Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Clinical Guideline From the American College of Physicians.

DESCRIPTION: The American College of Physicians (ACP) developed this clinical guideline to update recommendations on newer pharmacologic treatments of type 2 diabetes. This clinical guideline is based on the best available evidence for effectiveness, comparative benefits and harms, consideration of patients' values and preferences, and costs. METHODS: This clinical guideline is based on a systematic review of the effectiveness and harms of newer pharmacologic treatments of type 2 diabetes, including glucagon-like peptide-1 (GLP-1) agonists, a GLP-1 agonist and glucose-dependent insulinotropic polypeptide agonist, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and long-acting insulins, used either as monotherapy or in combination with other medications. The Clinical Guidelines Committee prioritized the following outcomes, which were evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach: all-cause mortality, major adverse cardiovascular events, myocardial infarction, stroke, hospitalization for congestive heart failure, progression of chronic kidney disease, serious adverse events, and severe hypoglycemia. Weight loss, as measured by percentage of participants who achieved at least 10% total body weight loss, was a prioritized outcome, but data were insufficient for network meta-analysis and were not rated with GRADE. AUDIENCE AND PATIENT POPULATION: The audience for this clinical guideline is physicians and other clinicians. The population is nonpregnant adults with type 2 diabetes. RECOMMENDATION 1: ACP recommends adding a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) agonist to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control (strong recommendation; high-certainty evidence). • Use an SGLT-2 inhibitor to reduce the risk for all-cause mortality, major adverse cardiovascular events, progression of chronic kidney disease, and hospitalization due to congestive heart failure. • Use a GLP-1 agonist to reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke. RECOMMENDATION 2: ACP recommends against adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control to reduce morbidity and all-cause mortality (strong recommendation; high-certainty evidence).

Informing the US Medicare drug price negotiation for apixaban and rivaroxaban: Methodological considerations for value assessments many years after launch.

OBJECTIVES: To demonstrate how health technology assessment (HTA) methods can be used to support Medicare's price negotiations for apixaban and rivaroxaban. METHODS: Following the statutory outline of evidence that will be considered by Medicare, we conducted a systematic literature review, network meta-analyses (NMAs), and decision analyses to evaluate the health outcomes and costs associated with apixaban and rivaroxaban compared to warfarin and dabigatran for patients with non-valvular atrial fibrillation. Our methods inform discussions about the therapeutic impact of apixaban and rivaroxaban and suggest price premiums above their therapeutic alternatives over a range of cost-effectiveness thresholds. RESULTS: NMAs found apixaban resulted in a lower risk of major bleeding compared to warfarin and dabigatran, and a lower risk of stroke/systemic embolism compared to warfarin, but not compared to dabigatran. Rivaroxaban resulted in a lower risk of stroke/systemic embolism versus warfarin but not dabigatran, and there was no difference in major bleeding. Decision-analytic modeling of apixaban suggested annual price premiums up to $4,350 above the price of warfarin and up to $530 above the price for dabigatran at cost-effectiveness thresholds up to $200,000 per equal value of life years gained. Analyses of rivaroxaban showed an annual price premium of up to $3,920 above warfarin, and no premium above that paid for dabigatran. CONCLUSIONS: Although HTA is typically performed near the time of regulatory approval, with modifications, we produced comparative clinical and relative cost-effectiveness findings to help guide negotiations on a "fair" price for drugs on the market for over a decade.

Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass to Prevent Fractures in Adults: A Living Clinical Guideline From the American College of Physicians.

