Eugene Z. Oddone

The Role of Antineutrophil Cytoplasmic Antibody (c-ANCA) Testing in the Diagnosis of Wegener Granulomatosis: A Literature Review and Meta-analysis

Wegener granulomatosis is a serious systemic vasculitis that is uniformly fatal if untreated. In 1983, Fauci and colleagues [1] reported their success with a combination of corticosteroid and cyclophosphamide therapy in 85 patients with Wegener granulomatosis. Since then, the recognition among clinicians of Wegener granulomatosis and its expanded clinical spectrum has improved, making early diagnosis and treatment possible. Patients with the classic Wegener triad have necrotizing granulomatous vasculitis of the upper and lower respiratory tract associated with glomerulonephritis; patients with limited Wegener granulomatosis may have vasculitis limited to the respiratory tract [2]. Because of the potential clinical overlap with other diseases, the diagnostic algorithm for patients with suspected Wegener granulomatosis has traditionally included biopsy of the upper airway, lung, or kidney to confirm the diagnosis and to rule out other entities, such as systemic infections and malignancies, that may respond adversely to cyclophosphamide therapy [3]. Antineutrophil cytoplasmic antibody (ANCA), first described in 1982 in patients with systemic vasculitis and glomerulonephritis, has emerged as a new diagnostic tool and marker of disease activity for vasculitis [4, 5]. Originally thought to be a response to arboviral infection, ANCA was later identified as a seromarker for Wegener granulomatosis [4, 6]. It is currently believed that the presence of ANCA is an important factor in the pathogenesis of this disease [5]. Two ANCA patterns may be seen with indirect immunofluorescence of ethanol-fixed neutrophils: a cytoplasmic pattern (c-ANCA) and the artifactual perinuclear pattern (p-ANCA) [7, 8]. The major antigen for c-ANCA is a 29-kd serine protease, known as proteinase 3, which is found within the azurophilic granules of the neutrophil [9]. The major antigen for p-ANCA is myeloperoxidase, a lysosomal enzyme found in neutrophils [7, 10]. Some clinical overlap has been seen, but the two patterns have different disease associations. The c-ANCA pattern has predominantly been associated with Wegener granulomatosis, and p-ANCA has been associated with microscopic polyarteritis, other vasculitides, idiopathic necrotizing and crescentic glomerulonephritis, and other diseases [7, 11-13]. Early studies of c-ANCA in patients with Wegener granulomatosis, especially those with active disease, have been promising. Reported sensitivities and specificities have exceeded 90% [10-12, 14-18]. Because of the morbidity and expense associated with biopsy, c-ANCA has attracted interest as a rapid and noninvasive way to diagnose Wegener granulomatosis. In fact, some investigators advocate immunosuppressive therapy for patients with positive c-ANCA test results and symptoms compatible with Wegener granulomatosis, even in the absence of biopsy results [19-21]. The history of c-ANCA testing appears to mirror the natural history of many new diagnostic tests. Important and early pioneering studies of new tests are typically done in highly selected patients with confirmed disease to determine the tests operating characteristics. However, when the new test is subsequently applied to unselected populations, clinical experience and additional studies often provide a less optimistic picture of its diagnostic power. Several recent reports [22-27] document false-positive c-ANCA test results in patients with tuberculosis, Hodgkin lymphoma, human immunodeficiency virus infection, nasal septal perforation, monoclonal gammopathies, and drug-induced Wegener-like disease. Similarly, additional reports [28, 29] describe negative c-ANCA test results in patients with Wegener granulomatosis, even those with active disease. Given the current enthusiasm for a serologic diagnosis of Wegener granulomatosis, underrecognition of the rate of false-positive c-ANCA test results may lead to inappropriate immunosuppressive therapy in some patients who do not have Wegener granulomatosis. Conversely, underappreciation of the frequency of false-negative c-ANCA test results may delay therapy for patients who have clinical features compatible with Wegener granulomatosis. We did a literature review and meta-analysis to assess the utility of c-ANCA as a diagnostic marker for Wegener granulomatosis overall and in relation to disease activity. Methods As noted above, two ANCA patterns have been described in the literature, and each has separate disease associations. Patients with Wegener granulomatosis often have c-ANCA, whereas p-ANCA is found in patients with various syndromes with and without vasculitis [7, 30, 31]. Because c-ANCA is thought to have a higher test sensitivity than p-ANCA for the diagnosis of Wegener granulomatosis, we focused only on c-ANCA. Search Strategy We could not determine a systematic approach for identifying unpublished data on c-ANCA, and thus we selected only published