Providence in Medicine

Using High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia in Symptomatic Patients: A Cohort Study: Annals of Internal Medicine: Vol 172, No 3

Background: The optimal noninvasive method for surveillance in symptomatic patients with stable coronary artery disease (CAD) is unknown. Objective: To apply a novel approach using very low concentrations of high-sensitivity cardiac troponin I (hs-cTnI) for exclusion of inducible myocardial ischemia in symptomatic patients with CAD. Design: Prospective diagnostic cohort study. (ClinicalTrials.gov: NCT01838148) Setting: University hospital. Patients: 1896 consecutive patients with CAD referred with symptoms possibly related to inducible myocardial ischemia. Measurements: Presence of inducible myocardial ischemia was adjudicated using myocardial perfusion imaging with single-photon emission computed tomography, as well as coronary angiography and fractional flow reserve measurements where available. Staff blinded to adjudication measured circulating hs-cTn concentrations. An hs-cTnI cutoff of 2.5 ng/L, derived previously in mostly asymptomatic patients with CAD, was assessed. Predefined target performance criteria were at least 90% negative predictive value (NPV) and at least 90% sensitivity for exclusion of inducible myocardial ischemia. Sensitivity analyses were based on measurements with an hs-cTnT assay and an alternative hs-cTnI assay with even higher analytic sensitivity (limit of detection, 0.1 ng/L). Results: Overall, 865 patients (46%) had inducible myocardial ischemia. The hs-cTnI cutoff of 2.5 ng/L provided an NPV of 70% (95% CI, 64% to 75%) and a sensitivity of 90% (CI, 88% to 92%) for exclusion of inducible myocardial ischemia. No hs-cTnI cutoff reached both performance characteristics predefined as targets. Similarly, using the alternative assays for hs-cTnI or hs-cTnT, no cutoff achieved the target performance: hs-cTnT concentrations less than 5 ng/L yielded an NPV of 66% (CI, 59% to 72%), and hs-cTnI concentrations less than 2 ng/L yielded an NPV of 68% (CI, 62% to 74%). Limitation: Data were generated in a large single-center diagnostic study using central adjudication. Conclusion: In symptomatic patients with CAD, very low hs-cTn concentrations, including hs-cTnI concentrations less than 2.5 ng/L, do not generally allow users to safely exclude inducible myocardial ischemia. Primary Funding Source: European Union, Swiss National Science Foundation, Kommission für Technologie und Innovation (Innosuisse), Swiss Heart Foundation, Cardiovascular Research Foundation Basel, University of Basel, University Hospital Basel, Roche, Abbott, and Singulex.

A Pound of Prevention? Assessing the Value of New Cholesterol-Lowering Drugs

Recommended Adult Immunization Schedule, United States, 2019*

Hepatitis C Virus Screening and Care: Complexity of Implementation in Primary Care Practices Serving Disadvantaged Populations

Background: Hepatitis C virus (HCV) disproportionately affects disadvantaged communities. Objective: To examine processes and outcomes of Screen, Treat, Or Prevent Hepatocellular Carcinoma (STOP HCC), a multicomponent intervention for HCV screening and care in safety-net primary care practices. Design: Mixed-methods retrospective analysis. Setting: 5 federally qualified health centers (FQHCs) and 1 family medicine residency program serving low-income communities in diverse locations with largely Hispanic populations. Patients: Persons born in 1945 through 1965 (baby boomers) who had never been tested for HCV and were followed through May 2018. Intervention: The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) model guided implementation and evaluation. Test costs were covered for uninsured patients. Measurements: All practices tested patients for anti-HCV antibody (anti-HCV) and HCV RNA. For uninsured patients with chronic HCV in 4 practices, quantitative data also enabled assessment of HCV staging, specialist teleconsultation, direct-acting antiviral (DAA) treatment, and sustained virologic response (SVR). Implementation fidelity and adaptation were assessed qualitatively. Results: Anti-HCV screening was done in 13 334 of 27 700 baby boomers (48.1%, varying by practice from 19.8% to 71.3%). Of 695 anti-HCV–positive patients, HCV RNA was tested in 520 (74.8%; 48.9% to 92.9% by practice), and 349 persons (2.6% of those screened) were diagnosed with chronic HCV. In 4 FQHCs, 174 (84.9%) of 205 uninsured patients with chronic HCV had disease staging, 145 (70.7%) had teleconsultation review, 119 (58.0%) were recommended to start DAA therapy, 82 (40.0%) initiated free DAA therapy, 74 (36.1%) completed therapy (27.8% to 60.0% by practice), and 70 (94.6% of DAA completers) achieved SVR. Implementation was promoted by multilevel practice engagement, patient navigation, and anti-HCV screening with reflex HCV RNA testing. Limitation: No control practices were included, and data were missing for some variables. Conclusion: Despite a similar framework for STOP HCC implementation, performance varied widely across safety-net practices, which may reflect practice engagement as well as infrastructure or cost challenges beyond practice control. Primary Funding Source: Cancer Prevention & Research Institute of Texas and Centers for Medicare & Medicaid Services.

