The Coronary Artery Disease-Reporting and Data System (CAD-RADS): Prognostic and Clinical Implications Associated With Standardized Coronary Computed Tomography Angiography Reporting.

OBJECTIVES: This study sought to assess clinical outcomes associated with the novel Coronary Artery Disease-Reporting and Data System (CAD-RADS) scores used to standardize coronary computed tomography angiography (CTA) reporting and their potential utility in guiding post-coronary CTA care. BACKGROUND: Clinical decision support is a major focus of health care policies aimed at improving guideline-directed care. Recently, CAD-RADS was developed to standardize coronary CTA reporting and includes clinical recommendations to facilitate patient management after coronary CTA. METHODS: In the multinational CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry, 5,039 patients without known coronary artery disease (CAD) underwent coronary CTA and were stratified by CAD-RADS scores, which rank CAD stenosis severity as 0 (0%), 1 (1% to 24%), 2 (25% to 49%), 3 (50% to 69%), 4A (70% to 99% in 1 to 2 vessels), 4B (70% to 99% in 3 vessels or ≥50% left main), or 5 (100%). Kaplan-Meier and multivariable Cox models were used to estimate all-cause mortality or myocardial infarction (MI). Receiver-operating characteristic (ROC) curves were used to compare CAD-RADS to the Duke CAD Index and traditional CAD classification. Referrals to invasive coronary angiography (ICA) after coronary CTA were also assessed. RESULTS: Cumulative 5-year event-free survival ranged from 95.2% to 69.3% for CAD-RADS 0 to 5 (p < 0.0001). Higher scores were associated with elevations in event risk (hazard ratio: 2.46 to 6.09; p < 0.0001). The ROC curve for prediction of death or MI was 0.7052 for CAD-RADS, which was noninferior to the Duke Index (0.7073; p = 0.893) and traditional CAD classification (0.7095; p = 0.783). ICA rates were 13% for CAD-RADS 0 to 2, 66% for CAD-RADS 3, and 84% for CAD-RADS ≥4A. For CAD-RADS 3, 58% of all catheterizations occurred within the first 30 days of follow-up. In a patient subset with available medication data, 57% of CAD-RADS 3 patients who received 30-day ICA were either asymptomatic or not receiving antianginal therapy at baseline, whereas only 32% had angina and were receiving medical therapy. CONCLUSIONS: CAD-RADS effectively identified patients at risk for adverse events. Frequent ICA use was observed among patients without severe CAD, many of whom were asymptomatic or not taking antianginal drugs. Incorporating CAD-RADS into coronary CTA reports may provide a novel opportunity to promote evidence-based care post-coronary CTA.

Novel Emergency Department Risk Score Discriminates Acute Coronary Syndrome Among Chest Pain Patients With Known Coronary Artery Disease.

BACKGROUND: Patients with known coronary artery disease presenting to the emergency department (ED) with chest pain are often admitted, yet may not be having an acute coronary syndrome (ACS). METHODS: We assessed whether the use of a novel risk score and a modified thrombolysis in myocardial infarction risk score obtained in the ED could discriminate which of these high-risk patients have ACS. Chart review was performed on a cohort of 285 patients with known coronary artery disease presenting to the ED with chest pain thought to be of ischemic origin and admitted to the hospital. The ED variables were assessed with logistic regression for their association with eventual ACS diagnosis at hospital discharge. ACS was diagnosed in 74 (26%) of the patients. RESULTS: Non-ACS patients had a 2-day median length of stay and $6875 median inpatient (post ED) hospital charges (not including physician fees), totaling 566 hospital bed days and $1,871,250 for the 211 (74%) non-ACS patients. A novel risk score, including (1) history of prior revascularization, (2) comorbid chronic kidney disease, (3) onset of chest discomfort at rest, (4) dynamic electrocardiogram changes in the ED, (5) elevated troponin I (>0.05 ng/mL) in the ED, and (6) associated illness at presentation, discriminated ACS and non-ACS with a c statistic of 0.767; the c statistic for a modified thrombolysis in myocardial infarction risk score was 0.712. CONCLUSIONS: Application of these risk scores may reduce the number of potentially avoidable admissions and their associated hazards and costs.