articles for our literature review. We did a MEDLINE search for English-language studies done in humans and published between 1966 and June 1993. Three searches were done: 1) a textword and registry search for antineutrophil cytoplasmic antibody [ANCA], anticytoplasmic antibody, and antineutrophil antibody; 2) a combination of search terms antibodies, neutrophils and keywords such as pulmonary-renal syndrome, or Wegener granulomatosis, or vasculitis, or glomerulonephritis; and 3) a search using the keyword pulmonary-renal syndrome alone. Using this initial search strategy, we identified 720 citations. Manual examination of the reference lists of included articles and the bibliographies of review articles and standard texts yielded an additional 27 studies, for a total of 747. Article Selection To be included in the analysis, all articles had to pass through a four-stage review (Table 1). First, the titles and abstracts of the 747 articles were independently examined by two reviewers. One reviewer was a rheumatologist, and the other was a health services researcher with a PhD who had experience in the critical appraisal of medical literature. Articles were excluded at this stage if they were not pertinent to the topic (for example, if they addressed antineutrophil antibodies and malignancy) or if they did not present patient-level data (for example, if they were reports of tissue culture experiments). If a cited article did not have a published abstract but appeared to be relevant, or if either reviewer included it, it was retained for further review. Of the original 747 articles, 407 were excluded and 340 were retained for second-level review. Table 1. Summary of the Results of Protocol for Selection of Articles for Meta-analysis In stage 2 of the review process, the complete articles were photocopied and reviewed by a rheumatologist. Articles were excluded if they were case reports (n = 64), reviews (n = 75), or letters to the editor (n = 58), or if they were irrelevant to our topic (n = 81). Sixty-two of the 340 articles remained for potential inclusion. In stage 3, a rheumatologist (JKR) and an investigator with a PhD reviewed the methods section of each article in detail. The methodologic criteria required for inclusion at this stage were specification of the patient selection method and the use of standard reference criteria to define Wegener granulomatosis. For casecontrol and cohort studies, the authors had to have described a systematic method of patient selection (for example, consecutive patients or a random sample based on prespecified criteria) [32]. Thus, case-series studies (such as those defining persons with a common feature nonsystematically without the presence of a control group) were excluded. Authors also had to specify standard reference criteria for establishing Wegener granulomatosis exclusive of the c-ANCA test result. Acceptable reference criteria included the Ear, Nose, Throat, Lung, and Kidney staging system [2], the Fauci criteria [1], and the American College of Rheumatology criteria [33]. The Ear, Nose, Throat, Lung, and Kidney system and the American College of Rheumatology criteria require biopsy confirmation of Wegener granulomatosis, and the Fauci criteria are clinicopathologic in nature. Thirty-nine articles were excluded at this stage for the following reasons: case-series design (n = 24); the method of patient selection was not clearly stated (n = 4); a reference standard was not specified (n = 7); or the article was irrelevant to our review (n = 4). If either reader included an article, it was retained for further review. In stage 4, three physicians each independently read the remaining 23 articles. Articles were excluded at this stage if a 2 2 contingency table, needed to calculate the operating characteristics, could not be constructed from the results (n = 8). Thus, 15 articles remained for detailed review [10, 11, 14, 15, 28, 34-43]. For these 15 articles, 2 2 contingency tables were constructed for patients with and without Wegener granulomatosis compared with patients with and without positive c-ANCA test results. Disagreements between reviewers were resolved by consensus. Definition of Wegener Granulomatosis We included only those studies that specified standard reference criteria for defining Wegener granulomatosis independent of the patients c-ANCA test result [1, 2, 33]. Patients with Wegener granulomatosis can be further divided into two subtypes: those with classic and those with limited disease [2]. In classic Wegener granulomatosis, glomerulonephritis and inflammation of the upper or lower respiratory tract, or both, are present. In limited disease, the kidneys are not involved, but inflammation of the upper or lower respiratory tract, or both, is present. Only 6 of the 15 studies separated patients by subtype. Furthermore, 2 of these 6 studies did not separate the c-ANCA test results by Wegener granulomatosis subtype. Because of these inconsistencies, we considered a single classification (overall Wegener granulomatosis) to repres

