Potential Medicare Part D Savings on Generic Drugs From the Mark Cuban Cost Plus Drug Company

A Framework for the Development of Living Practice Guidelines in Health Care

Background: Living practice guidelines are increasingly being used to ensure that recommendations are responsive to rapidly emerging evidence. Objective: To develop a framework that characterizes the processes of development of living practice guidelines in health care. Design: First, 3 background reviews were conducted: a scoping review of methods papers, a review of handbooks of guideline-producing organizations, and an analytic review of selected living practice guidelines. Second, the core team drafted the first version of the framework. Finally, the core team refined the framework through an online survey and online discussions with a multidisciplinary international group of stakeholders. Setting: International. Participants: Multidisciplinary group of 51 persons who have experience with guidelines. Measurements: Not applicable. Results: A major principle of the framework is that the unit of update in a living guideline is the individual recommendation. In addition to providing definitions, the framework addresses several processes. The planning process should address the organization's adoption of the living methodology as well as each specific guideline project. The production process consists of initiation, maintenance, and retirement phases. The reporting should cover the evidence surveillance time stamp, the outcome of reassessment of the body of evidence (when applicable), and the outcome of revisiting a recommendation (when applicable). The dissemination process may necessitate the use of different venues, including one for formal publication. Limitation: This study does not provide detailed or practical guidance for how the described concepts would be best implemented. Conclusion: The framework will help guideline developers in planning, producing, reporting, and disseminating living guideline projects. It will also help research methodologists study the processes of living guidelines. Primary Funding Source: None.

Comparative Effectiveness and Safety Between Apixaban, Dabigatran, Edoxaban, and Rivaroxaban Among Patients With Atrial Fibrillation: A Multinational Population-Based Cohort Study: Annals of Internal Medicine: Vol 175, No 11

Background: Current guidelines recommend using direct oral anticoagulants (DOACs) over warfarin in patients with atrial fibrillation (AF), but head-to-head trial data do not exist to guide the choice of DOAC. Objective: To do a large-scale comparison between all DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) in routine clinical practice. Design: Multinational population-based cohort study. Setting: Five standardized electronic health care databases, which covered 221 million people in France, Germany, the United Kingdom, and the United States. Participants: Patients who were newly diagnosed with AF from 2010 through 2019 and received a new DOAC prescription. Measurements: Database-specific hazard ratios (HRs) of ischemic stroke or systemic embolism, intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB), and all-cause mortality between DOACs were estimated using a Cox regression model stratified by propensity score and pooled using a random-effects model. Results: A total of 527 226 new DOAC users met the inclusion criteria (apixaban, n = 281 320; dabigatran, n = 61 008; edoxaban, n = 12 722; and rivaroxaban, n = 172 176). Apixaban use was associated with lower risk for GIB than use of dabigatran (HR, 0.81 [95% CI, 0.70 to 0.94]), edoxaban (HR, 0.77 [CI, 0.66 to 0.91]), or rivaroxaban (HR, 0.72 [CI, 0.66 to 0.79]). No substantial differences were observed for other outcomes or DOAC–DOAC comparisons. The results were consistent for patients aged 80 years or older. Consistent associations between lower GIB risk and apixaban versus rivaroxaban were observed among patients receiving the standard dose (HR, 0.72 [CI, 0.64 to 0.82]), those receiving a reduced dose (HR, 0.68 [CI, 0.61 to 0.77]), and those with chronic kidney disease (HR, 0.68 [CI, 0.59 to 0.77]). Limitation: Residual confounding is possible. Conclusion: Among patients with AF, apixaban use was associated with lower risk for GIB and similar rates of ischemic stroke or systemic embolism, ICH, and all-cause mortality compared with dabigatran, edoxaban, and rivaroxaban. This finding was consistent for patients aged 80 years or older and those with chronic kidney disease, who are often underrepresented in clinical trials. Primary Funding Source: None.

