identifiable by echocardiography, both the rate of recurrent stroke associated with these lesions and the effectiveness of therapy in lowering the recurrent stroke rate are largely unknown. Because of the cost of these procedures, as well as the discomfort and potential risk associated with TEE, the appropriate choice of echocardiographic procedure (TTE, TEE, or a combination), and their use within particular patient subgroups, are important issues.
Similar questions arise regarding the use of carotid imaging procedures to determine patient subgroups most likely to benefit from carotid endarterectomy (CEA). Although cerebral angiography is considered the gold standard for determining the level of carotid stenosis, it is an expensive, invasive test that is not risk-free. Some physicians have advocated greater use of non-invasive procedures such as CUS and magnetic resonance angiography (MRA). Although MRA is more expensive than CUS ($900 to $1,200 versus $200 to $250), both procedures are less expensive but also less accurate than cerebral angiography ($2,000 to $2,500). This introduces the possibility of inappropriate surgery when noninvasive tests are used alone to select patients for CEA, which carries a relatively small risk of death, but a higher and more variable risk of perioperative stroke.
This evidence report analyzes the available data on the effectiveness and cost-effectiveness of imaging strategies in the evaluation and management of new stroke patients. Investigators at the Oregon Health & Science University and the Kaiser Permanente Center for Health Research, both in Portland, OR, collaborated on this report.
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Reporting the Evidence
This report addresses key questions in two areas:
- Which clinically inapparent abnormalities identified by echocardiography among patients presenting with a new ischemic brain syndrome represent risk factors for recurrent stroke?
- What is the yield of echocardiography in detecting potential sources of cardioembolism among patients with a new ischemic brain syndrome?
- What are the operating characteristics (sensitivities, specificities, and likelihood ratios) of transthoracic and transesophageal echocardiography in detecting potential sources of cardioembolic stroke?
- What are the incidence and nature of complications associated with transesophageal echocardiography?
- Are there clinically identifiable groups of patients with new ischemic brain syndrome who benefit from anticoagulation?
- Are there echocardiographically identifiable groups of patients with new ischemic brain syndrome who benefit from anticoagulation?
- What are the operating characteristics of available tests for measuring carotid artery stenosis?
- What is the incidence of complications associated with cerebral angiography?
- What is the efficacy of carotid endarterectomy in reducing the rate of recurrent stroke among symptomatic patients with carotid artery stenosis?
- What is the incidence of complications associated with carotid endarterectomy?
- Does timing affect the safety of carotid endarterectomy?
The overarching question for the cost-effectiveness analyses of both echocardiography and carotid imaging in patients with stroke is: what is the cost-effectiveness of routine vs. selective imaging procedures in patients with a new ischemic stroke or transient ischemic attack (TIA)? The following is a list of subquestions:
- Of routine, selective, and no imaging, what is the most cost-effective strategy to reduce the risk of recurrent stroke associated with modifiable risk factors potentially identifiable by imaging?
- How do cost-effectiveness estimates change with differences in clinical and demographic factors?
- How do cost-effectiveness estimates change with differences in treatment effectiveness?
- How do cost-effectiveness estimates change with differences in other uncertain model parameters?
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A technical expert advisory group helped refine the key questions. The group included two neurologists, a vascular surgeon, a cardiologist, a primary care clinician who is medical director of a managed care plan, and a patient who had recently had a stroke.
MEDLINE®, HealthSTAR, the Cochrane Controlled Trials Register, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effectiveness, and Health Technology Assessment from 1966 or their inception were searched. Searches were limited to humans and the English language, and editorials and case reports were excluded.
Three searches were related to echocardiography. A search on echocardiography and stroke identified studies relevant to echocardiography questions 1, 2, and 3. A search on transesophageal echocardiography complications identified studies relevant to question 4. For questions 5 and 6, a series of six small searches were related to anticoagulation therapy and stroke.
Three searches identified studies relevant to the carotid imaging key questions. A search on carotid imaging found studies for question 1. A search on cerebral angiography complications identified studies relevant to question 2, and a search on carotid endarterectomy complications found studies relevant to questions 4 and 5. For question 3 on CEA efficacy, existing systematic reviews were used.
In addition, searches focused on the economic aspects of echocardiography and stroke, anticoagulation, carotid imaging, and carotid endarterectomy. Three databases, MEDLINE®, HealthSTAR, and the NHS Economic Evaluation Database, were searched to find papers related to costs and cost analysis, quality of life, and life expectancy and mortality to use in conducting the cost analyses.