Are Health&Related Quality-of-life Measures Affected by the Mode of Administration?

While measures of health-related quality of life (HRQOL) are increasingly being used as outcomes in clinical trials, it is unknown whether HRQOL assessments are influenced by the method of administration. We compared telephone, face-to-face, and self-administration of a commonly-used HRQOL measure, the SF-36. Veterans (N = 172) receiving care in the General Medicine Clinic were randomized into groups differing only in order of administration. All patients were asked to complete the SF-36 three times over a 4-week period. The SF-36 demonstrated high internal consistency, regardless of mode of administration, but showed large variation over short intervals. This variation may: (1) increase dramatically sample size requirements to detect between-group differences in randomized trials and (2) reduce the SF-36s usefulness for clinicians wishing to follow individual patients over time.

Predicting complications of carotid endarterectomy.

BACKGROUND AND PURPOSE Carotid endarterectomy has been shown to be beneficial in patients with high-grade carotid stenosis and ipsilateral transient ischemic attack or stroke. This benefit will be realized only if the operation is performed safely. We sought to determine the extent to which clinically significant adverse events occurring after carotid endarterectomy can be predicted from clinical data available before surgery. METHODS Eleven hundred sixty patients were randomly selected from all patients who underwent carotid endarterectomy and were discharged during the calendar years 1988, 1989, and 1990 in 12 academic medical centers in 10 states. Clinical data abstracted from hospital charts were analyzed retrospectively. A model was developed and validated to predict the occurrence of stroke, myocardial infarction, or death during the postoperative period of hospitalization. RESULTS Eight patients (6.9%) suffered at least one adverse event. Rates for individual complications were as follows: death, 1.4%; nonfatal stroke, 3.4%; nonfatal myocardial infarction, 2.1%; and nonfatal stroke or death, 4.8%. Significant predictors of adverse events were age 75 years or older, symptom status (ipsilateral symptoms versus asymptomatic or nonipsilateral symptoms), severe hypertension (preoperative diastolic blood pressure of greater than 110 mm Hg), carotid endarterectomy performed in preparation for coronary artery bypass surgery, history of angina, evidence of internal carotid artery thrombus, and internal carotid artery stenosis near the carotid siphon. The presence of two or more of these risk factors was associated with a nearly twofold increase in risk of an adverse event (relative risk, 1.7; 95% confidence interval, 1.0 to 3.0). CONCLUSIONS Clinical data can be used to stratify patients undergoing carotid endarterectomy according to risk of postoperative in-hospital stroke, myocardial infarction, or death.