Low Testosterone in Men with Cardiovascular Disease or Risk Factors: To Treat or Not To Treat?

OPINION STATEMENT: Current evidence supports the use of testosterone replacement in men with the clinical-biochemical syndrome of hypogonadism, defined as low testosterone serum levels and symptoms such as fatigue, exercise intolerance, erectile dysfunction, low libido, or depression. Although the evidence consistently shows that hypogonadism is associated with elevated cardiovascular risk, evidence is mixed regarding whether testosterone (T) replacement provides cardiovascular (CV) benefit or harm. For a man with symptomatic hypogonadism in the setting of CV disease, clinical heart failure, and/or traditional CV risk factors (hypertension, diabetes, and hyperlipidemia), a balanced approach would be to counsel him that overall, the evidence should not dissuade him from utilizing T replacement for non-cardiac symptom relief but that more data are needed before a definitive recommendation can be made about T replacement for CV benefit. The preponderance of available evidence, reviewed in this article, suggests that T replacement, at appropriate doses and with monitored response, is likely to be safe for men with CV disease or CV risk factors and may even reduce major adverse cardiovascular events (MACE). The 2015 American Association of Clinical Endocrinologists and American College of Endocrinology position statement supports this stance and calls for improved prospective data. There is a clear need for a large, prospective randomized trial evaluating the impact of T replacement on MACE, for men both with and without CV disease or CV risk factors. Clinicians should be aware that all men who elect to take T replacement therapy require regular follow-up with the prescribing physician to include both clinical assessment and surveillance laboratory assessment of total T level, complete blood count, and prostate specific antigen.

Practice-Level Variation in Outpatient Cardiac Care and Association With Outcomes.

BACKGROUND: Utilization of cardiac services varies across regions and hospitals, yet little is known regarding variation in the intensity of outpatient cardiac care across cardiology physician practices or the association with clinical endpoints, an area of potential importance to promote efficient care. METHODS AND RESULTS: We included 7 160 732 Medicare beneficiaries who received services from 5635 cardiology practices in 2012. Beneficiaries were assigned to practices providing the plurality of office visits, and practices were ranked and assigned to quartiles using the ratio of observed to predicted annual payments per beneficiary for common cardiac services (outpatient intensity index). The median (interquartile range) outpatient intensity index was 1.00 (0.81-1.24). Mean payments for beneficiaries attributed to practices in the highest (Q4) and lowest (Q1) quartile of outpatient intensity were: all cardiac payments (Q4 $1272 vs Q1 $581; ratio, 2.2); cardiac catheterization (Q4 $215 vs Q1 $64; ratio, 3.4); myocardial perfusion imaging (Q4 $253 vs Q1 $83; ratio, 3.0); and electrophysiology device procedures (Q4 $353 vs Q1 $142; ratio, 2.5). The adjusted odds ratios (95% CI) for 1 incremental quartile of outpatient intensity for each outcome was: cardiac surgical/procedural hospitalization (1.09 [1.09, 1.10]); cardiac medical hospitalization (1.00 [0.99, 1.00]); noncardiac hospitalization (0.99 [0.99, 0.99]); and death at 1 year (1.00 [0.99, 1.00]). CONCLUSION: Substantial variation in the intensity of outpatient care exists at the cardiology practice level, and higher intensity is not associated with reduced mortality or hospitalizations. Outpatient cardiac care is a potentially important target for efforts to improve efficiency in the Medicare population.

National surveillance definitions for hypertension prevalence and control among adults.

