Karin Flobbe

Accuracy of Computed Tomographic Angiography and Magnetic Resonance Angiography for Diagnosing Renal Artery Stenosis

Context Physicians sometimes use computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) to diagnose renal artery stenosis. Contribution This prospective multicenter study compared CTA and MRA with digital subtraction angiography (the reference standard) in 402 hypertensive patients with suspected renal artery stenosis. Multiple experienced physicians sometimes disagreed about whether the CTA and MRA tests showed renal artery stenosis. The sensitivity estimates of CTA and MRA for detecting renal artery stenosis were 64% and 62%. Implications In this study, even trained physicians had difficulty interpreting some CTA and MRA tests, and neither test was sensitive enough to rule out renal artery stenosis. Renal artery stenosis may cause renovascular hypertension and renal impairment. Accurate detection and treatment of clinically relevant stenoses may cure or improve hypertension and preserve renal function. Current treatment options include surgery, percutaneous transluminal renal angioplasty with or without stent placement, and medical therapy. Despite the availability of several other diagnostic tests, intra-arterial digital subtraction angiography (DSA) remains the reference standard for anatomic diagnosis of renal artery stenosis. This test, however, is an invasive procedure that carries a risk for serious complications and is burdensome for patients (1, 2). For this reason, less invasive diagnostic alternatives, such as computed tomographic angiography (CTA) and 3-dimensional contrast-enhanced magnetic resonance angiography (MRA), are widely used for diagnostic work-up in patients with suspected renal artery stenosis. A recent meta-analysis (3) found that CTA and MRA were significantly better than non-contrast-enhanced magnetic resonance angiographic techniques, ultrasonography, captopril renal scintigraphy, and the captopril test at identifying renal artery stenosis when DSA was used as the reference standard. To date, however, only a limited number of small, well-designed studies have been published on the diagnostic accuracy of either CTA or MRA for detection of renal artery stenosis in patients with suspected renovascular hypertension (4-14). Because CTA and MRA seemed to be promising techniques with the potential to reduce the number of patients requiring conventional angiography, we set up a large-scale multicenter study to investigate the diagnostic performance of these tests, using DSA as reference standard, in hypertensive patients clinically deemed at risk for renal artery stenosis. The purpose of our study was to determine the interobserver agreement and diagnostic accuracy of CTA and MRA in comparison with DSA and to examine whether CTA or MRA can be used as an initial test for detection of renal artery stenosis. Methods We performed a prospective comparative study among CTA, MRA, and the reference standard, DSA, for the detection of renal artery stenosis. Each included patient underwent all 3 diagnostic tests. Participants Over a 3-year period, patients were prospectively recruited from the internal medicine outpatient clinics of 3 large teaching hospitals and 3 university hospitals in the Netherlands. The ethical review board of each hospital approved the study, and written informed consent was obtained from all participants. At the 2 hospitals that recruited most of the participating patients, enrollment was consecutive; the other participating hospitals included patients by using nonsystematic convenience samples. At the 6 participating centers, all hypertensive patients between 18 and 75 years of age with a diastolic blood pressure greater than 95 mm Hg were routinely screened for predefined clinical clues indicating renal artery stenosis, as described by the Working Group on Renovascular Hypertension (15) and others (16, 17). Patients were eligible for participation in the study if they exhibited at least 1 clinical clue. Exclusion criteria were known allergy to iodinated contrast agents; pregnancy; contraindications to MRA, CTA, or DSA (18, 19); contraindications to intervention; or previous participation in the study. All included patients were scheduled to have CTA, MRA, and DSA within a 3-month window. At the coordinating center (Maastricht University Hospital), included patients were scheduled to undergo CTA and MRA on the same day, followed by DSA the next day. At the other centers, the tests were performed on the basis of availability. No treatments that could affect the test results were allowed before all tests were completed. The case record forms for all patients were collected at the coordinating center, and the information was entered into a database. Imaging Techniques Each participating hospital was equipped with state-of-the art magnetic resonance scanners (1.0 or 1.5 Tesla), helical computed tomography scanners (single- or multi-detector row systems), and DSA equipment. In addition, hospitals