Developing a PRogram to Educate and Sensitize Caregivers to Reduce the Inappropriate Prescription Burden in the Elderly with Alzheimer's Disease (D-PRESCRIBE-AD): Trial protocol and rationale of an open-label pragmatic, prospective randomized controlled trial.

CONTEXT: Potentially inappropriate prescribing of medications in older adults, particular those with dementia, can lead to adverse drug events including falls and fractures, worsening cognitive impairment, emergency department visits, and hospitalizations. Educational mailings from health plans to patients and their providers to encourage deprescribing conversations may represent an effective, low-cost, "light touch", approach to reducing the burden of potentially inappropriate prescription use in older adults with dementia. OBJECTIVES: The objective of the Developing a PRogram to Educate and Sensitize Caregivers to Reduce the Inappropriate Prescription Burden in Elderly with Alzheimer's Disease (D-PRESCRIBE-AD) trial is to evaluate the effect of a health plan based multi-faceted educational outreach intervention to community dwelling patients with dementia who are currently prescribed sedative/hypnotics, antipsychotics, or strong anticholinergics. METHODS: The D-PRESCRIBE-AD is an open-label pragmatic, prospective randomized controlled trial (RCT) comparing three arms: 1) educational mailing to both the health plan patient and their prescribing physician (patient plus physician arm, n = 4814); 2) educational mailing to prescribing physician only (physician only arm, n = 4814); and 3) usual care (n = 4814) among patients with dementia enrolled in two large United States based health plans. The primary outcome is the absence of any dispensing of the targeted potentially inappropriate prescription during the 6-month study observation period after a 3-month black out period following the mailing. Secondary outcomes include dose-reduction, polypharmacy, healthcare utilization, mortality and therapeutic switching within targeted drug classes. CONCLUSION: This large pragmatic RCT will contribute to the evidence base on promoting deprescribing of potentially inappropriate medications among older adults with dementia. If successful, such light touch, inexpensive and highly scalable interventions have the potential to reduce the burden of potentially inappropriate prescribing for patients with dementia. ClinicalTrials.gov Identifier: NCT05147428.

An Open-Source Framework for Mass Calculation of Antibody-Based Therapeutic Molecules.

Biotherapeutic masses are a means of verifying identity and structural integrity. Mass spectrometry (MS) of intact proteins or protein subunits provides an easy analytical tool for different stages of biopharmaceutical development. The protein's identity is confirmed when the experimental mass from MS is within a pre-defined mass error range of the theoretical mass. While several computational tools exist for the calculation of protein and peptide molecular weights, they either were not designed for direct application to biotherapeutic entities, have access limitations due to paid licenses, or require uploading protein sequences to host servers. We have developed a modular mass calculation routine that enables the easy determination of the average or monoisotopic masses and elemental compositions of therapeutic glycoproteins, including monoclonal antibodies (mAb), bispecific antibodies (bsAb), and antibody-drug conjugates (ADC). The modular nature of this Python-based calculation framework will allow the extension of this platform to other modalities such as vaccines, fusion proteins, and oligonucleotides in the future, and this framework could also be useful for the interrogation of top-down mass spectrometry data. By creating an open-source standalone desktop application with a graphical user interface (GUI), we hope to overcome the restrictions around use in environments where proprietary information cannot be uploaded to web-based tools. This article describes the algorithms and application of this tool, mAbScale, to different antibody-based therapeutic modalities.

Pragmatic guidance for embedding pragmatic clinical trials in health plans: Large simple trials aren't so simple.

BACKGROUND: There are unique opportunities related to the design and conduct of pragmatic trials embedded in health insurance plans, which have longitudinal data on member/patient demographics, dates of coverage, and reimbursed medical care, including prescription drug dispensings, vaccine administrations, behavioral healthcare encounters, and some laboratory results. Such trials can be large and efficient, using these data to identify trial-eligible patients and to ascertain outcomes. METHODS: We use our experience primarily with the National Institutes of Health Pragmatic Trials Collaboratory Distributed Research Network, which comprises health plans that participate in the US Food & Drug Administration's Sentinel System, to describe lessons learned from the conduct and planning of embedded pragmatic trials. RESULTS: Information is available for research on more than 75 million people with commercial or Medicare Advantage health plans. We describe three studies that have used or plan to use the Network, as well as a single health plan study, from which we glean our lessons learned. CONCLUSIONS: Studies that are conducted in health plans provide much-needed evidence to drive clinically meaningful changes in care. However, there are many unique aspects of these trials that must be considered in the planning, implementation, and analytic phases. The type of trial best suited for studies embedded in health plans will be those that require large sample sizes, simple interventions that could be disseminated through health plans, and where data available to the health plan can be leveraged. These trials hold potential for substantial long-term impact on our ability to generate evidence to improve care and population health.