DESCRIPTION: This guideline updates the 2017 American College of Physicians (ACP) recommendations on pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults. METHODS: The ACP Clinical Guidelines Committee based these recommendations on an updated systematic review of evidence and graded them using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. AUDIENCE AND PATIENT POPULATION: The audience for this guideline includes all clinicians. The patient population includes adults with primary osteoporosis or low bone mass. RECOMMENDATION 1A: ACP recommends that clinicians use bisphosphonates for initial pharmacologic treatment to reduce the risk of fractures in postmenopausal females diagnosed with primary osteoporosis (strong recommendation; high-certainty evidence). RECOMMENDATION 1B: ACP suggests that clinicians use bisphosphonates for initial pharmacologic treatment to reduce the risk of fractures in males diagnosed with primary osteoporosis (conditional recommendation; low-certainty evidence). RECOMMENDATION 2A: ACP suggests that clinicians use the RANK ligand inhibitor (denosumab) as a second-line pharmacologic treatment to reduce the risk of fractures in postmenopausal females diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of bisphosphonates (conditional recommendation; moderate-certainty evidence). RECOMMENDATION 2B: ACP suggests that clinicians use the RANK ligand inhibitor (denosumab) as a second-line pharmacologic treatment to reduce the risk of fractures in males diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of bisphosphonates (conditional recommendation; low-certainty evidence). RECOMMENDATION 3: ACP suggests that clinicians use the sclerostin inhibitor (romosozumab, moderate-certainty evidence) or recombinant PTH (teriparatide, low-certainty evidence), followed by a bisphosphonate, to reduce the risk of fractures only in females with primary osteoporosis with very high risk of fracture (conditional recommendation). RECOMMENDATION 4: ACP suggests that clinicians take an individualized approach regarding whether to start pharmacologic treatment with a bisphosphonate in females over the age of 65 with low bone mass (osteopenia) to reduce the risk of fractures (conditional recommendation; low-certainty evidence).

Screening for Colorectal Cancer in Asymptomatic Average-Risk Adults: A Guidance Statement From the American College of Physicians (Version 2).

DESCRIPTION: The purpose of this updated guidance statement is to guide clinicians on screening for colorectal cancer (CRC) in asymptomatic average-risk adults. The intended audience is all clinicians. The population is asymptomatic adults at average risk for CRC. METHODS: This updated guidance statement was developed using recently published and critically appraised clinical guidelines from national guideline developers since the publication of the American College of Physicians' 2019 guidance statement, "Screening for Colorectal Cancer in Asymptomatic Average-Risk Adults." The authors searched for national guidelines from the United States and other countries published in English using PubMed and the Guidelines International Network library from 1 January 2018 to 24 April 2023. The authors also searched for updates of guidelines included in the first version of our guidance statement. The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument was used to assess the quality of eligible guidelines. Two guidelines were selected for adoption and adaptation by raters on the basis of the highest average overall AGREE II quality scores. The evidence reviews and modeling studies for these 2 guidelines were also used to synthesize the evidence of diagnostic test accuracy, effectiveness, and harms of CRC screening interventions and to develop our guidance statements. GUIDANCE STATEMENT 1: Clinicians should start screening for colorectal cancer in asymptomatic average-risk adults at age 50 years. GUIDANCE STATEMENT 2: Clinicians should consider not screening asymptomatic average-risk adults between the ages of 45 to 49 years. Clinicians should discuss the uncertainty around benefits and harms of screening in this population. GUIDANCE STATEMENT 3: Clinicians should stop screening for colorectal cancer in asymptomatic average-risk adults older than 75 years or in asymptomatic average-risk adults with a life expectancy of 10 years or less. GUIDANCE STATEMENT 4A: Clinicians should select a screening test for colorectal cancer in consultation with their patient based on a discussion of benefits, harms, costs, availability, frequency, and patient values and preferences. GUIDANCE STATEMENT 4B: Clinicians should select among a fecal immunochemical or high-sensitivity guaiac fecal occult blood test every 2 years, colonoscopy every 10 years, or flexible sigmoidoscopy every 10 years plus a fecal immunochemical test every 2 years as a screening test for colorectal cancer. GUIDANCE STATEMENT 4C: Clinicians should not use stool DNA, computed tomography colonography, capsule endoscopy, urine, or serum screening tests for colorectal cancer.

Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians.

DESCRIPTION: The purpose of this guideline from the American College of Physicians (ACP) is to present updated clinical recommendations on nonpharmacologic and pharmacologic interventions as initial and second-line treatments during the acute phase of a major depressive disorder (MDD) episode, based on the best available evidence on the comparative benefits and harms, consideration of patient values and preferences, and cost. METHODS: The ACP Clinical Guidelines Committee based these recommendations on an updated systematic review of the evidence. AUDIENCE AND PATIENT POPULATION: The audience for this guideline includes clinicians caring for adult patients in the acute phase of MDD in ambulatory care. The patient population includes adults in the acute phase of MDD. RECOMMENDATION 1A: ACP recommends monotherapy with either cognitive behavioral therapy or a second-generation antidepressant as initial treatment in patients in the acute phase of moderate to severe major depressive disorder (strong recommendation; moderate-certainty evidence). RECOMMENDATION 1B: ACP suggests combination therapy with cognitive behavioral therapy and a second-generation antidepressant as initial treatment in patients in the acute phase of moderate to severe major depressive disorder (conditional recommendation; low-certainty evidence). The informed decision on the options of monotherapy with cognitive behavioral therapy versus second-generation antidepressants or combination therapy should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients' specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences. RECOMMENDATION 2: ACP suggests monotherapy with cognitive behavioral therapy as initial treatment in patients in the acute phase of mild major depressive disorder (conditional recommendation; low-certainty evidence). RECOMMENDATION 3: ACP suggests one of the following options for patients in the acute phase of moderate to severe major depressive disorder who did not respond to initial treatment with an adequate dose of a second-generation antidepressant: • Switching to or augmenting with cognitive behavioral therapy (conditional recommendation; low-certainty evidence) • Switching to a different second-generation antidepressant or augmenting with a second pharmacologic treatment (see Clinical Considerations) (conditional recommendation; low-certainty evidence) The informed decision on the options should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients' specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences.

Colonoscopy for Diagnostic Evaluation and Interventions to Prevent Recurrence After Acute Left-Sided Colonic Diverticulitis: A Clinical Guideline From the American College of Physicians.

DESCRIPTION: The American College of Physicians (ACP) developed this guideline to provide clinical recommendations on the role of colonoscopy for diagnostic evaluation of colorectal cancer (CRC) after a presumed diagnosis of acute left-sided colonic diverticulitis and on the role of pharmacologic, nonpharmacologic, and elective surgical interventions to prevent recurrence after initial treatment of acute complicated and uncomplicated left-sided colonic diverticulitis. This guideline is based on the current best available evidence about benefits and harms, taken in the context of costs and patient values and preferences. METHODS: The ACP Clinical Guidelines Committee (CGC) based these recommendations on a systematic review on the role of colonoscopy after acute left-sided colonic diverticulitis and pharmacologic, nonpharmacologic, and elective surgical interventions after initial treatment. The systematic review evaluated outcomes rated by the CGC as critical or important. This guideline was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. TARGET AUDIENCE AND PATIENT POPULATION: The target audience is all clinicians, and the target patient population is adults with recent episodes of acute left-sided colonic diverticulitis. RECOMMENDATION 1: ACP suggests that clinicians refer patients for a colonoscopy after an initial episode of complicated left-sided colonic diverticulitis in patients who have not had recent colonoscopy (conditional recommendation; low-certainty evidence). RECOMMENDATION 2: ACP recommends against clinicians using mesalamine to prevent recurrent diverticulitis (strong recommendation; high-certainty evidence). RECOMMENDATION 3: ACP suggests that clinicians discuss elective surgery to prevent recurrent diverticulitis after initial treatment in patients who have either uncomplicated diverticulitis that is persistent or recurs frequently or complicated diverticulitis (conditional recommendation; low-certainty evidence). The informed decision whether or not to undergo surgery should be personalized based on a discussion of potential benefits, harms, costs, and patient's preferences.