were allowed to optimize scan protocols during the study when new insights emerged or when equipment was upgraded, an approach that conforms to usual clinical practice. Changes in scan protocols occurred twice (Appendix Table 1). To ensure state-of-the art magnetic resonance imaging, all scan protocols had to meet minimal quality standards in terms of spatial resolution and scan duration. The quality standards were defined by the coordinating center and were based on the protocols that were published at the start of the study. During the entire study, the coordinating center continuously monitored the quality of all images. Information about manufacturers, scan protocols, and contrast agents is shown in Appendix Table 1. All imaging was performed or supervised by experienced radiologists and radiologic technologists. Renal CTA, MRA, and DSA had already been part of clinical routine before the start of the study. Image Evaluation At the conclusion of study enrollment, 2 panels of 3 observers evaluated the CTA and MRA image data at the coordinating center. All observers had more than 3 years of experience evaluating such data on a regular basis, and for each method 1 observer had more than 6 years of experience. Each observer independently performed the evaluations and was blinded to all other results, including clinical information and DSA results. Digital image data for all CTA and MRA examinations were evaluated by using a work station equipped with all commonly used image-processing tools (EasyVision, release 4.2.1, Philips Medical Systems, Best, the Netherlands). Source images had to be examined in all cases before a final diagnosis could be made. The DSA images were evaluated by 4 vascular radiologists, all with more than 10 years of experience in this particular field. The first observer was the radiologist who actually performed the test; the evaluation took place during the DSA procedure. The second and third observers who judged each DSA examination knew the first observers judgment. If discrepancies existed among the first 3 observers with respect to the number of renal arteries involved or the nature, location, or severity of disease (differences of >10% in the degree of stenosis), a fourth radiologist, who had access to the diagnoses of the other observers, made the final diagnosis. This consensus approach has been used in several other CTA and MRA studies (6, 7, 12-14). All DSA observers were blinded to the results of CTA and MRA. To determine the degree of stenosis, the diameter of the most severely affected part of a renal artery was measured and related to the reference diameter, which was defined as the diameter of a representative nonaffected portion of the artery, preferably immediately distal to the stenosis (that is, beyond the site of poststenotic dilatation, if present). Fibromuscular dysplasia was diagnosed when multiple aneurysms separated by focal narrowing (string-of-beads sign) were observed. For CTA, MRA, and DSA, luminal narrowing of at least 50%, as well as all cases of fibromuscular dysplasia, was defined as clinically relevant renal artery stenosis (3). For each patient, the observers first recorded the number of renal arteries. Subsequently, these arteries were judged with respect to the presence or absence of stenosis (expressed as percentage of luminal narrowing), the nature of the stenosis (atherosclerotic or fibromuscular dysplasia), the location of the stenosis (ostial or truncal), and the level of confidence in the diagnosis (high, moderate, or poor) (6). Inconclusive examination results were noted on the standardized form used to collect all relevant data. Statistical Analysis The severity of the stenoses as seen on CTA and MRA was categorized on a 5-point scale (grade 1, 0% to 19%; grade 2, 20% to 49%; grade 3, 50% to 74% or fibromuscular dysplasia; grade 4, 75% to 99%; and grade 5, total occlusion [100% stenosis]). The Cohen weighted analysis was used to test for agreement beyond that of chance among the 3 observers of MRA and among the 3 observers of CTA (20). Unless stated otherwise, all analyses on the diagnostic accuracy of CTA and MRA (sensitivity, specificity, and receiver-operating curve [ROC] analysis) compared with DSA are based on patients as the unit of analysis. In the by-patient analysis, a patient was classified as having positive results if 1 or more renal arteries were found to be stenotic ( 50%) on DSA. The most severe stenosis per patient was used for analysis. Inconclusive CTA and MRA results were considered as positive test results because further diagnostic work-up would be required in clinical practice and these patients would be referred for DSA. Exact 2-sided 95% CIs for proportions were calculated by using a binomial distribution. Overall estimates of sensitivity, specificity, positive predictive value, and negative predictive value for all observers per method, including 95% CIs, were calculated by using the cluster option of Stata, version 8.2 (Stata Corp., College Station, Texas) (21). This