Noninvasive Carotid Artery Testing: A Meta-analytic Review

An estimated 500 000 people in the United States have a new or recurrent stroke each year; there are currently approximately 3 million stroke survivors, many of whom have a substantial disability [1]. Most strokes occur in the carotid distribution [2]. Among patients with carotid territory symptoms or a high degree of stenosis (70% or more on carotid angiography), endarterectomy has been shown to effectively reduce strokes [3-5]. Noninvasive tests are often used for preliminary screening before carotid endarterectomy. The value of these tests rests largely in their ability to accurately identify patients with high-grade stenosis. An earlier comparison of the various noninvasive imaging tests of the carotid arteries indicated that carotid duplex and carotid Doppler ultrasonography were superior [6]. However, new studies of older technologies and the emergence of new noninvasive tests justify a re-evaluation of published data about noninvasive testing of the carotid arteries. Our purpose was to estimate the sensitivity and specificity of noninvasive carotid artery tests using formal meta-analysis and to determine which tests are the most discriminating in the detection of carotid artery occlusion and severe disease (defined as >70% stenosis) using composite receiver operating characteristic (ROC) analysis and a summary measure of test effectiveness. Methods Noninvasive Tests Selected for Study The six noninvasive tests we selected assess carotid artery stenosis either by detecting the carotid artery, the flow within it, or both (direct tests) or by evaluating flow through collateral vessels (indirect tests). Carotid Doppler ultrasonography assesses the velocity changes in blood flow associated with stenosis in the carotid arteries using either a continuous wave, a single-gated pulsed wave, or directional color modes [7-33]. Real-time B-mode ultrasonographic imaging allows for direct visualization of the carotid artery and calculation of the widths of obstructed and unobstructed arteries and of the lesions themselves; thus, investigators can determine the percentage of stenosis [34, 35]. Duplex ultrasonography combines the direct visualization capabilities of B-mode ultrasonography and the blood-flow velocity measurements of Doppler ultrasonography [26-28, 31, 36-56]. Magnetic resonance angiography is a relatively new technique that directly assesses both carotid and intracranial arterial stenosis by building up images from many thin-layer, two-dimensional slices or from a smaller quantity of three-dimensional volumes [29-31, 55-67]. The tests that indirectly assess the carotid artery include supraorbital Doppler ultrasonography and oculoplethysmography. Supraorbital Doppler ultrasonography was the first noninvasive technology available to evaluate carotid artery stenosis; it indirectly assesses blood flow from collateral branches of the internal carotid artery through the supraorbital vessels. The test is done by placing a directional Doppler probe over a supraorbital artery and observing the flow with and without compression of neighboring arteries [32, 68-71]. Oculoplethysmography indirectly evaluates the patency of the internal carotid artery by graphically recording ocular pulses obtained from corneal cups held in place by mild suction. Concomitant ear-lobe pulses are also recorded for timing comparison [33, 51, 70, 71]. The results of these studies can be translated into estimates of carotid patency. Identification of Articles We searched the MEDLINE database for English-language articles about the diagnostic testing of extracranial carotid artery disease that were published between 1977 and 1993. The keywords used were oculoplethysmography, ultrasonography, digital subtraction angiography, cerebral angiography, and magnetic resonance imaging (as they relate to disease involving the cerebral arteries); and vertebral arteries, basilar arteries, and carotid arteries in humans. Additional articles listed in the bibliographies of standard neurology texts and references cited in accepted articles were also included among the articles considered. All articles passed through a multilevel, systematic review by teams of nurses and physicians (Figure 1). Articles were excluded if 1) results from the test used were not compared with the results of conventional carotid angiography or intra-arterial digital subtraction carotid angiography; 2) the angiographic results were not separated to allow for specific identification of occluded arteries; or 3) the reference standard test results could not be classified into a contingency table according to degree of stenosis. Through the MEDLINE, textbook reference, and bibliography searches, we initially identified 568 articles, 354 of which were initially rejected, either because the noninvasive test was not compared with carotid angiography or because carotid artery occlusion was not reported as a separate category. The remaining 214 articles were