Diagnosis and Management of Acute Left-Sided Colonic Diverticulitis: A Clinical Guideline From the American College of Physicians.

DESCRIPTION: The American College of Physicians (ACP) developed this guideline to provide clinical recommendations on the diagnosis and management of acute left-sided colonic diverticulitis in adults. This guideline is based on current best available evidence about benefits and harms, taken in the context of costs and patient values and preferences. METHODS: The ACP Clinical Guidelines Committee (CGC) developed this guideline based on a systematic review on the use of computed tomography (CT) for the diagnosis of acute left-sided colonic diverticulitis and on management via hospitalization, antibiotic use, and interventional percutaneous abscess drainage. The systematic review evaluated outcomes that the CGC rated as critical or important. This guideline was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. TARGET AUDIENCE AND PATIENT POPULATION: The target audience is all clinicians, and the target patient population is adults with suspected or known acute left-sided colonic diverticulitis. RECOMMENDATION 1: ACP suggests that clinicians use abdominal CT imaging when there is diagnostic uncertainty in a patient with suspected acute left-sided colonic diverticulitis (conditional recommendation; low-certainty evidence). RECOMMENDATION 2: ACP suggests that clinicians manage most patients with acute uncomplicated left-sided colonic diverticulitis in an outpatient setting (conditional recommendation; low-certainty evidence). RECOMMENDATION 3: ACP suggests that clinicians initially manage select patients with acute uncomplicated left-sided colonic diverticulitis without antibiotics (conditional recommendation; low-certainty evidence).

A case-case analysis of women with breast cancer: predictors of interval vs screen-detected cancer.

PURPOSE: The Breast Cancer Surveillance Consortium (BCSC) model is a widely used risk model that predicts 5- and 10-year risk of developing invasive breast cancer for healthy women aged 35-74 years. Women with high BCSC risk may also be at elevated risk to develop interval cancers, which present symptomatically in the year following a normal screening mammogram. We examined the association between high BCSC risk (defined as the top 2.5% by age) and breast cancers presenting as interval cancers. METHODS: We conducted a case-case analysis among women with breast cancer in which we compared the mode of detection and tumor characteristics of patients in the top 2.5% BCSC risk by age with age-matched (1:2) patients in the lower 97.5% risk. We constructed logistic regression models to estimate the odds ratio (OR) of presenting with interval cancers, and poor prognosis tumor features, between women from the top 2.5% and bottom 97.5% of BCSC risk. RESULTS: Our analysis included 113 breast cancer patients in the top 2.5% of risk for their age and 226 breast cancer patients in the lower 97.5% of risk. High-risk patients were more likely to have presented with an interval cancer within one year of a normal screening, OR 6.62 (95% CI 3.28-13.4, p < 0.001). These interval cancers were also more likely to be larger, node positive, and higher stage than the screen-detected cancers. CONCLUSION: Breast cancer patients in the top 2.5% of BCSC risk for their age were more likely to present with interval cancers. The BCSC model could be used to identify healthy women who may benefit from intensified screening.

Comparing Mammographic Density Assessed by Digital Breast Tomosynthesis or Digital Mammography: The Breast Cancer Surveillance Consortium.