Epstein–Barr Viral Load Monitoring Strategy and the Risk for Posttransplant Lymphoproliferative Disease in Adult Liver Transplantation: A Cohort Study: Annals of Internal Medicine: Vol 176, No 2

Background: Primary infection with or reactivation of Epstein–Barr virus (EBV) can occur after liver transplant (LT) and can lead to posttransplant lymphoproliferative disease (PTLD). In pediatric LT, an EBV-DNA viral load (EBV VL) monitoring strategy, including the reduction of immunosuppression, has led to a lower incidence of PTLD. For adult LT recipients with less primary infection and more EBV reactivation, it is unknown whether this strategy is effective. Objective: To examine the effect of an EBV VL monitoring strategy on the incidence of PTLD after LT in adults. Design: Cohort study. Setting: Two university medical centers in the Netherlands. Patients: Adult recipients of first LT in Leiden between September 2003 and January 2017 with an EBV VL monitoring strategy formed the monitoring group (M1), recipients of first LT in Rotterdam between January 2003 and January 2017 without such a strategy formed the contemporary control group (C1), and those who had transplants in Leiden between September 1992 and September 2003 or Rotterdam between 1986 and January 2003 formed the historical control groups (M0 and C0, respectively). Measurements: Influence of EBV VL monitoring on incidence of PTLD. Results: After inverse probability of treatment weighting of the 4 groups to achieve a balance among the groups for important patient characteristics, differences within hospitals between the historical and recent era in cumulative incidences—expressed as the number of events per 1000 patients measured at 5-, 10-, and 15-year follow-up—showed fewer events in the contemporary era in both centers. This difference was considerably larger in the monitoring center, whereas the 95% CI included the null value of 0 for point estimates. Limitation: Retrospective, low statistical power, and incompletely balanced groups, and non-EBV PTLD cannot be prevented. Conclusion: Monitoring EBV VL may reduce PTLD incidence after LT in adults; larger studies are warranted. Primary Funding Source: None.

Apixaban Versus Rivaroxaban in Patients With Atrial Fibrillation and Valvular Heart Disease: A Population-Based Study: Annals of Internal Medicine: Vol 175, No 11

Background: Although apixaban and rivaroxaban are commonly used in patients with atrial fibrillation (AF) and valvular heart disease (VHD), there is limited evidence comparing the 2 drugs in these patients. Objective: To emulate a target trial of effectiveness and safety of apixaban and rivaroxaban in patients with AF and VHD. Design: New-user, active comparator, cohort study design. Setting: Commercial health insurance database from 1 January 2013 to 31 December 2020. Patients: New users of apixaban or rivaroxaban who had a diagnosis of AF and VHD before initiation of anticoagulant therapy. Measurements: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of gastrointestinal or intracranial bleeding. Cox proportional hazards regression with a robust variance estimator was used to estimate hazard ratios (HRs) and 95% CIs. Results: When compared with rivaroxaban in a propensity score–matched cohort of 19 894 patients (9947 receiving each drug), apixaban was associated with a lower rate of ischemic stroke or systemic embolism (HR, 0.57 [95% CI, 0.40 to 0.80]) and bleeding (HR, 0.51 [CI, 0.41 to 0.62]). The absolute reduction in the probability of stroke or systemic embolism with apixaban compared with rivaroxaban was 0.0026 within 6 months and 0.011 within 1 year of treatment initiation. The absolute reduction in the probability of bleeding events with apixaban compared with rivaroxaban was 0.012 within 6 months and 0.019 within 1 year of treatment initiation. Limitation: Short follow-up time and inability to ascertain some types of VHD. Conclusion: In this study of patients with AF and VHD, patients receiving apixaban had a lower risk for ischemic stroke or systemic embolism and for bleeding when compared with those receiving rivaroxaban. Primary Funding Source: National Institutes of Health.

Adenoma Detection Rate and Risk for Interval Postcolonoscopy Colorectal Cancer in Fecal Immunochemical Test–Based Screening: A Population-Based Cohort Study: Annals of Internal Medicine: Vol 175, No 10