then analyzed by one of four physicians. An additional 110 of these articles were eliminated, most because the reported data were not sufficient to permit construction of contingency tables. When an article was included, data about patient demographics, study design, sites of patient enrollment, blinding of reviewers to test outcomes, and specific results were abstracted. The reliability of the first exclusion was assessed by randomly selecting 22 (10%) of the rejected articles and submitting them to another physician for a second review. Agreement about the appropriateness of the exclusions was 100%. Figure 1. Article review flow chart. The 104 articles initially included by the first physician reviewers were then examined and abstracted by second physician reviewers. Discrepancies between the two reviews were resolved by discussions. As a result of these discussions, 34 additional articles were rejected, 15 because contingency tables could not be reliably constructed from the reported data and 18 because of overlapping populations (in these cases, the most recently reported of the studies or the study with the larger population was included). One article was rejected because the diagnostic test reports were given as a single result that reflected the output of many concurrent tests. Therefore, the results of 70 studies form the basis of this review. Quality Criteria for Evaluating Study Methods Criteria used to rate the quality of the study methods were based on previously defined standards [72]. Each article was rated on the methods used by the investigators, the site of patient enrollment, the degree of blinding between interpretation of the noninvasive test and the reference standard, and the disease spectrum of the patients enrolled. In most studies, the site of patient enrollment was the radiology or surgery unit. Methods of patient enrollment were specified or implied in all 70 articles: Forty-one percent used consecutive series and 59% used convenience or retrospective samples. Blinding of the reviewers was rarely mentioned in any study; because of the sequence of enrollment, we speculated that the reviewers interpreting noninvasive tests were blinded to the results of invasive tests in 84% of the studies. The indications for the testing of patients were listed in 53% of the studies and included recent stroke or transient ischemic attack and asymptomatic carotid bruits. In a secondary analysis, we examined the results of the meta-analysis by comparing studies in which the reviewers interpreting the noninvasive tests were blinded to the angiograms with those in which they were not blinded and by comparing studies in which patients were enrolled consecutively with those in which another method of patient enrollment was used. Statistical Analysis Results from angiographic and noninvasive tests were classified into as many of the following categories as possible: carotid artery occlusion, 99% to 70% stenosis, 70% to 50% stenosis, and 50% to 0% stenosis. Sensitivity and specificity were the primary measures of test performance; carotid angiography was the reference standard. To facilitate comparisons among noninvasive tests, values for sensitivity and specificity (with CIs) were calculated by classifying all lesions above a given cut-point as positive. For the purposes of this comparison, occlusion was considered positive [6]. Articles relating to one particular test type were summarized by pooling estimates of sensitivity and specificity [73]. Confidence intervals were derived using exact methods for proportions [74]. A chi-square test for homogeneity was done on the data from each study at the 100%, 70% (or equivalent), and 50% stenosis cut-points. Sensitivity and specificity were estimated using a random-effects or a fixed-effects model according to the homogeneity of the test results [73, 75]: When the pooled estimate was heterogeneous, a random-effects model was used. Composite ROC curves were constructed; the reference standard of carotid angiography was defined as positive at 70% stenosis. This cut-point was chosen because of the entry criteria for the North American Symptomatic Carotid Endarterectomy Trial (NASCET) [3]. Noninvasive tests were then selected as positive at 50% stenosis, 70% stenosis, or carotid artery occlusion, and true-positive and false-positive rates were calculated because these distinctions provide the most information for clinicians who choose to refer patients for angiography at different thresholds. The tests for homogeneity and methods of meta-analytic combination mentioned earlier were then used to derive the pooled true-positive and false-positive rates for each test type [75, 76]. These were plotted as ROC curves, and the points were connected using a nonparametric assumption [77]. Areas under the ROC curves were derived using a trapezoidal method [77, 78]. We also calculated a new measure for diagnostic tests termed test effectiveness, which attempts to avert the forced tradeoffs between sensi