Background Consistency in reporting Breast Imaging Reporting and Data System (BI-RADS) breast density on mammograms is important because breast density is used for breast cancer risk assessment and is reported directly to women and clinicians to inform decisions about supplemental screening. Purpose To assess the consistency of BI-RADS density reporting between digital breast tomosynthesis (DBT) and digital mammography (DM) and evaluate density as a breast cancer risk factor when assessed using DM versus DBT. Materials and Methods The Breast Cancer Surveillance Consortium is a prospective cohort study of women undergoing mammography with DM or DBT. This secondary analysis included women aged 40-79 years who underwent at least two screening mammography examinations less than 36 months apart. Percentage agreement and κ statistic were estimated for pairs of BI-RADS density assessments. Cox proportional hazards regression was used to calculate hazard ratios (HRs) of breast density as a risk factor for invasive breast cancer. Results A total of 403 326 pairs of mammograms from 342 149 women were evaluated. There were no significant differences in breast density assessment in pairs consisting of one DM and one DBT examination (57 516 of 74 729 [77%]; κ = 0.64), two DM examinations (238 678 of 301 743 [79%]; κ = 0.67), and two DBT examinations (20 763 of 26 854 [77%]; κ = 0.65). Results were similar when restricting the analyses to pairs read by the same radiologist. The breast cancer HRs for breast density were similar for DM and DBT (P = .45 for interaction). The HRs for density acquired using DM and DBT, respectively, were 0.55 (95% CI: 0.49, 0.63) and 0.37 (95% CI: 0.21, 0.66) for almost entirely fat, 1.47 (95% CI: 1.37, 1.58) and 1.36 (95% CI: 1.02, 1.82) for heterogeneously dense, and 1.72 (95% CI: 1.54, 1.93) and 2.05 (95% CI: 1.25, 3.36) for extremely dense breasts. Conclusion Radiologist reporting of Breast Imaging Reporting and Data System density obtained with digital breast tomosynthesis did not differ from that obtained with digital mammography. © RSNA, 2021 Online supplemental material is available for this article.

Appropriate Use of Point-of-Care Ultrasonography in Patients With Acute Dyspnea in Emergency Department or Inpatient Settings: A Clinical Guideline From the American College of Physicians.

DESCRIPTION: The American College of Physicians (ACP) developed this guideline to provide clinical recommendations on the appropriate use of point-of-care ultrasonography (POCUS) in patients with acute dyspnea in emergency department (ED) or inpatient settings to improve the diagnostic, treatment, and health outcomes of those with suspected congestive heart failure, pneumonia, pulmonary embolism, pleural effusion, or pneumothorax. METHODS: The ACP Clinical Guidelines Committee based this guideline on a systematic review on the benefits, harms, and diagnostic test accuracy of POCUS; patient values and preferences; and costs of POCUS. The systematic review evaluated health outcomes, diagnostic timeliness, treatment decisions, and test accuracy. The critical health, diagnostic, and treatment outcomes evaluated were in-hospital mortality, time to diagnosis, and time to treatment. The important outcomes evaluated were intensive care unit admissions, correctness of diagnosis, disease-specific outcomes, hospital readmissions, length of hospital stay, and quality of life. The critical test accuracy outcomes included false-positive results for suspected pneumonia, pneumothorax, and pulmonary embolism and false-negative results for suspected congestive heart failure, pneumonia, pneumothorax, and pulmonary embolism. Important test accuracy outcomes included false-positive results for suspected congestive heart failure and false-negative and false-positive results for suspected pleural effusion. This guideline was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. TARGET AUDIENCE AND PATIENT POPULATION: The target audience is all clinicians, and the target patient population is adult patients with acute dyspnea in ED or inpatient settings. RECOMMENDATION: ACP suggests that clinicians may use point-of-care ultrasonography in addition to the standard diagnostic pathway when there is diagnostic uncertainty in patients with acute dyspnea in emergency department or inpatient settings (conditional recommendation; low-certainty evidence).

Appropriate Use of High-Flow Nasal Oxygen in Hospitalized Patients for Initial or Postextubation Management of Acute Respiratory Failure: A Clinical Guideline From the American College of Physicians.