Background: The adenoma detection rate (ADR) is an essential quality indicator for endoscopists performing colonoscopies for colorectal cancer (CRC) screening as it is associated with postcolonoscopy CRCs (PCCRCs). Currently, data on ADRs of endoscopists performing colonoscopies in fecal immunochemical testing (FIT)-based screening, the most common screening method, are scarce. Also, the association between the ADR and PCCRC has not been demonstrated in this setting. Objective: To evaluate the association between the ADR and PCCRC risk in colonoscopies done after a positive FIT result. Design: Population-based cohort. Setting: Dutch, FIT-based, CRC screening program. Participants: Patients undergoing colonoscopy, done by accredited endoscopists, after a positive FIT result. Measurements: Quality indicator performance and PCCRC incidence for colonoscopies in FIT-positive screenees were assessed. The PCCRCs were classified as interval, a cancer detected before recommended surveillance, or noninterval. The association between ADR and interval PCCRC was evaluated with a multivariable Cox regression model and PCCRC incidence was determined for different ADRs. Results: 362 endoscopists performed 116 360 colonoscopies with a median ADR of 67%. In total, 209 interval PCCRCs were identified. The ADR was associated with interval PCCRC, with an adjusted hazard ratio of 0.95 (95% CI, 0.92 to 0.97) per 1% increase in ADR. For every 1000 patients undergoing colonoscopy, the expected number of interval PCCRC diagnoses after 5 years was approximately 2 for endoscopists with ADRs of 70%, compared with more than 2.5, almost 3.5, and more than 4.5 for endoscopists with ADRs of 65%, 60%, and 55%, respectively. Limitation: The relative short duration of follow-up (median, 52 months) could be considered a limitation. Conclusion: The ADR of endoscopists is inversely associated with the risk for interval PCCRC in FIT-positive colonoscopies. Endoscopists performing colonoscopy in FIT-based screening should aim for markedly higher ADRs compared with primary colonoscopy. Primary Funding Source: None.

QUAPAS: An Adaptation of the QUADAS-2 Tool to Assess Prognostic Accuracy Studies

Whereas diagnostic tests help detect the cause of signs and symptoms, prognostic tests assist in evaluating the probable course of the disease and future outcome. Studies to evaluate prognostic tests are longitudinal, which introduces sources of bias different from those for diagnostic accuracy studies. At present, systematic reviews of prognostic tests often use the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool to assess risk of bias and applicability of included studies because no equivalent instrument exists for prognostic accuracy studies. QUAPAS (Quality Assessment of Prognostic Accuracy Studies) is an adaptation of QUADAS-2 for prognostic accuracy studies. Questions likely to identify bias were evaluated in parallel and collated from QUIPS (Quality in Prognosis Studies) and PROBAST (Prediction Model Risk of Bias Assessment Tool) and paired to the corresponding question (or domain) in QUADAS-2. A steering group conducted and reviewed 3 rounds of modifications before arriving at the final set of domains and signaling questions. QUAPAS follows the same steps as QUADAS-2: Specify the review question, tailor the tool, draw a flow diagram, judge risk of bias, and identify applicability concerns. Risk of bias is judged across the following 5 domains: participants, index test, outcome, flow and timing, and analysis. Signaling questions assist the final judgment for each domain. Applicability concerns are assessed for the first 4 domains. The authors used QUAPAS in parallel with QUADAS-2 and QUIPS in a systematic review of prognostic accuracy studies. QUAPAS improved the assessment of the flow and timing domain and flagged a study at risk of bias in the new analysis domain. Judgment of risk of bias in the analysis domain was challenging because of sparse reporting of statistical methods.

Race, Genotype, and Azathioprine Discontinuation: A Cohort Study: Annals of Internal Medicine: Vol 175, No 8

Background: Thiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an ACKR1 variant (rs2814778-CC) is common among persons of African ancestries. Objective: To test whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing. Design: Retrospective cohort study. Setting: Two tertiary care centers. Patients: Thiopurine users with White or Black race. Measurements: Azathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted final dose, leukocyte count, and change in leukocyte count. Results: The rate of azathioprine discontinuation attributed to hematopoietic toxicity was 3.92 per 100 person-years among patients with the CC genotype (n = 101) and 1.34 per 100 person-years among those with the TT or TC genotype (n = 1365) (hazard ratio [HR] from competing-risk model, 2.92 [95% CI, 1.57 to 5.41]). The risk remained significant after adjustment for race (HR, 2.61 [CI, 1.01 to 6.71]). The risk associated with race alone (HR, 2.13 [CI, 1.21 to 3.75]) was abrogated by adjustment for genotype (HR, 1.13 [CI, 0.48 to 2.69]). Lower last leukocyte count and lower dosing were significant among patients with the CC genotype. Lower dosing was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukemia. The CC genotype was independently associated with lower 6-MP dose intensity relative to the target daily dose of 75 mg/m2 (median, 0.83 [IQR, 0.70 to 0.94] for the CC genotype vs. 0.94 [IQR, 0.72 to 1.13] for the TT or TC genotype; P = 0.013). Limitations: Unmeasured confounding; data limited to tertiary centers. Conclusion: Patients with the CC genotype had higher risk for azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine doses. Genotype was associated with those risks, even after adjustment for race. Primary Funding Source: National Institutes of Health.