The role of ultrasonography as an adjunct to mammography in the detection of breast cancer. a systematic review.

The aim of this review was to summarise the diagnostic performance of ultrasonography as an adjunct to mammography in the detection of breast cancer and to identify clinical indications. A systematic review was performed of all publications in MEDLINE and EMBASE between 1990 and 2000 on the role of ultrasonography as an adjunct to mammography. 22 studies were included, showing a large variety of indications for ultrasonography and variations in the diagnostic performance of mammography and ultrasonography. There were six studies comparing a combined diagnosis of mammography and ultrasonography together with mammography alone, of which three studies had an increased sensitivity at the cost of a lower specificity. The methods of selecting the study population and interpretation of ultrasonography significantly influenced the diagnostic performance of mammography and ultrasonography relative to each other (P=0.003, P=0.03, respectively). Based on the studies reviewed, little evidence-based support was found to confirm the well recognised value of ultrasonography as an adjunct to mammography in the detection of breast cancer in clinical practice. Furthermore, no clinical indications for additional ultrasonography could be defined. The heterogeneity in the diagnostic performance in these studies may be explained by the methods of patient selection and ultrasonography interpretation, as well as by their poor quality.

Renovascular disease in patients with hypertension: detection with duplex ultrasound.

The aim of this study was to evaluate the accuracy of duplex ultrasound for the diagnosis of renovascular disease in a cohort of hypertensive patients. In 78 patients suspected of renovascular hypertension on clinical grounds duplex ultrasound examination of the renal arteries was performed. Renal angiography was used as the standard of reference. Duplex ultrasound was inconclusive in 11 kidneys (7%). None of the supernumerary renal arteries was detected with duplex ultrasound. The overall prevalence of significant renovascular disease (⩾50% stenosis) was 20%. Based on the combination of parameters at thresholds commonly applied in current literature: ie PSVmax >180 cm/sec and RAR >3.5 the overall sensitivity of duplex ultrasound for detection of haemodynamically significant renovascular disease was 50.0% with a specificity of 91.3% (PPV: 87.9%; NPV: 59.1). Lowering the thresholds for both parameters improved the test results at the cost of a significant increase of false positive examinations. In a population of hypertensive patients clinically suspected of renovascular hypertension, only limited results for duplex ultrasound could be acquired in the detection of renovascular disease. This result, in combination with the wide range of sensitivities and specificities published in international literature and the relatively large number of incomplete examinations does not support the general application of duplex ultrasound as a screening procedure for detection and assessment of renovascular disease.

Diagnostic value of radiological breast imaging in a non-screening population

The aim of this study was to assess the diagnostic performance of breast imaging in the diagnosis of breast cancer in a non‐screening population. In a consecutive set of patients referred for mammography in one year, the results of palpation and radiological breast imaging were scored on a 5‐point grading scale and linked to pathology as gold standard after a follow up period of one year. The diagnostic performance was studied by logistic regression analysis and ROC‐curves. There were 1,944 breast examinations in 1,890 patients and 3,816 breasts. Pathology results reported 118 malignancies in 115 women. With a cut‐off point between benign and uncertain benign a sensitivity of 89% and a specificity of 98% was found for radiological imaging. ROC‐curves showed a significant increase in diagnostic performance when radiology was added to results of palpation and age (p = 0.007). Radiological imaging tests have a large diagnostic value in the detection of breast cancer in addition to palpation and age. A sensitivity close to 100% could be reached.