DESCRIPTION: The American College of Physicians (ACP) developed this guideline to provide clinical recommendations on the appropriate use of high-flow nasal oxygen (HFNO) in hospitalized patients for initial or postextubation management of acute respiratory failure. It is based on the best available evidence on the benefits and harms of HFNO, taken in the context of costs and patient values and preferences. METHODS: The ACP Clinical Guidelines Committee based these recommendations on a systematic review on the efficacy and safety of HFNO. The patient-centered health outcomes evaluated included all-cause mortality, hospital length of stay, 30-day hospital readmissions, hospital-acquired pneumonia, days of intubation or reintubation, intensive care unit (ICU) admission and ICU transfers, patient comfort, dyspnea, delirium, barotrauma, compromised nutrition, gastric dysfunction, functional independence at discharge, discharge disposition, and skin breakdown. This guideline was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. TARGET AUDIENCE AND PATIENT POPULATION: The target audience is all clinicians, and the target patient population is adult patients with acute respiratory failure treated in a hospital setting (including emergency departments, hospital wards, intermediate or step-down units, and ICUs). RECOMMENDATION 1A: ACP suggests that clinicians use high-flow nasal oxygen rather than noninvasive ventilation in hospitalized adults for the management of acute hypoxemic respiratory failure (conditional recommendation; low-certainty evidence). RECOMMENDATION 1B: ACP suggests that clinicians use high-flow nasal oxygen rather than conventional oxygen therapy for hospitalized adults with postextubation acute hypoxemic respiratory failure (conditional recommendation; low-certainty evidence).

Validation of the breast cancer surveillance consortium model of breast cancer risk.

PURPOSE: In order to use a breast cancer prediction model in clinical practice to guide screening and prevention, it must be well calibrated and validated in samples independent from the one used for development. We assessed the accuracy of the breast cancer surveillance consortium (BCSC) model in a racially diverse population followed for up to 10 years. METHODS: The BCSC model combines breast density with other risk factors to estimate a woman's 5- and 10-year risk of invasive breast cancer. We validated the model in an independent cohort of 252,997 women in the Chicago area. We evaluated calibration using the ratio of expected to observed (E/O) invasive breast cancers in the cohort and discrimination using the area under the receiver operating characteristic curve (AUROC). RESULTS: In an independent cohort of 252,997 women (median age 50 years, 26% non-Hispanic Black), the BCSC model was well calibrated (E/O = 0.94, 95% confidence interval [CI] 0.90-0.98), but underestimated the incidence of invasive breast cancer in younger women and in women with low mammographic density. The AUROC was 0.633, similar to that observed in prior validation studies. CONCLUSIONS: The BCSC model is a well-validated risk assessment tool for breast cancer that may be particularly useful when assessing the utility of supplemental screening in women with dense breasts.

Joint relative risks for estrogen receptor-positive breast cancer from a clinical model, polygenic risk score, and sex hormones.

BACKGROUND: Models that predict the risk of estrogen receptor (ER)-positive breast cancers may improve our ability to target chemoprevention. We investigated the contributions of sex hormones to the discrimination of the Breast Cancer Surveillance Consortium (BCSC) risk model and a polygenic risk score comprised of 83 single nucleotide polymorphisms. METHODS: We conducted a nested case-control study of 110 women with ER-positive breast cancers and 214 matched controls within a mammography screening cohort. Participants were postmenopausal and not on hormonal therapy. The associations of estradiol, estrone, testosterone, and sex hormone binding globulin with ER-positive breast cancer were evaluated using conditional logistic regression. We assessed the individual and combined discrimination of estradiol, the BCSC risk score, and polygenic risk score using the area under the receiver operating characteristic curve (AUROC). RESULTS: Of the sex hormones assessed, estradiol (OR 3.64, 95% CI 1.64-8.06 for top vs bottom quartile), and to a lesser degree estrone, was most strongly associated with ER-positive breast cancer in unadjusted analysis. The BCSC risk score (OR 1.32, 95% CI 1.00-1.75 per 1% increase) and polygenic risk score (OR 1.58, 95% CI 1.06-2.36 per standard deviation) were also associated with ER-positive cancers. A model containing the BCSC risk score, polygenic risk score, and estradiol levels showed good discrimination for ER-positive cancers (AUROC 0.72, 95% CI 0.65-0.79), representing a significant improvement over the BCSC risk score (AUROC 0.58, 95% CI 0.50-0.65). CONCLUSION: Adding estradiol and a polygenic risk score to a clinical risk model improves discrimination for postmenopausal ER-positive breast cancers.