Characteristics of High-Need, High-Cost Patients: A “Best-Fit” Framework Synthesis: Annals of Internal Medicine: Vol 175, No 12

Background: Accurately identifying high-need, high-cost (HNHC) patients to reduce their preventable or modifiable health care use for their chronic conditions is a priority and a challenge for U.S. policymakers, health care delivery systems, and payers. Purpose: To identify characteristics and criteria to distinguish HNHC patients. Data Sources: Searches of multiple databases and gray literature from 1 January 2000 to 22 January 2022. Study Selection: English-language studies of characteristics and criteria to identify HNHC adult patients, defined as those with high use (emergency department, inpatient, or total services) or high cost. Data Extraction: Independent, dual-review extraction and quality assessment. Data Synthesis: The review included 64 studies comprising multivariate exposure studies (n = 47), cluster analyses (n = 11), and qualitative studies (n = 6). A National Academy of Medicine (NAM) taxonomy was an initial “best-fit” framework for organizing the synthesis of the findings. Patient characteristics associated with being HNHC included number and severity of comorbid conditions and having chronic clinical conditions, particularly heart disease, chronic kidney disease, chronic lung disease, diabetes, cancer, and hypertension. Patients' risk for being HNHC was often amplified by behavioral health conditions and social risk factors. The reviewers revised the NAM taxonomy to create a final framework, adding chronic pain and prior patterns of high health care use as characteristics associated with an increased risk for being HNHC. Limitation: Little evidence distinguished potentially preventable or modifiable health care use from overall use. Conclusion: A combination of characteristics can be useful for identifying HNHC patients. Because of the complexity of their conditions and circumstances, improving their quality of care will likely also require an individualized assessment of care needs and availability of support services. Primary Funding Source: Agency for Healthcare Research and Quality. (PROSPERO: CRD42020161179)

The Role of Hemostatic Powder in Endoscopic Hemostasis of Nonvariceal Upper Gastrointestinal Bleeding

Spontaneous Ectopic Paraumbilical Variceal Bleeding in a Patient With Cirrhosis | Annals of Internal Medicine: Clinical Cases

Ectopic variceal hemorrhage is a rare sequela of portal hypertension, accounting for 5% of variceal bleeding events. Although mortality rates are high for this condition, there is no established management protocol. We present a patient case of spontaneous external hemorrhage from an ectopic paraumbilical varicosity in the setting of portal hypertension secondary to decompensated alcoholic cirrhosis that was treated effectively with transjugular intrahepatic portosystemic shunt placement.

A Rare Manifestation of Chronic Gastric Ischemia With Ulceration | Annals of Internal Medicine: Clinical Cases

We present the patient case of a woman with significant cardiovascular disease, chronic abdominal pain, and repeated episodes of gastrointestinal bleeding, who was ultimately diagnosed with chronic gastric ischemia with recurrent gastric ulcers. The current literature suggests that gastric ischemia is more common than previously thought. A higher degree of suspicion for this relatively rare presentation may be required in the clinical setting.

Hyperplastic Polyps Discovered Because of Unprovoked Acute Upper Gastrointestinal Bleeding as an Unusual Presentation of Malignancy | Annals of Internal Medicine: Clinical Cases

Gastric hyperplastic polyps are small (<1 cm), asymptomatic, and found incidentally on esophagogastroduodenoscopy. Patients can present with dyspepsia, abdominal pain, anemia from chronic occult bleeding, and, rarely, acute upper gastrointestinal bleeding. Helicobacter pylori, autoimmune gastritis, and long-term use of proton-pump inhibitors can increase the risk for hyperplastic polyps. Dysplasia and carcinoma in the surrounding gastric mucosa with concomitant hyperplastic polyps can be seen but carcinoma and dysplasia within the hyperplastic polyp itself are extremely rare. We report on a 70-year-old White woman who presented with melena from what appeared to be hyperplastic polyps on esophagogastroduodenoscopy, but pathology reported frank intramucosal adenocarcinoma.