Validation of a prediction rule for renal artery stenosis.

Objectives We previously developed a prediction rule to estimate the probability of renal artery stenosis. This rule should be validated before it can be used reliably to select hypertensive patients for renal angiography. We determined the validity of the prediction rule in recent patients and in other settings. Design We studied three aspects of validity (agreement between predicted and observed probability of stenosis, discriminative ability, and clinical usefulness) in 180 consecutive patients with drug-resistant hypertension and normal or mildly impaired renal function, who visited six hypertension clinics of academic and community hospitals in the Netherlands. Thirty-five patients (19%) had a significant stenosis. Results The clinical characteristics in the rule (age, sex, vascular disease, recent onset of hypertension, smoking, body mass index, abdominal bruit, serum creatinine concentration, and hypercholesterolemia) had similar predictive value in the validation sample and development sample. The predicted probabilities of stenosis agreed well with the observed frequencies (Hosmer–Lemeshow goodness-of-fit test, P = 0.87). The prediction rule discriminated reasonably between patients with and without stenosis in the validation sample with an area under the receiver operating characteristic curve of 0.71. If only patients with predicted probabilities of stenosis of 5% or more were referred for renal angiography, the number of referrals was reduced by 20%, while 9% of patients with a stenosis were missed. Conclusions The prediction rule was valid in more recently treated patients in other settings. If used conservatively, the rule can reliably exclude a small proportion of patients from angiography.

Clinical impact of the use of additional ultrasonography in diagnostic breast imaging.

The degree of adherence with evidence-based guidelines for the use of breast ultrasonography was determined in clinical practice of radiologists in six hospitals. Additional ultrasonography was performed in 2,272 (53%) of all 4,257 patients referred for mammography. High adherence rates (mean: 95%) were observed for guidelines recommending ultrasonography in patients referred for palpable breast masses and abnormal screening and diagnostic mammograms. Lower adherence rates (mean: 81%, Pearson correlation coefficient = −0.57; p = 0.001) were found for guidelines advising against additional ultrasonography in patients referred for breast symptoms, a known benign abnormality, a family history or anxiety of breast cancer. The overuse of ultrasonography in 442 patients and underuse in 95 patients led to five additional false-positive results. It was concluded that the guidelines seem workable and feasible in clinical practice and that the current daily routine of diagnostic breast imaging corresponded to a great extent to the guidelines proposed.

Strategies for digital mammography interpretation in a clinical patient population

Mammography is the basic imaging modality for early detection of breast cancer. The aim of this prospective study was to evaluate the impact of different mammogram reading strategies on the diagnostic yield in a consecutive patient population referred for digital mammography to a hospital. First, the effect of using computer‐aided detection (CAD) software on the performance of mammogram readers was studied. Furthermore, the impact of employing technologists as either prereaders or double readers was assessed, as compared to the conventional strategy of single reading by a radiologist. Digital mammograms of 1,048 consecutive patients were evaluated by a radiologist and 3 technologists with and without the use of CAD software. ROC analysis was used to study the effects of the different strategies. In the conventional strategy, an overall area under the curve (AUC) of 0.92 was found, corresponding to a sensitivity of 84% and specificity of 94%. When applying CAD software, the AUCs were similar before and after CAD for all readers (mean of 0.95). Employing technologists in prereading and double reading of mammograms resulted in a mean AUC of 0.91 and 0.96, respectively. In the prereading strategy, the corresponding sensitivity and specificity were 81 and 96%; in the double reading strategy they were 96 and 79%, respectively. Concluding, in this clinical population, systematic application of CAD software by either radiologist or technologists failed to improve the diagnostic yield. Furthermore, employing technologists as double readers of mammograms was the most effective strategy in improving breast cancer detection in daily clinical practice.