BACKGROUND: Clear and consistent definitions of hypertension and hypertension control are crucial to guide diagnosis, treatment, and surveillance. A variety of surveillance definitions are in frequent use, resulting in variation of reported hypertension prevalence and control, even when based on the same data set. METHODS AND RESULTS: To assess the variety of published surveillance definitions and rates, we performed a literature search for studies and reports that used National Health and Nutrition Examination Surveys (NHANES) data from at least as recent as the 2003 to 2004 survey cycle. We identified 19 studies that used various criteria for defining hypertension and hypertension control, as well as different parameters for age adjustment and inclusion of subpopulations. This resulted in variation of reported age-standardized hypertension prevalence from 28.9% to 32.1% and hypertension control from 35.1% to 64%. We then assessed the effects of varying the definitions of hypertension and hypertension control, parameters for age adjustment, and inclusion of subpopulations on NHANES data from both 2007 to 2008 (n=5645) and 2005 to 2008 (n=10 365). We propose standard surveillance definitions and age-adjustment parameters for hypertension and hypertension control. By using our recommended approach with NHANES 2007 to 2008 data, the age-standardized prevalence of hypertension in the United States was 29.8% (SE, 0.62%) and the rate of hypertension control was 45.8% (SE, 4.03%). CONCLUSIONS: Surveillance definitions of hypertension and hypertension control vary in the literature. We present standard definitions of hypertension prevalence and control among adults and standard parameters for age-adjustment and population composition that will enable meaningful population comparisons and monitoring of trends.

Analytic validity of genetic tests to identify factor V Leiden and prothrombin G20210A.

The objective of this study is to systematically review methods for detecting Factor V Leiden or prothrombin G20210A. English-language literature from MEDLINE, EMBASE, The Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, PsycInfo(c), 2000-December 2008. Studies assessed methods for detection of these mutations in at least 10 human blood samples and reported concordance, discordance, or reproducibility. Two investigators abstracted data on the sample selection criteria, test operators, DNA extraction, experimental test, reference standard, commercial instruments, concordance rates, explanation of any discordance, and whether discordance resolved after repetition. We assessed strength of the evidence using the GRADE criteria. We reviewed 7,777 titles and included 66 articles. The majority of the reviewed studies used PCR-RFLP or AS-PCR as the reference standard. The studies demonstrated that commercially available and precommercial tests have high analytic validity with all having greater than 99% concordance with the reference standard. With a few exceptions, discordance resolved with repetition of the test, suggesting operator or administrative errors were responsible for the discordant results. In the quality assurance studies, greater than 98% of laboratories demonstrated high, even perfect, accuracy when asked to diagnose a sample with a known mutation. The majority of errors came from a limited number of laboratories. Although not all methods may be accurate, there is high-grade evidence that genetic tests for the detection of FVL and prothrombin G20210A have excellent analytic validity. There is high-grade evidence that most, but not all, clinical laboratories test for FVL and prothrombin G20210A accurately.

Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review.

CONTEXT: Testing for genetic risks for venous thromboembolism (VTE) is common, but the safety and utility of such testing need review. OBJECTIVES: To define rates of recurrent VTE among adults with VTE with a factor V Leiden (FVL) or prothrombin G20210A mutation compared with those without such mutations; to define rates of VTE among family members of adults with a FVL or prothrombin G20210A mutation according to presence or absence of a mutation; and to assess whether testing adults with VTE for FVL or prothrombin G20210A improves outcomes. DATA SOURCES: We searched MEDLINE, EMBASE, the Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, and PsycInfo through December 2008. STUDY SELECTION: Studies were included if they assessed rates of VTE in individuals with a history of VTE who were tested for FVL or prothrombin G20210A or in family members of individuals with these mutations. Studies assessing the harms and benefits associated with testing were also included. DATA EXTRACTION: Two investigators abstracted data and assessed study quality. We pooled the odds of VTE associated with the mutations using random-effects models. We assessed the strength of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. RESULTS: We reviewed 7777 titles and included 46 articles. Heterozygosity (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.14-2.12) and homozygosity (OR, 2.65; 95% CI, 1.2-6.0) for FVL in probands are predictive of recurrent VTE compared with individuals without FVL. Heterozygosity for FVL predicts VTE in family members (OR, 3.5; 95% CI, 2.5-5.0), as does homozygosity for FVL (OR, 18; 95% CI, 7.8-40) compared with family members of adults without FVL. Heterozygosity for prothrombin G20210A is not predictive of recurrent VTE in probands compared with individuals without prothrombin G20210A (OR, 1.45; 95% CI, 0.96-2.2). Evidence is insufficient regarding the predictive value of prothrombin G20210A homozygosity for recurrent VTE and the risk of VTE in family members of individuals with prothrombin G20210A. High-grade evidence supports that anticoagulation reduces recurrent VTE events in probands with either mutation. Low-grade evidence supports that this risk reduction is similar to that in individuals with a history of VTE and without mutations. CONCLUSIONS: Patients with FVL are at increased risk of recurrent VTE compared with patients with VTE without this mutation. However, it is unknown whether testing for FVL or prothrombin G20210A improves outcomes in adults with VTE or in family members of those with a mutation.