For each key question, two investigators independently reviewed the titles and abstracts retrieved by the database searches, using predetermined inclusion/exclusion criteria, and then compared results. Differences were resolved by a discussion between the two reviewers for that question.
For all key questions excluding those related to echocardiographic yield, complications of testing and treatment, and cost analyses, the quality criteria developed by the current U.S. Preventive Services Task Force (USPSTF) were used. In this rating system, the internal validity and applicability (external validity) of each study is rated as good, fair, or poor, based on specific criteria for that type of study design. Then the overall evidence about the question is rated as good, fair, or poor.
The USPSTF criteria for case-control and cohort studies was modified to assess internal validity of articles reporting the diagnostic yield of echocardiography and those reporting complication rates for carotid endarterectomy, cerebral angiography, and transesophageal echocardiography. Supplemental analyses were performed to determine the relative influence of each of the quality ratings criteria and the overall quality score on reported complication rates.
Two separate semi-Markov decision models analyzed the cost-effectiveness of:
- Echocardiographic strategies in the evaluation of patients with stroke or transient ischemic attack to identify a potential cardioembolic source of stroke.
- Carotid imaging strategies in the evaluation of such patients to identify a potential carotid source of stroke.
A Markov model is a state-transition model in which persons entering the model cycle within and between different health states according to specified probabilities. Markov models in decision analyses related to health care interventions are typically used to simulate the natural history of a disease or condition. The prognosis of the patient (or cohort) in the analysis is described by the health states, the permissible transitions between states, and the rates of transition. Markov models can illustrate the relationship between the risk reduction of an intervention and the cost of a diagnostic or treatment strategy over the appropriate time horizon. In a pure Markov model, transition probabilities are fixed over time. Semi-Markov models for this report use a generalization of Markov processes in which transition rates between states are not fixed, but rather, can change with time (e.g., the probability of death in our model increases over time, as subjects in the model became older).
Testing procedures in the echocardiography model were TTE and TEE; in the carotid imaging model, they were CUS, MRA, and cerebral angiography. Treatment options in the echocardiography model were anticoagulation or standard medical treatment; in the carotid imaging model, they were carotid endarterectomy or standard medical treatment. Both models followed a hypothetical cohort of stroke patients over time to simulate the time sequence of health states, survival, and associated costs. This process was repeated for each study arm, which represented a different diagnostic testing strategy, not a different treatment once diagnosed. Sensitivity analyses were performed on various model parameters.
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The effectiveness of echocardiography as a tool in the evaluation of patients with cerebral ischemia or infarction has not been established directly. Specifically, there have been no clinical trials comparing outcomes among patients managed with and without echocardiography after stroke or TIA. Assessing the usefulness of echocardiography in such patients therefore involves examining the evidence for several assertions that serve as links in a causal pathway between echocardiography and clinical outcomes, particularly recurrent stroke. These assertions are as follows:
- Clinically inapparent abnormalities identified by echocardiography convey increased risk of recurrent stroke.
- The prevalence of these abnormalities is not inconsequential.
- Echocardiography is accurate in diagnosing these abnormalities.
- Adverse events associated with echocardiography are small or infrequent compared to its benefits.
- Efficacious treatments exist that reduce morbidity and mortality associated with potential sources of cardioembolic stroke identified by echocardiography.
Adverse events associated with these treatments are small or infrequent compared to their benefits.
Key Question 1. Which clinically inapparent abnormalities identified by echocardiography among patients presenting with new ischemic brain syndrome represent risk factors for recurrent stroke?
Approximately 15 percent of strokes are thought to be attributable to cardioembolic sources. Some of the processes that give rise to cardioembolic stroke, most notably atrial fibrillation, are usually clinically apparent at the time a patient presents with a stroke. Other conditions, however, are clinically occult but may be identifiable with the use of imaging procedures such as echocardiography. The usefulness of echocardiography in the management of stroke depends on the ability to identify cardiac lesions and on the presence and modifiability of recurrent stroke risk conveyed by those lesions.