Costs and effects of using specialized breast technologists in prereading mammograms in a clinical patient population

OBJECTIVES The aim of this study was to assess the costs and effects of using specialized breast technologists in prereading mammograms to reduce the increasing workload of radiologists in daily clinical practice. Mammography is the most widely used imaging modality for early detection and diagnosis of breast cancer. METHODS A total of 1389 mammograms of consecutive patients were evaluated by two technologists trained in mammogram interpretation. The costs and effects of four different experimental strategies of prereading mammograms by technologists were analyzed by decision analytic modeling and compared with the conventional strategy of standard evaluation by the radiologist on duty. RESULTS Overall, the employment of technologists in this patient population resulted in a potential time saving up to 73 percent (1019/1389) for the radiologist. No additional false-negative imaging results were found as compared to the conventional strategy. The total diagnostic costs in the conventional strategy were determined at euro150,602. The experimental strategies resulted in cost savings up to 17.2 percent (range, euro122,494-euro139,781). CONCLUSIONS The employment of technologists in prereading mammograms in a clinical patient population could be effective to reduce the workload of radiologists without jeopardizing the detection of malignancies. Furthermore, diagnostic costs can be reduced considerably.

Costs and effects of ultrasonography in the evaluation of palpable breast masses

OBJECTIVE To study the costs and effects of incorporating ultrasonography in the triple assessment of palpable breast masses. METHODS A decision analytic model was designed to compare a conventional strategy of performing fine-needle aspiration cytology after clinical examination and mammography, with three different experimental strategies of preceding ultrasonography. Empirical data were used from a prospective study in 522 breasts in 492 patients with a palpable mass, including 93 malignancies. In strategy 1, cases with probably benign, suspect malignant, and malignant ultrasonography results were referred for fine-needle aspiration cytology; in strategy 2, benign cases were also referred for fine-needle aspiration cytology; and in strategy 3, ultrasonography was only performed in patients with benign results on clinical examination and mammography, whereas immediate fine-needle aspiration cytology was performed in patients with suspicious lesions. Outcome variables included the total costs and the expected number of life years. Sensitivity analysis was performed on all parameters in the model. RESULTS All strategies reported a similar life expectancy of 31.0 years. Cost-minimization demonstrated that experimental strategy 3 was the least expensive strategy (3013 Euro). Experimental strategy 2 was the most costly one (3512 Euro). Compared with the conventional strategy of immediate fine-needle aspiration cytology (3087 Euro), both ultrasonography strategies 1 and -3 were preferred. CONCLUSIONS Incorporating ultrasonography in the triple assessment of palpable breast masses can result in a reduction of the total costs for the diagnosis and treatment of breast cancer.

Association between guideline adherence and clinical outcome for patients referred for diagnostic breast imaging

Objective To assess the adherence to a guideline for additional breast ultrasonography in a cross-sectional survey among hospitals in The Netherlands. Furthermore, consequences of current practice non-adherence for the patient outcome of diagnostic breast imaging were studied. Methods Current practice was compared with a guideline made up of three recommendations for the use of ultrasonography after mammography and three recommendations for not using ultrasonography. All patients referred for mammography to the radiology departments of the participating hospitals during 2 months in 2004 were eligible for the study. No data on the gold standard for breast cancer were analysed, but clinical consequences were estimated by using a probability model based on the data of a former prospective clinical study. Results In total, 17 of the 66 hospitals approached were participating in the study. Of the 13 694 patients assessed for eligibility, 6457 were included. High adherence rates (81–97%, mean 94%) were observed for the recommendations, which indicate additional ultrasonography, whereas lower adherence rates (68–94%, mean 83%) were seen for the recommendations which do not advise additional ultrasonography. Overall, in all included hospitals, non-adherence would result in 27.2 false-positive and 1.1 false-negative imaging results. Conclusion Current daily practice of diagnostic breast imaging in the hospitals in this survey corresponds to a great extent to the guideline proposed. Non-adherence in current practice results in a relatively small number of false-positive and false-negative imaging results.