Multicenter Review of Preoperative Risk Factors for Endarterectomy for Asymptomatic Carotid Artery Stenosis

BACKGROUND AND PURPOSE The benefit of carotid endarterectomy is highly dependent on surgical risk. However, little data are available concerning factors affecting the risk of endarterectomy performed for asymptomatic carotid artery stenosis outside the setting of a randomized controlled trial. The purpose of this study was to analyze the impact of potential preoperative risk factors on the frequency of postoperative complications in patients undergoing the operation for asymptomatic disease in academic medical centers. METHODS Data regarding postoperative complications were systematically abstracted from the medical records of a random sample of patients who underwent carotid endarterectomy at 12 academic medical centers. RESULTS Of 1160 procedures reviewed, 463 (40%) were performed for asymptomatic disease. Postoperative stroke or death occurred in 13 (2.8%), and myocardial infarction occurred in 8 (1.7%). The rate of postoperative stroke or death was lower in asymptomatic patients than in those with a history of cerebrovascular symptoms in a different vascular distribution, but the difference was not significant (1.8% versus 4.2%; P=.21). There were no significant differences in these rates based on race, a history of angina, recent myocardial infarction, chronic obstructive pulmonary disease, hypertension, the degree of stenosis of the contralateral or ipsilateral carotid artery, or the presence of angiographically recognized ulceration, intraluminal thrombus, or siphon stenosis in the ipsilateral vessel (chi(2); P>.05). Postoperative stroke or death was more frequent in women (5.3% versus 1.6% in men; P=.02), in those aged 75 years or older (7.8% versus 1.8% in those younger than 75 years; P=.01), and in those with a history of congestive heart failure (8.6% versus 2.3% in those without a history of congestive heart failure; P=.03). The risk of stroke or death was higher in the 16 patients who had carotid endarterectomy performed in combination with coronary artery bypass surgery than in those who had only endarterectomy (18.7% versus 2.1%; P<.001). CONCLUSIONS The overall risk of postoperative stroke or death was nearly twice that reported by Asymptomatic Carotid Atherosclerosis Study (ACAS) investigators in the setting of a clinical trial but was within acceptable guidelines. Women were at higher postoperative risk than men, which supported ACAS findings. Additional high-risk groups were those aged 75 years or older, those with a history of congestive heart failure, and those undergoing prophylactic endarterectomy for asymptomatic stenosis in combination with coronary surgery. Knowledge of these rates may help to better assess an individuals postoperative risk and therefore the anticipated benefit of surgery.

Two self-management interventions to improve hypertension control: a randomized trial.

In this trial, 636 patients with hypertension were randomly assigned to receive usual care; a telephone-delivered, nurse-administered behavioral self-management intervention; home blood pressure se...

Multicenter review of preoperative risk factors for carotid endarterectomy in patients with ipsilateral symptoms.

Background and Purpose Randomized clinical trials have shown that carotid endarterectomy decreases the risk of subsequent stroke in patients with high-grade carotid stenosis and ipsilateral transient ischemic attack or minor stroke. The benefit of surgery is highly dependent on surgical risk. We previously found that patients with ipsilateral hemispheric symptoms were at greater risk of carotid endarterectomy complications compared with those who were asymptomatic or had nonipsilateral symptoms. The goals of the present study were (1) to identify preoperative clinical factors that may increase the risk of complications after carotid endarterectomy in patients with ipsilateral hemispheric symptoms and (2) to develop a risk index based on this patient-level data. Methods Records from 1160 carotid endarterectomies performed at 12 academic medical centers composed the primary data set. Hospital charts for the admission during which carotid endarterectomy was performed were systematically reviewed by abstractors using a defined protocol. The present analysis was carried out on data from the subset of patients who had carotid endarterectomy for ipsilateral hemispheric symptoms. Candidate variables were identified based on univariate Fishers exact tests or x2 tests. A risk index was then developed using those variables with a greater than 90% probability of being associated with adverse outcomes. Results Of the 697 patients with ipsilateral symptoms, 8.5% had either stroke, myocardial infarction, or died during the postoperative period of hospitalization. Those over the age of 75 had a greater risk of myocardial infarction (6.6% versus 2.3%, P=.024) but not of stroke or death (P<.10). The overall frequencies of adverse outcomes were also higher in the 5 patients with complete ipsilateral carotid occlusions (40% versus 8.2%, p<.01), the 28 patients with ipsilateral intraluminal thrombus (17.9% versus 8.1%, P=.01), and the 65 patients with ipsilateral carotid siphon stenosis (13.9% versus 7.9%, P=.10). There were no differences in adverse outcomes among those with different degrees of ipsilateral stenosis (30% to 49%, 50% to 69%, and 70% to 99%). Adverse outcome rates were similar regardless of the type of symptom (transient ischemic attack, recent ipsilateral minor stroke, remote ipsilateral minor stroke). There were no significant differences in adverse outcome rates based on sex, race, history of angina, recent myocardial infarction, congestive heart failure, chronic obstructive pulmonary disease, hypertension, degree of stenosis of the contralateral carotid artery, or presence of ulceration in the ipsilateral artery (Fishers exact tests, P>.10). A count of variables with greater than 90% probability of being associated with adverse outcomes (age ≤75 years or angiographic evidence of ipsilateral carotid occlusion, stenosis in the region of the carotid siphon, or intraluminal thrombus) was used to form a simple risk index. “High-risk” patients (one or more risk factors) had more than two times the risk of complications compared with “low-risk” patients who had no risk factors (odds ratio, 2.18; 95% confidence interval, 1.25 to 3.81). Conclusions Certain preoperative clinical variables may place patients with ipsilateral symptoms at greater risk of perioperative complications after carotid endarterectomy. Prospective validation of a simple risk index would provide an additional method for assessing preoperative risk in endarterectomy candidates.