Several different cardiac and aortic abnormalities identifiable by echocardiography have been studied as potential sources of cardioembolic stroke. There is fair overall evidence that left ventricular thrombus (LVT) is associated with an increased risk of systemic embolization, including stroke. Evidence regarding the presence and degree of stroke risk associated with left atrial thrombus (LAT) is insufficient to draw firm conclusions. There is fair evidence that complex aortic atheromas (ulcerated, mobile, or > 4 mm in thickness) represent risk factors for stroke, independent of coexisting carotid artery disease. There is also fair evidence for an association between atrial septal aneurysm (ASA) and stroke, particularly in the presence of coexisting patent foramen ovale (PFO). PFO alone may be an important risk factor for stroke in young patients, but evidence for an association is conflicting. Epidemiological studies of left atrial myxoma and stroke are lacking, but several case series suggest a substantially higher prevalence of stroke in patients with myxoma than in the general population.
Evidence for an independent association of left ventricular aneurysm, spontaneous echocardiographic contrast, and valvular strands with stroke is insufficient. Previously documented associations between mitral valve prolapse (MVP) and stroke were likely due to inaccuracy in the determination of MVP with early echocardiographic techniques. Finally, mitral annular calcification appears to be an indicator of atherosclerotic vascular disease rather than an independent cause of stroke.
It must be emphasized that the absence of sufficient evidence regarding an association between a cardiac abnormality and stroke does not necessarily indicate that an association does not exist. When biomedical knowledge and experience suggest a high likelihood that a particular lesion, such as intracardiac thrombus, is an independent risk factor for stroke, that likelihood remains high in the face of inconclusive evidence.
Key Question 2. What is the yield of echocardiography in detecting potential sources of cardioembolism among patients with a new ischemic brain syndrome?
The review of echocardiographic yield focused primarily on intracardiac thrombi, ASA, complex aortic atheroma, and atrial myxoma (lesions for which there was fair to good evidence of an independent association with stroke). Researchers analyzed the prevalence of these lesions as detected by TTE and TEE, in unselected patients, patients with and without cardiac disease, patients without significant carotid artery stenosis, and young patients (under 50) with stroke. The yield of intracardiac thrombi using TTE was highly variable. In one study of good quality from Japan, the prevalence of intracardiac thrombus in consecutive patients with stroke or TIA undergoing TTE was 2.1 percent (95 percent confidence interval [CI], 0.8 to 4.6 percent). In three fair-quality studies, no cases of thrombus were diagnosed in patients without heart disease. Among patients with heart disease, the prevalence of thrombus was highly variable, ranging from 0 to 36 percent. This variability, as well as small sample sizes, made it difficult to derive a reliable estimate of the yield of TTE among patients with a history of cardiac disease or without significant carotid disease. One atrial myxoma was diagnosed among 721 patients in eight studies. In most studies, LAT, ASA, and aortic atheroma were not found using TTE in patients without AF.
In two studies of TTE among young patients (aged 15 to 45) with stroke, the pooled prevalence of intracardiac thrombus in 180 patients was 2.2 percent (similar to that in unselected patients). No left atrial myxomas were detected. The prevalence of any unsuspected thrombus, tumor, valvular vegetation, or cardiomyopathy was 4.4 percent (95 percent CI, 2.1 to 8.2).
The overall yield of intracardiac thrombus using TEE in consecutive stroke patients was 1.7 percent (95 percent CI, 0.5 to 5.3 percent). The prevalence of heart disease was not reported in most studies of TEE, making it difficult to determine the importance of this variable. In four studies of patients without significant carotid disease, the prevalence of intracardiac thrombus on TEE was highly variable, ranging from 1.5 to 18 percent. One myxoma was detected among approximately 1,200 patients examined. The yield of ASA (3.8 to 21.6 percent) and complex aortic atheroma (1.9 to 17.2 percent) using TEE varied widely across studies. One study of patients under 60 with negative TTE reported a prevalence of ASA of 28 percent, with 15 percent having both ASA and PFO. The prevalence of complex aortic atheroma in this study excluding elderly patients was 3.4 percent.
The finding from previous reviews of a higher yield of intracardiac thrombus and other potential sources of stroke using TEE largely reflects the inclusion in those reviews of patients with AF. Findings in the current review suggest that in patients without AF, TEE may be less useful than previously described. TEE may have advantages in patients who have insignificant or no carotid disease or who have a negative TTE. There is little information on the yield of TEE in patients with pre-existing heart disease other than AF.
Key Question 3. What are the operating characteristics (sensitivities, specificities, and likelihood ratios) of transthoracic and transesophageal echocardiography in detecting potential sources of cardioembolic stroke?