Outcomes of genetic testing in adults with a history of venous thromboembolism.

OBJECTIVE: To address whether Factor V Leiden (FVL) testing alone, or in combination with prothrombin G20210A testing, leads to improved clinical outcomes in adults with a personal history of venous thromboembolism (VTE) or to improved clinical outcomes in adult family members of mutation-positive individuals. DATA SOURCES: Searches of MEDLINE, EMBASE, The Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, and PsycInfo through December 2008. REVIEW METHODS: We focused on the analytic validity, clinical validity, and clinical utility of these tests. Each included article underwent double review for data abstraction and assessment of study quality. We pooled the results of studies addressing the clinical validity of these tests when there were sufficient data. Other evidence was summarized in evidence tables. We graded the evidence by adapting a scheme recommended by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group by assessing the limitations affecting individual study quality, the certainty regarding the directness of the observed effects in the studies, the precision and strength of the findings, and the availability (or lack) of data to answer the relevant key question. Evidence for each sub-question was graded as high, moderate, or low. RESULTS: We reviewed 7,777 titles and included 124 articles. No direct evidence addressed the primary objective. However, high-grade evidence supported the conclusion that tests for the detection of FVL and prothrombin G20210A have excellent analytic validity. Most clinical laboratories test for these mutations accurately. Heterozygosity [odds ratio (OR) =1.56 (95 percent confidence interval (CI) 1.14 to 2.12)] and homozygosity [OR=2.65 (95 percent C.I. 1.2 to 6.0)] for FVL in probands are predictive of recurrent VTE. Heterozygosity for FVL predicts VTE in family members [OR=3.5 (95 percent C.I. 2.5 to 5.0)] as does homozygosity for FVL [OR=18 (95 percent C.I. 7.8 to 40)]. Heterozygosity for prothrombin G20210A is not predictive of recurrence in probands [OR=1.45 (95 percent C.I. 0.96-2.2)]. Evidence is insufficient about heterozygosity for prothrombin G20210A in family members and insufficient about homozygosity for prothrombin G20210A. A single study supported the hypothesis that clinicians might change management based on test results. There was high-grade evidence that anticoagulation reduces recurrent events in probands with FVL or prothrombin G20210A, however, there was low-grade evidence that the relative reduction with treatment is comparable to that seen in individuals without mutations. There was moderate evidence to support the conclusion that neither harms nor benefits of testing have been demonstrated conclusively. Decision-analysis models suggest that testing may be cost-effective in select individuals. CONCLUSIONS: There is no direct evidence that testing for these mutations leads to improved clinical outcomes in adults with a history of VTE or their adult family members. The literature supports the conclusion that while these assays have high analytic validity, the test results have variable clinical validity for predicting VTE in these populations and have only weak clinical utility.

CD8+ T-Cell responses to Trypanosoma cruzi are highly focused on strain-variant trans-sialidase epitopes.

CD8+ T cells are crucial for control of a number of medically important protozoan parasites, including Trypanosoma cruzi, the agent of human Chagas disease. Yet, in contrast to the wealth of information from viral and bacterial infections, little is known about the antigen specificity or the general development of effector and memory T-cell responses in hosts infected with protozoans. In this study we report on a wide-scale screen for the dominant parasite peptides recognized by CD8+ T cells in T. cruzi-infected mice and humans. This analysis demonstrates that in both hosts the CD8+ T-cell response is highly focused on epitopes encoded by members of the large trans-sialidase family of genes. Responses to a restricted set of immunodominant peptides were especially pronounced in T. cruzi-infected mice, with more than 30% of the CD8+ T-cell response at the peak of infection specific for two major groups of trans-sialidase peptides. Experimental models also demonstrated that the dominance patterns vary depending on the infective strain of T. cruzi, suggesting that immune evasion may be occurring at a population rather than single-parasite level.