Assessing the value of mepolizumab for severe eosinophilic asthma: a cost-effectiveness analysis.

BACKGROUND: Adding mepolizumab to standard treatment with inhaled corticosteroids and controller medications could decrease asthma exacerbations and use of long-term oral steroids in patients with severe disease and increased eosinophils; however, mepolizumab is costly and its cost effectiveness is unknown. OBJECTIVE: To estimate the cost effectiveness of mepolizumab. METHODS: A Markov model was used to determine the incremental cost per quality-adjusted life year (QALY) gained for mepolizumab plus standard of care (SoC) and for SoC alone. The population, adults with severe eosinophilic asthma, was modeled for a lifetime time horizon. A responder scenario analysis was conducted to determine the cost effectiveness for a cohort able to achieve and maintain asthma control. RESULTS: Over a lifetime treatment horizon, 23.96 exacerbations were averted per patient receiving mepolizumab plus SoC. Avoidance of exacerbations and decrease in long-term oral steroid use resulted in more than $18,000 in cost offsets among those receiving mepolizumab, but treatment costs increased by more than $600,000. Treatment with mepolizumab plus SoC vs SoC alone resulted in a cost-effectiveness estimate of $386,000 per QALY. To achieve cost effectiveness of approximately $150,000 per QALY, mepolizumab would require a more than 60% price discount. At current pricing, treating a responder cohort yielded cost-effectiveness estimates near $160,000 per QALY. CONCLUSION: The estimated cost effectiveness of mepolizumab exceeds value thresholds. Achieving these thresholds would require significant discounts from the current list price. Alternatively, treatment limited to responders improves the cost effectiveness toward, but remains still slightly above, these thresholds. Payers interested in improving the efficiency of health care resources should consider negotiations of the mepolizumab price and ways to predict and assess the response to mepolizumab.

Breast cancer risk prediction using a clinical risk model and polygenic risk score.

Breast cancer risk assessment can inform the use of screening and prevention modalities. We investigated the performance of the Breast Cancer Surveillance Consortium (BCSC) risk model in combination with a polygenic risk score (PRS) comprised of 83 single nucleotide polymorphisms identified from genome-wide association studies. We conducted a nested case-control study of 486 cases and 495 matched controls within a screening cohort. The PRS was calculated using a Bayesian approach. The contributions of the PRS and variables in the BCSC model to breast cancer risk were tested using conditional logistic regression. Discriminatory accuracy of the models was compared using the area under the receiver operating characteristic curve (AUROC). Increasing quartiles of the PRS were positively associated with breast cancer risk, with OR 2.54 (95 % CI 1.69-3.82) for breast cancer in the highest versus lowest quartile. In a multivariable model, the PRS, family history, and breast density remained strong risk factors. The AUROC of the PRS was 0.60 (95 % CI 0.57-0.64), and an Asian-specific PRS had AUROC 0.64 (95 % CI 0.53-0.74). A combined model including the BCSC risk factors and PRS had better discrimination than the BCSC model (AUROC 0.65 versus 0.62, p = 0.01). The BCSC-PRS model classified 18 % of cases as high-risk (5-year risk ≥3 %), compared with 7 % using the BCSC model. The PRS improved discrimination of the BCSC risk model and classified more cases as high-risk. Further consideration of the PRS's role in decision-making around screening and prevention strategies is merited.

Identifying women with dense breasts at high risk for interval cancer: a cohort study.