Because of the relatively low prevalence of intracardiac thrombus in patients with stroke, it is difficult to assess the accuracy of TTE and TEE in this population. Studies attempting to determine the accuracy of these tests for LAT and LVT, as detected by direct intracardiac inspection, have necessarily examined populations in which the prevalence of thrombus is high. These populations, patients undergoing surgery for severe mitral valve disease or left ventricular aneurysms, are not representative of the general population of patients with stroke, and thrombi occurring in these patients may differ substantially from those likely to affect patients with cardioembolic stroke. It is therefore possible that the reported accuracy estimates in these studies differ from the accuracy of TTE and TEE in patients with stroke.
The average sensitivity and specificity of TEE in detecting LAT in these studies were 93 and 97 percent, respectively. For TTE, sensitivity and specificity averaged 42 and 99 percent. The low sensitivity of TTE was largely due to missed left atrial appendage thrombi. For the diagnosis of LVT, TTE had an average sensitivity of 78 percent and specificity of 87 percent. When results from individual studies were plotted on a summary receiver operating characteristic (SROC) curve, however, it appeared that varying accuracy across studies may have been partly due to differing diagnostic thresholds. Using the SROC curve to estimate the accuracy, the sensitivity and specificity of TTE for diagnosing LVT were 77 and 95 percent, respectively. It should be noted, however, that approximately 15 percent of TTE examinations in studies of LVT were deemed inadequate for interpretation, limiting the diagnostic utility of this test. No studies of the accuracy of TEE in diagnosing LVT were identified.
When the prevalence of intracardiac thrombi in patients with stroke is assumed to be 2 percent or less, as many as or more patients will receive unnecessary treatment due to false positive tests than will receive potentially beneficial treatment for a true positive test, if echocardiographic technology is used to select patients for treatment with anticoagulants. Under current estimates of test accuracy, the prevalence of LAT would have to exceed 15 percent and the prevalence of LVT 37 percent in order to achieve 90 percent predictive value.
Studies examining the accuracy of echocardiography in diagnosing ASA and aortic atheroma are lacking. However, given that the association with stroke has been established for the echocardiographic, rather than anatomic, definitions of these lesions, it may be argued that TEE represents the gold standard for the diagnosis of these lesions as they relate to cardioembolic stroke. Few studies have assessed the accuracy of echocardiography in diagnosing left atrial myxoma. These studies suggest accuracy approaching 100 percent, though one study found disagreement between TTE and TEE in 2 of 11 cases.
Key Question 4. What are the incidence and nature of complications associated with transesophageal echocardiography?
In observational studies of poor and fair quality, the pooled risk of periprocedural death associated with TEE was 0.014 percent. The risk of death in patients specifically undergoing TEE for evaluation of possible cardiac embolus could not be directly calculated. Data were insufficient to determine whether the risk of death was higher in elderly or critically ill patients.
From observational studies of fair quality, the average risk of major (requiring treatment) cardiovascular, pulmonary, and gastrointestinal complications from TEE was 0.7 percent. The rates of major complications in elderly and critically ill patients were 0.4 percent and 0.8 percent, respectively. Neither of these rates was significantly different from the overall rates. No cases of infective endocarditis or systemic infection were found in 775 patients followed after TEE. Approximately 1.9 percent of TEE were unsuccessfully attempted, and an additional 0.9 percent were stopped for complications, most frequently patient intolerance. The rate of minor complications (most commonly patient intolerance) requiring discontinuation of the procedure was not consistently reported, but appears to be about three times the rate of major complications.
Although the estimates of risk came from studies of poor or fair methodological quality (no included study was assessed as having overall good quality), no other data were available to provide more reliable estimates. Data are insufficient to determine whether complication rates are different in patients presenting with particular indications such as cerebral ischemic syndromes.
Key Question 5. What is the efficacy of anticoagulant therapy in reducing the rate of recurrent stroke among patients with potential sources of cardioembolism?
For any given patient with stroke, the potential usefulness of echocardiography in detecting a source of cardioembolism depends on the absence of clinically apparent indications for treatment (i.e., anticoagulation). There is substantial evidence, for instance, that for patients with stroke and AF, anticoagulant drugs confer net benefit, making echocardiographic identification of lesions warranting anticoagulation in these patients superfluous. Whether anticoagulation is beneficial in stroke patients without AF is less clear.