Effect of Mailing Educational Material to Patients With Atrial Fibrillation and Their Clinicians on Use of Oral Anticoagulants: A Randomized Clinical Trial.

Importance: Only about half of patients with atrial fibrillation (AF) who are at increased risk for stroke are treated with an oral anticoagulant (OAC), despite guideline recommendations for their use. Educating patients with AF about prevention of stroke with OACs may enable them as agents of change to initiate OAC treatment. Objective: To determine whether an educational intervention directed to patients and their clinicians stimulates the use of OACs in patients with AF who are not receiving OACs. Design, Setting, and Participants: The Implementation of a Randomized Controlled Trial to Improve Treatment With Oral Anticoagulants in Patients With Atrial Fibrillation (IMPACT-AFib) trial was a prospective, multicenter, open-label, pragmatic randomized clinical trial conducted from September 25, 2017, to May 1, 2019, embedded in health plans that participate in the US Food and Drug Administration's Sentinel System. It used the distributed database comprising health plan members to identify eligible patients, their clinicians, and outcomes. IMPACT-AFib enrolled patients with AF, a CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point] or ≥75 years [2 points], diabetes, and stroke, transient ischemic attack or thromboembolism [2 points]-vascular disease, and sex category [female]) score of 2 or more, no evidence of OAC prescription dispensing in the preceding 12 months, and no hospitalization-related bleeding event within the prior 6 months. Interventions: Randomization to a single mailing of patient and/or clinician educational materials vs control. Main Outcomes and Measures: Analysis was performed on a modified intention-to-treat basis. The primary end point was the proportion of patients with at least 1 OAC prescription dispensed or at least 4 international normalized ratio test results within 1 year of the intervention. Results: Among 47 333 patients, there were 24 909 men (52.6%), the mean (SD) age was 77.9 (9.7) years, mean (SD) CHA2DS2-VASc score was 4.5 (1.7), 22 404 patients (47.3%) had an ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score of 5 or more, and 8890 patients (18.8%) had a history of hospitalization for bleeding. There were 2328 of 23 546 patients (9.9%) in the intervention group with initiation of OAC at 1 year compared with 2330 of 23 787 patients (9.8%) in the control group (adjusted OR, 1.01 [95% CI, 0.95-1.07]; P = .79). Conclusions and Relevance: Among a large population with AF with a guideline indication for OACs for stroke prevention who were randomized to a mailed educational intervention or to usual care, there was no clinically meaningful, numerical, or statistically significant difference in rates of OAC initiation. More-intensive interventions are needed to try and address the public health issue of underuse of anticoagulation for stroke prevention among patients with AF. Trial Registration: ClinicalTrials.gov Identifier: NCT03259373.

Identifying prescribing cascades in Alzheimer's disease and related dementias: The calcium channel blocker-diuretic prescribing cascade.

PURPOSE: Prescribing cascades occur when a physician prescribes a new drug to address the side-effect of another drug. Persons with Alzheimer's disease and related dementias (ADRD) are at increased risk for prescribing cascades. Our objective was to develop an approach to estimating the proportion of calcium channel blocker-diuretic (CCB-diuretic) prescribing cascades among persons with ADRD in two U.S. health plans. METHODS: We identified patients aged ≥50 on January 1, 2017, dispensed a drug to treat ADRD in the 365-days prior to/on cohort entry date. Patients had medical/pharmacy coverage for 1 year before and through cohort entry. We excluded individuals with an institutional stay encounter in the 45 days prior to cohort entry and censored patients based on: disenrollment from coverage, death, or end of data. We identified incident and prevalent CCB use in the 183-days following cohort entry, and identified subsequent incident diuretic use among incident and prevalent CCB-users within 365-days from cohort entry. RESULTS: There were 121 538 eligible patients. Approximately 62% were female, with a mean age of 79.5 (SD ±8.6). Overall 2.1% of the cohort experienced a prevalent CCB-diuretic prescribing cascade with 1586 incident diuretic-users among 36 462 prevalent CCB-users (4.3%, 95% CI 4.1-4.6%]); and there were161 incident diuretic-users among 3304 incident CCB-users (4.9%, 95% CI 4.2-5.7%) (incident CCB-diuretic cascade). CONCLUSIONS: We describe an approach to identify prescribing cascades in persons with ADRD, which can be used to assess the proportion of prescribing cascades in large cohorts. We determined the proportion of CCB-diuretic prescribing cascades was low.