Utility of hemoglobin A1c in predicting diabetes risk

AbstractBACKGROUND: There is controversy surrounding the issue of whether, and how, to screen adults for type 2 diabetes. Our objective was to measure the incidence of new diabetes among outpatients enrolled in a health care system, and to determine whether hemoglobin A1c (HbA1c) values would allow risk stratification for patients’ likelihood of developing diabetes over 3 years. METHODS: We conducted a prospective cohort study with 3-year follow-up at a single large, tertiary care, Department of Veterans Affairs Medical Center (VAMC). A convenience sample of 1,253 outpatients without diabetes, age 45 to 64, with a scheduled visit at the VAMC, were screened for diabetes using an initial HbA1c measurement. All subjects with HbA1c ≥6.0% (normal, 4.0% to 6.0%) were invited for follow-up fasting plasma glucose (FPG). We then surveyed patients annually for 3 years to ascertain interval diagnosis of diabetes by a physician. The baseline screening process was repeated 3 years after initial screening. After the baseline screening, new cases of diabetes were defined as either the self-report of a physician’s diagnosis of diabetes, or by HbA1c ≥7.0% or FPG ≥7.0 mmol/L at 3-year follow-up. The incidence of diabetes was calculated as the number of new cases per person-year of follow-up. RESULTS: One thousand two hundred fifty-three patients were screened initially, and 56 (4.5%) were found to have prevalent unrecognized diabetes at baseline. The 1,197 patients without diabetes at baseline accrued 3,257 person-years of follow-up. There were 73 new cases of diabetes over 3 years of follow-up, with an annual incidence of 2.2% (95% confidence interval [CI], 1.7% to 2.7%). In a multivariable logistic regression model, baseline HbA1c and baseline body mass index (BMI) were the only significant predictors of new onset diabetes, with HbA1c having a greater effect than BMI. The annual incidence of diabetes for patients with baseline HbA1c ≤ 5.5 was 0.8% (CI, 0.4% to 1.2%); for HbA1c 5.6 to 6.0, 2.5% (CI, 1.6% to 3.5%); and for HbA1c 6.1 to 6.9, 7.8% (CI, 5.2% to 10.4%). Obese patients with HbA1c 5.6 to 6.0 had an annual incidence of diabetes of 4.1% (CI, 2.2% to 6.0%). CONCLUSIONS: HbA1c testing helps predict the likelihood that patients will develop diabetes in the future. Patients with normal HbA1c have a low incidence of diabetes and may not require rescreening in 3 years. However, patients with elevated HbA1c who do not have diabetes may need more careful follow-up and possibly aggressive treatment to reduce the risk of diabetes. Patients with high-normal HbA1c may require follow-up sooner than 3 years, especially if they are significantly overweight or obese. This predictive value suggests that HbA1c may be a useful test for periodic diabetes screening.