BACKGROUND: Twenty-one states have laws requiring that women be notified if they have dense breasts and that they be advised to discuss supplemental imaging with their provider. OBJECTIVE: To better direct discussions of supplemental imaging by determining which combinations of breast cancer risk and Breast Imaging Reporting and Data System (BI-RADS) breast density categories are associated with high interval cancer rates. DESIGN: Prospective cohort. SETTING: Breast Cancer Surveillance Consortium (BCSC) breast imaging facilities. PATIENTS: 365,426 women aged 40 to 74 years who had 831,455 digital screening mammography examinations. MEASUREMENTS: BI-RADS breast density, BCSC 5-year breast cancer risk, and interval cancer rate (invasive cancer ≤12 months after a normal mammography result) per 1000 mammography examinations. High interval cancer rate was defined as more than 1 case per 1000 examinations. RESULTS: High interval cancer rates were observed for women with 5-year risk of 1.67% or greater and extremely dense breasts or 5-year risk of 2.50% or greater and heterogeneously dense breasts (24% of all women with dense breasts). The interval rate of advanced-stage disease was highest (>0.4 case per 1000 examinations) among women with 5-year risk of 2.50% or greater and heterogeneously or extremely dense breasts (21% of all women with dense breasts). Five-year risk was low to average (0% to 1.66%) for 51.0% of women with heterogeneously dense breasts and 52.5% with extremely dense breasts, with interval cancer rates of 0.58 to 0.63 and 0.72 to 0.89 case per 1000 examinations, respectively. LIMITATION: The benefit of supplemental imaging was not assessed. CONCLUSION: Breast density should not be the sole criterion for deciding whether supplemental imaging is justified because not all women with dense breasts have high interval cancer rates. BCSC 5-year risk combined with BI-RADS breast density can identify women at high risk for interval cancer to inform patient-provider discussions about alternative screening strategies. PRIMARY FUNDING SOURCE: National Cancer Institute.

Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease.

IMPORTANCE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were recently approved for lowering low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD) and have potential for broad ASCVD prevention. Their long-term cost-effectiveness and effect on total health care spending are uncertain. OBJECTIVE: To estimate the cost-effectiveness of PCSK9 inhibitors and their potential effect on US health care spending. DESIGN, SETTING, AND PARTICIPANTS: The Cardiovascular Disease Policy Model, a simulation model of US adults aged 35 to 94 years, was used to evaluate cost-effectiveness of PCSK9 inhibitors or ezetimibe in heterozygous FH or ASCVD. The model incorporated 2015 annual PCSK9 inhibitor costs of $14,350 (based on mean wholesale acquisition costs of evolocumab and alirocumab); adopted a health-system perspective, lifetime horizon; and included probabilistic sensitivity analyses to explore uncertainty. EXPOSURES: Statin therapy compared with addition of ezetimibe or PCSK9 inhibitors. MAIN OUTCOMES AND MEASURES: Lifetime major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, or stroke), incremental cost per quality-adjusted life-year (QALY), and total effect on US health care spending over 5 years. RESULTS: Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent 316,300 MACE at a cost of $503,000 per QALY gained compared with adding ezetimibe to statins (80% uncertainty interval [UI], $493,000-$1,737,000). In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE compared with adding ezetimibe at $414,000 per QALY (80% UI, $277,000-$1,539,000). Reducing annual drug costs to $4536 per patient or less would be needed for PCSK9 inhibitors to be cost-effective at less than $100,000 per QALY. At 2015 prices, PCSK9 inhibitor use in all eligible patients was estimated to reduce cardiovascular care costs by $29 billion over 5 years, but drug costs increased by an estimated $592 billion (a 38% increase over 2015 prescription drug expenditures). In contrast, initiating statins in these high-risk populations in all statin-tolerant individuals who are not currently using statins was estimated to save $12 billion. CONCLUSIONS AND RELEVANCE: Assuming 2015 prices, PCSK9 inhibitor use in patients with heterozygous FH or ASCVD did not meet generally acceptable incremental cost-effectiveness thresholds and was estimated to increase US health care costs substantially. Reducing annual drug prices from more than $14,000 to $4536 would be necessary to meet a $100,000 per QALY threshold.