Antidopaminergic-Antiparkinsonian Medication Prescribing Cascade in Persons with Alzheimer's Disease.

OBJECTIVES: Persons living with Alzheimer's disease (AD) may be at increased risk for prescribing cascades due to greater multimorbidity, polypharmacy, and the need for more complex care. Our objective was to assess the proportion of the antidopaminergic-antiparkinsonian medication prescribing cascades among persons living with Alzheimer's disease. SETTING: Two large administrative claims databases in the United States. PARTICIPANTS: We identified patients aged ≥50 on January 1, 2017, who were dispensed a drug used to treat Alzheimer's disease for at least 1 day in the 365 days prior to or on cohort entry date and who had medical and pharmacy coverage in the 365 days prior to the cohort entry date. We excluded individuals with a recent institutional stay. We identified incident antidopaminergic (antipsychotic/metoclopramide) use in the 183 days following cohort entry and identified subsequent incident antiparkinsonian drug use within 8 to 365 days. RESULTS: There were 121,538 patients with Alzheimer's disease eligible for inclusion. Approximately 62% were women with a mean age of 79.5 (SD ± 8.6). The mean number of drugs dispensed was 9.2 (SD ± 4.9). There were 36 incident antiparkinsonian users among 4,534 incident antipsychotic/metoclopramide users (0.8%). CONCLUSION: We determined that the proportion of antidopaminergic-antiparkinsonian medication prescribing cascades, widely considered as high-priority, was low. Our approach can be used to assess the proportion of prescribing cascades in populations considered to be at high risk and to prioritize system-level interventional efforts to improve medication safety in these patients.

Underuse of oral anticoagulants in privately insured patients with atrial fibrillation: A population being targeted by the IMplementation of a randomized controlled trial to imProve treatment with oral AntiCoagulanTs in patients with Atrial Fibrillation (IMPACT-AFib).

BACKGROUND: Many studies showing underuse of oral anticoagulants (OACs) in patients with atrial fibrillation (AF) predated the advent of the non-vitamin K antagonist OACs. We retrospectively examined use of OACs in a large commercially insured population. METHODS: Administrative claims data from 4 research partners participating in FDA-Catalyst, a program of the Sentinel Initiative, were queried in September 2017. Patients were included if they were ≥30 years old with ≥365 days of medical/pharmacy coverage, and had ≥2 diagnosis codes for AF, a CHA2DS2-VASc score ≥2, absence of contraindications to OAC use, and no evidence of OAC use in the 365 days before the index AF diagnosis. The main outcome measures of the current analysis were rates of OAC use in the prior 12 months of cohort identification and factors associated with non-use. RESULTS: A total of 197,806 AF patients met the eligibility criteria prior to assessment of OAC treatment. Of these, 179,580 (91%) patients were ≥65 years old and 73,286 (37%) patients were ≥80 years old. Half of the patients (98,903) were randomized to the early intervention arm in the IMPACT-AFib trial and constitute the cohort for this analysis. Of these, 32,295 (33%) had no evidence of OAC use in the prior 12 months. Compared with patients with evidence of OAC use in the prior 12 months, patients without OAC use were more likely to be ≥80 years old, women, and have a history of anemia (51% vs 47%) and less likely to have diabetes (41% vs 44%), history of stroke or TIA (15% vs 19%), and history of heart failure (39% vs 48%). CONCLUSIONS: Despite a high risk of stroke, one-third of privately insured patients with AF and no obvious contraindications to an OAC were not treated with an OAC. There is an unmet need for evidence-based interventions that could lead to greater use of OACs in patients with AF at risk for stroke.

FDA-Catalyst-Using FDA's Sentinel Initiative for large-scale pragmatic randomized trials: Approach and lessons learned during the planning phase of the first trial.