Improving the quality of anticoagulation of patients with atrial fibrillation in managed care organizations: results of the managing anticoagulation services trial.

Randomized trials have indicated that well-managed anticoagulation with warfarin could prevent more than half of the strokes related to atrial fibrillation. However, many patients with atrial fibrillation who are eligible for this therapy either do not receive it or are not maintained within an optimal prothrombin time-international normalized ratio (INR) range. We sought to determine whether an anticoagulation service within a managed care organization would be a feasible alternative for providing anticoagulation care. We performed a multi-site randomized trial in six large managed care organizations in the United States. Subjects were aged 65 years or older and had nonvalvular atrial fibrillation. At each site, physician practices were divided into two geographically defined practice clusters; each site was randomly assigned to have one intervention and one control cluster. The intervention cluster received an anticoagulation service that satisfied specifications for high-quality anticoagulation care and was coordinated through the managed care organization. Control clusters continued with their usual provider-based care. We measured the proportion of time that warfarin-treated patients in each of the clusters (intervention and control) were in the target range for the INR at baseline, and again during a follow-up period. Five of the six selected sites succeeded at developing an anticoagulation service. Patients in the intervention and control clusters had similar demographic characteristics, contraindications to warfarin, and risk factors for stroke. Among patients (n = 144 in the intervention clusters; n = 118 in the control clusters) for whom data were available during the baseline and follow-up periods, the changes in percentages of time in the target range were similar for those in the intervention clusters (baseline: 47.7%; follow-up: 55.6%) and in the control clusters (baseline: 49.1%; follow-up: 52.3%; intervention effect: 5%; 95% confidence interval: -5% to 14%; P = 0.32). Although it was feasible in a managed care organization to implement anticoagulation services that were tailored to local circumstances, provision of this service did not improve anticoagulation care compared with usual care. The effect of the anticoagulation service was limited by the utilization of the service, the degree to which the referring physician supports strict adherence to recommended target ranges for the INR, and the ability of the anticoagulation service to identify and to respond to out-of-range values promptly.

Home Blood Pressure Management and Improved Blood Pressure Control Results From a Randomized Controlled Trial

BACKGROUND To determine which of 3 interventions was most effective in improving blood pressure (BP) control, we performed a 4-arm randomized trial with 18-month follow-up at the primary care clinics at a Veterans Affairs Medical Center. METHODS Eligible patients were randomized to either usual care or 1 of 3 telephone-based intervention groups: (1) nurse-administered behavioral management, (2) nurse- and physician-administered medication management, or (3) a combination of both. Of the 1551 eligible patients, 593 individuals were randomized; 48% were African American. The intervention telephone calls were triggered based on home BP values transmitted via telemonitoring devices. Behavioral management involved promotion of health behaviors. Medication management involved adjustment of medications by a study physician and nurse based on hypertension treatment guidelines. RESULTS The primary outcome was change in BP control measured at 6-month intervals over 18 months. Both the behavioral management and medication management alone showed significant improvements at 12 months-12.8% (95% confidence interval [CI], 1.6%-24.1%) and 12.5% (95% CI, 1.3%-23.6%), respectively-but not at 18 months. In subgroup analyses, among those with poor baseline BP control, systolic BP decreased in the combined intervention group by 14.8 mm Hg (95% CI, -21.8 to -7.8 mm Hg) at 12 months and 8.0 mm Hg (95% CI, -15.5 to -0.5 mm Hg) at 18 months, relative to usual care. CONCLUSIONS Overall intervention effects were moderate, but among individuals with poor BP control at baseline, the effects were larger. This study indicates the importance of identifying individuals most likely to benefit from potentially resource intensive programs. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00237692.