There is fair evidence that unselected patients with stroke do not benefit from anticoagulation as compared to antiplatelet therapy. Evidence from a large, fair-quality international trial suggests that subcutaneous heparin given acutely to patients with stroke is not associated with improved outcomes when compared to aspirin. The two therapies used in combination may confer net benefit, but further study is needed to confirm this finding. A good-quality multicenter trial comparing chronic anticoagulation (target INR 1.4-2.8) and aspirin (325 mg) found no differences in either benefits or harms between the two treatments. Another good-quality trial employing higher degrees of anticoagulation (target INR 3.0-4.5) was stopped early due to increased rates of ICH and death with anticoagulation as compared to aspirin.
No fair- or good-quality studies were found examining the effectiveness of anticoagulation in the prevention of recurrent stroke among patients with stroke and cardiac conditions other than AF. Studies of primary stroke prevention among patients with MI (myocardial infarction) suggest that when compared to aspirin, anticoagulation either alone or in combination with aspirin does not confer net benefit. For patients with dilated cardiomyopathy (DCM), evidence regarding anticoagulation for primary stroke prevention comes from observational studies that provide conflicting results. The only good-quality study found that anticoagulation was more effective than aspirin in the primary prevention of stroke, particularly for patients with moderate and severe cardiomyopathy, after acute MI.
Overall, there was fair evidence that neither acute nor chronic anticoagulation confers net benefit, as compared to aspirin, for unselected patients with stroke. Also, there was insufficient evidence to reach conclusions regarding the effectiveness of anticoagulation for secondary prevention of stroke among patients with stroke and clinically apparent cardiac conditions other than AF. Studies of primary prevention suggest that anticoagulation may be beneficial for patients with DCM but is probably not beneficial in patients with MI; however, results from studies of primary stroke prevention may not be generalizable to patients who have already experienced stroke and are candidates for secondary prevention. Given these findings, it appears that the scope of patients for whom echocardiography may be useful, if it can effectively identify treatable sources of recurrent stroke, includes all stroke patients except those with AF.
Key Question 6. Are there echocardiographically identifiable groups of patients with new ischemic brain syndrome who benefit from anticoagulation?
Studies of the effectiveness of anticoagulation for echocardiographically identifiable lesions were all observational in design. Pooled data from five retrospective cohort studies suggest that warfarin, and possibly surgical PFO closure, may reduce the rate of recurrent stroke or TIA among patients with stroke and PFO. However, these studies were generally of poor quality and did not account for differences in baseline characteristics that may have given rise to differences in outcomes across treatment groups. A small, poor–quality cohort study of patients with stroke found to have mobile aortic atheromas revealed a trend toward lower recurrent stroke rates with warfarin as compared to aspirin, but no death. A poor-quality systematic review of primary stroke prevention in patients with intraventricular thrombus after acute MI suggested a net benefit with anticoagulation, but the reviewed studies were observational, and no adjustment for potential confounding was conducted.
Moreover, whether or not findings from studies of primary stroke prevention among patients with acute MI can be used to draw conclusions regarding secondary prevention among a general population of patients with stroke is not clear. Researchers found insufficient evidence to draw conclusions about the effectiveness of anticoagulation in reducing morbidity and mortality among stroke patients with echocardiographically identified lesions.
Cost-Effectiveness. Because of the lack of solid evidence for important components of effectiveness, it is difficult to accurately estimate the cost-effectiveness of echocardiography in the management of stroke. Where evidence was lacking or insufficient, informed assumptions were made to enable estimating cost-effectiveness. Assumptions include the following:
- Intracardiac thrombus conveys increased stroke risk for the first year after the initial stroke.
- Thrombus prevalence is 2 percent in unselected patients and 5 percent in patients with heart disease.
- Anticoagulant drugs reduce the risk of recurrent stroke by one-third.
Using those assumptions, one quality-adjusted life year (QALY) can be saved for an approximate incremental cost of $300,000, using TEE only in patients with heart disease. Other strategies were less cost-effective, though TTE in patients with heart disease was the preferred strategy under some plausible assumptions. The cost-effectiveness ratio for either echocardiographic procedure fell below $50,000 per QALY if the assumed relative risk reduction with anticoagulation was increased to 86 percent and the prevalence of thrombus was simultaneously increased to 6 percent. The cost per QALY of all strategies increased as average life expectancy diminished (e.g., with increasing age or comorbidity).
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