BACKGROUND: The US Food and Drug Administration's Sentinel Initiative is well positioned to support pragmatic clinical trials. FDA-Catalyst combines direct contact with health plan members and/or providers with data in the Sentinel infrastructure. Here, we describe the rationale, feasibility analyses, and lessons learned from the planning phase of the first large pragmatic trial conducted using the Sentinel Initiative's delivery system capabilities-IMplementation of a randomized controlled trial to imProve treatment with oral AntiCoagulanTs in patients with Atrial Fibrillation (the IMPACT-AFib trial). METHODS: During the planning phase, we convened representatives from five commercial health plans, FDA, study coordinating centers, and a patient representative for protocol development, institutional review board preparation, and other activities. Administrative claims data from the plans were included in a retrospective cohort analysis to assess sample size for the trial. Members ≥30 years old with ≥365 days of medical/pharmacy coverage, ≥2 diagnosis codes for atrial fibrillation, a guideline-based indication for oral anticoagulant use for stroke prevention, and no evidence of oral anticoagulant use in the 365 days prior to the index atrial fibrillation diagnosis in 2013 were included. Exclusions for the analysis included other conditions requiring anticoagulation, history of intracranial hemorrhage, and gastrointestinal bleed. We calculated rates of oral anticoagulant use, transient ischemic attack or stroke, and bleeding in the 365 days following the index atrial fibrillation diagnosis. RESULTS: A total of 44,786 members with atrial fibrillation with no evidence of recent oral anticoagulant use were identified. In total, 87% (n = 38,759) were classified as having a guideline-based indication for oral anticoagulants. Of those, 33% (n = 12,867) had a new oral anticoagulant dispensed during the following year, 15% (n = 5917) were hospitalized for stroke or transient ischemic attack, and 9% (n = 3469) for bleeding events. This information was used to develop the trial protocol including sample size, power calculations, and level of randomization. CONCLUSION: Sentinel infrastructure generated preliminary data that supported planning and implementation of a large pragmatic trial embedded in health plans. This planning identified unanticipated challenges that must be addressed in similar trials.

Impact of certified CME in atrial fibrillation on administrative claims.

OBJECTIVE: To determine whether changes in physician behavior associated with a continuing medical education (CME) activity on atrial fibrillation (AF) can be measured using an administrative claims database. STUDY DESIGN: A retrospective, analytical review of physician practice changes and AF patient- related healthcare utilization and costs derived from an administrative claims database was performed on a cohort of Humana health system physicians. METHODS: The Humana physicians participated in a specified CME activity on the management of patients with AF. Treatment patterns of these providers and clinical outcomes of a cohort of established AF patients were compared 6 months before and 6 months after physician participation in the AF CME activity. RESULTS: Analysis of administrative claims data from Humana providers who participated in an AF CME activity and their patients demonstrated a significant reduction in AF-related healthcare costs and utilization, including decreased length of stay. Humana providers, in addition to the other CME activity participants, demonstrated significant gains in knowledge of evidence-based care strategies when presented with real-world scenarios of patients with AF. CONCLUSIONS: The use of administrative claims data is an innovative way of measuring the effectiveness of CME. These observations support the need for further investigation into the drivers of change in patient outcomes that may be associated with CME activities, as well as the utility of healthcare claims data as a possible valid measure of the impact of CME on physician performance and patient outcomes.

A systematic review of validated methods for identifying ventricular arrhythmias using administrative and claims data.

BACKGROUND: Drug-induced pro-arrhythmia is a serious and unexpected event. Large administrative and claims databases can potentially identify drugs or interactions leading to cardiac arrhythmias. The purpose of this study is to evaluate the evidence supporting the validity of algorithms or codes to identify ventricular arrhythmias using administrative and claims data. METHODS: A search of MEDLINE database is supplemented by manual searches of bibliographies of key relevant articles. We selected all studies in which an administrative and claims data algorithm or code was validated against a medical record. We report the positive predictive value (PPV) for ICD-9 codes compared to medical records. RESULTS: Our search strategy yielded 664 studies, of which only seven met our eligibility criteria. Two additional studies were identified by peer reviewers. The most commonly included databases were Medicare and Medicaid, and the most commonly evaluated ICD-9 codes were 426.x and 427.x. The individual use of ICD-9 codes 427.x yielded a high PPV (78%-100%). The highest PPV was seen when both ICD-9 codes 427.x and 798.x were used (92%). The same codes yielded the highest PPV when found in the principal diagnosis position (100%). CONCLUSIONS: The use of ICD-9 codes 427.x, alone or in combination with code 798.x, in the principal position is appropriate for the identification of ventricular arrhythmias in administrative and claims databases.

A systematic review of validated methods for identifying venous thromboembolism using administrative and claims data.

BACKGROUND: Venous thromboembolism (VTE) is a serious complication. Large claims databases can potentially identify the effects that medications have on VTE. The purpose of this study is to evaluate the evidence supporting the validity of VTE codes. METHODS: A search of MEDLINE database is supplemented by manual searches of bibliographies of key relevant articles. We selected all studies in which a claim code was validated against a medical record. We reported the positive predictive value (PPV) for the VTE claim compared to the medical record. RESULTS: Our search strategy yielded 345 studies, of which only 19 met our eligibility criteria. All of the studies reported on ICD-9 codes, but only two studies reported on pharmacy codes, and one study reported on procedure codes. The highest PPV (65%-95%) was reported for the combined use of ICD-9 codes 415 (pulmonary embolism), 451, and 453 (deep vein thrombosis) as a VTE event. If a specific event like DVT (PPV 24%-92%) or PE (PPV 31%-97%) was evaluated, the PPV was lower than when the combined events were examined. Studies that included patients after orthopedic surgery reported the highest PPV (96%-100%). CONCLUSIONS: The use of ICD-9 415, 451, and 453 are appropriate for the identification of VTE in claims databases. The codes performed best when codes were evaluated in patients at higher risk of VTE.