A Tiered Approach for Preventing Methicillin-Resistant Staphylococcus aureus Infection

Methods for Development of the European Commission Initiative on Breast Cancer Guidelines: Recommendations in the Era of Guideline Transparency: Annals of Internal Medicine: Vol 171, No 4

Neither breast cancer prevention and early-detection programs, nor their outcomes, are uniform across Europe. This article describes the rationale, methods, and process for development of the European Commission (EC) Initiative on Breast Cancer Screening and Diagnosis Guidelines. To be consistent with standards set by the Institute of Medicine and others, the EC followed 6 general principles. First, the EC selected, via an open call, a panel with broad representation of areas of expertise. Second, it ensured that all recommendations were supported by systematic reviews. Third, the EC separately considered important subgroups of women, included patient advocates in the guidelines development group, and focused on good communication to inform women's decisions. Fourth, EC rules on conflicts of interest were followed and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision frameworks were used to structure the process and minimize the influence of competing interests. Fifth, it focused its recommendations on outcomes that matter to women, and certainty of the evidence is rated for each. Sixth, the EC elicited stakeholder feedback to ensure that the recommendations remain up to date and relevant to practice. This article describes the approach and highlights ways of disseminating and adapting the recommendations both within and outside Europe, using innovative information technology tools.

The Specter and the Goldfish

Risks and Benefits of Dolutegravir- and Efavirenz-Based Strategies for South African Women With HIV of Child-Bearing Potential: A Modeling Study: Annals of Internal Medicine: Vol 170, No 9

Background: Dolutegravir is superior to efavirenz for HIV antiretroviral therapy (ART) but may be associated with an increased risk for neural tube defects (NTDs) in newborns if used by women at conception. Objective: To project clinical outcomes of ART policies for women of child-bearing potential in South Africa. Design: Model of 3 strategies: efavirenz for all women of child-bearing potential (EFV), dolutegravir for all women of child-bearing potential (DTG), or World Health Organization (WHO)-recommended efavirenz without contraception or dolutegravir with contraception (WHO approach). Data Sources: Published data on NTD risks (efavirenz, 0.05%; dolutegravir, 0.67% [Tsepamo study]), 48-week ART efficacy with initiation (efavirenz, 60% to 91%; dolutegravir, 96%), and age-stratified fertility rates (2 to 139 per 1000 women). Target Population: 3.1 million South African women with HIV (aged 15 to 49 years) starting or continuing first-line ART, and their children. Time Horizon: 5 years. Perspective: Societal. Intervention: EFV, DTG, and WHO approach. Outcome Measures: Deaths among women and children, sexual and pediatric HIV transmissions, and NTDs. Results of Base-Case Analysis: Compared with EFV, DTG averted 13 700 women's deaths (0.44% decrease) and 57 700 sexual HIV transmissions, but increased total pediatric deaths by 4400 because of more NTDs. The WHO approach offered some benefits compared with EFV, averting 4900 women's deaths and 20 500 sexual transmissions while adding 300 pediatric deaths. Overall, combined deaths among women and children were lowest with DTG (358 000 deaths) compared with the WHO approach (362 800 deaths) or EFV (367 300 deaths). Results of Sensitivity Analysis: Women's deaths averted with DTG exceeded pediatric deaths added with EFV unless dolutegravir-associated NTD risk was 1.5% or greater. Limitation: Uncertainty in NTD risks and dolutegravir efficacy in resource-limited settings, each examined in sensitivity analyses. Conclusion: Although NTD risks may be higher with dolutegravir than efavirenz, dolutegravir will lead to many fewer deaths among women, as well as fewer overall HIV transmissions. These results argue against a uniform policy of avoiding dolutegravir in women of child-bearing potential. Primary Funding Source: National Institutes of Health, National Institute of Allergy and Infectious Diseases and Eunice Kennedy Shriver National Institute of Child Health and Human Development; Massachusetts General Hospital; and Harvard University Center for AIDS Research.

Comparison of Universal Versus Age-Restricted Screening of Colorectal Tumors for Lynch Syndrome Using Mismatch Repair Immunohistochemistry: A Cohort Study: Annals of Internal Medicine: Vol 171, No 1

Background: Guidelines recommend screening all patients with newly diagnosed colorectal cancer (CRC) for Lynch syndrome (LS). However, the efficiency of universal LS screening in elderly populations has not been well studied. Objective: To compare the performance of age-restricted and universal LS screening using reflex mismatch repair (MMR) immunohistochemistry (IHC) of CRC tumors. Design: Retrospective cohort study. Setting: A large, diverse, community-based health care system. Participants: 3891 persons with newly diagnosed CRC who had LS screening between 2011 and 2016. Measurements: Diagnostic yield of different LS screening strategies. Results: Sixty-three LS cases (diagnostic yield, 1.62%) were identified by universal screening, with only 5 (7.9%) detected after age 70 years and 1 (1.6%) detected after age 80 years. When all patients with CRC who had universal screening were used as the denominator, 58 LS cases (diagnostic yield, 1.49% [95% CI, 1.13% to 1.92%]) were identified in patients with CRC diagnosed at or before age 70 years, 60 LS cases (diagnostic yield, 1.54% [CI, 1.18% to 1.98%]) were identified in those with CRC diagnosed at or before age 75 years, and 62 LS cases (diagnostic yield, 1.59% [CI, 1.22% to 2.04%]) were identified in those with CRC diagnosed at or before age 80 years. Using 75 years as the upper age limit for screening missed 3 of 63 (4.8%) LS cases but resulted in 1053 (27.1%) fewer cases requiring tumor MMR IHC. Using 80 years as the upper age limit missed 1 of 63 (1.6%) LS cases and resulted in 668 (17.2%) fewer cases requiring tumor MMR IHC. Limitation: Persons who were eligible for but did not complete germline analysis were excluded from calculations of performance characteristics. Conclusion: The incremental diagnostic yield decreased substantially after age 70 to 75 years. Stopping reflex CRC screening for LS after age 80 years may be reasonable because of very low efficiency, particularly in resource-limited settings, but this merits further investigation. Studies evaluating the effect of diagnosing LS in elderly persons on their family members are needed. Primary Funding Source: Kaiser Permanente Northern California Division of Research.