Social integration and health behavioral change in San Luis, Honduras.

This study explores the effects of social integration on behavioral change in the course of an intensive, community-based public health intervention. The intervention trained volunteers and mobilized local organizations to promote 16 key family health practices in rural San Luis, Honduras, during 2004 to 2006. A mixed methods approach is used. Standard household sample surveys were performed in 22 villages before and after the intervention. Eight villages were then resurveyed. A household survey, focus groups, and key informant interviews measured health behaviors and several social structural and psychosocial variables. The villages were then ranked on their mean behavioral and social integration scores. The quantitative and qualitative rankings were in close agreement (Kendall's coefficient of concordance = .707, p < .001). Behaviors changed most markedly in the villages where respondents participated in local organizations, observed that others performed those behaviors, and depended on their neighbors for support. The results show that social integration conditions health behavioral change. Health interventions can be made more effective by analyzing these features a priori.

The health benefits of social mobilization: experiences with community-based Integrated Management of Childhood Illness in Chao, Peru and San Luis, Honduras.

This article reviews the implementation of the community component of the Integrated Management of Childhood Illness (IMCI) strategy in Chao, Peru (2001 to 2004) and San Luis, Honduras (2003 to 2005). An evaluation was conducted in 2005 and included a project documentation review, key-informant interviews, and a household level baseline and follow-up survey of the WHO/UNICEF key family practices in each intervention site. The promotion of the key family practices in Chao and San Luís demonstrated measurable success. In comparison with the initial survey in 2002, the percentage of participant mothers ( N = 78) in Chao in 2004 who knew that they should breastfeed exclusively for at least six months increased from 33% to 94%; the presentation of complete vaccination records for one-year-old children increased by 19%; the recognition of danger signs for pneumonia increased 18% and for diarrhea by 8%; and the percentage of mothers who received four or more prenatal check-ups increased by 25%. A dramatic reduction in malaria cases was also attributed to the intervention in Chao. In San Luis, a quasi-experimental, random household sample ( N = 300) showed that the incidence of diarrheal disease among children under five years old declined by 18% between survey rounds (from 44% in August 2004 to 26% in December 2005). Social mobilization has promoted inter-sector consensus-building around community health issues, especially those related to maternal and child health. The promotion of the participation of representatives from various organizations via the community IMCI social-actor methodology has led to increased civic cooperation. Positive changes in health behaviors have been documented through an increase in preventive health practices, greater demand for primary health care services, and concrete community actions to improve public health.

The health benefits of social mobilization: experiences with community-based Integrated Management of Childhood Iliness in Chao, Peru and San Luis, Honduras

This article reviews the implementation of the community component of the Integrated Management of Childhood Illness (IMCI) strategy in Chao, Peru (2001 to 2004) and San Luis, Honduras (2003 to 2005). An evaluation was conducted in 2005 and included a project documentation review, key informant interviews, and a household level baseline and follow up survey of the WHO UNICEF key family practices in each intervention site. The promotion of the key family practices in Chao and San Lu is demonstrated measurable success. In comparison with the initial survey in 2002, the percentage of participant mothers (N equal 78) in Chao in 2004 who knew that they should breastfeed exclusively for at least six months increased from 33 percent to 94 percent; the presentation of complete vaccination records for one year old children increased by 19 percent; the recognition of danger signs for pneumonia increased 18 percent and for diarrhea by 8 percent; and the percentage of mothers who received four or more prenatal check-ups increased by 25 percent. A dramatic reduction in malaria cases was also attributed to the intervention in Chao. In San Luis, a quasi experimental, random household sample (N equal 300) showed that the incidence of diarrheal disease among children under five years old declined by 18 percent between survey rounds (from 44 percent in August 2004 to 26 percent in December 2005). Social mobilization has promoted inter sector consensus building around community health issues, especially those related to maternal and child health. The promotion of the participation of representatives from various organizations via the community IMCI social actor methodology has led to increased civic cooperation. Positive changes in health behaviors have been documented through an increase in preventive health practices, greater demand for primary health care services, and concrete community actions to improve public health. (AU)