Contemporary Challenges in Polycythemia Vera Management From the Perspective of Patients and Physicians.

Although polycythemia vera (PV) is a chronic and incurable disease, effective management can allow most patients to maintain functional lives with near-normal life expectancy. However, there remain several inter-related factors that contribute to many ongoing challenges associated with the management of PV, which this review aims to explore. First, as a disease hallmarked by constitutive activation of the JAK/STAT pathway, PV is often accompanied by inflammatory symptoms that negatively impact quality of life. Next, patients often require recurrent therapeutic phlebotomies to maintain their hematocrit below the 45% threshold that has been associated with a decreased risk of thrombotic events. The need to closely monitor hematocrit and perform conditional therapeutic phlebotomies ties patients to the healthcare system, thereby limiting their autonomy. Furthermore, many patients describe therapeutic phlebotomies as burdensome and the procedure is often poorly tolerated, further contributing to quality-of-life decline. Phlebotomy needs can be reduced by utilizing cytoreductive therapy; however, standard first-line cytoreductive options (i.e., hydroxyurea and interferon) have not been shown to significantly improve symptom burden. Collectively, current PV management, while reducing thrombotic risk, often has a negative impact on patient quality of life. As researchers continue to advance towards the goal of developing a disease-modifying therapy for patients with PV, pursuit of nearer-term opportunities to shift the current treatment paradigm towards improving symptoms without compromising quality of life is also warranted, for example, by reducing or eliminating the frequent use of phlebotomy.

Frequency and clinicoeconomic impact of delays to definitive diagnosis of obstructive hypertrophic cardiomyopathy in the United States.

AIMS: The diagnostic history in the years leading up to the definitive diagnosis of patients with obstructive hypertrophic cardiomyopathy (HCM) has not been studied. METHODS: Patients with a delay in the definitive diagnosis of obstructive HCM from January 2009 to March 2019 were identified in the US IBM MarketScan Commercial and Medicare Supplemental Databases if they had an alternative diagnosis indicating a misdiagnosis during the 24 months before the definitive obstructive HCM diagnosis. Resource use and costs associated with the delay were estimated during the same period. RESULTS: Of 3,888 eligible patients with obstructive HCM, 59.5% had a delay in definitive diagnosis. Patients received a mean of 4.0 misdiagnoses before the definitive obstructive HCM diagnosis, most of which were other cardiovascular conditions. Consequently, 15.7% of patients may have received inappropriate treatment. Approximately 78.4% of patients visited a cardiologist (mean 4.7 visits) before the definitive obstructive HCM diagnosis. Additionally, 26.8% and 32.1% of patients had an inpatient and emergency room visit, respectively. Annualized healthcare costs associated with the delay were $4,379 per patient. LIMITATIONS: The current study used administrative claims data for a commercially insured population. Therefore, the results may not be generalizable to other populations (e.g. those insured by Medicare or Medicaid and the uninsured). Like other database studies, the current study may have suffered from miscoding or undercoding, which may have caused misclassification of patients. Owing to insufficient data, the study could not evaluate all potential consequences of a delay in definitive diagnosis. CONCLUSIONS: Most patients with obstructive HCM had a delay of ≤ 2 years before receiving the definitive diagnosis. The diagnostic journey involved multiple potential misdiagnoses, predominantly cardiovascular, as well as a substantial clinical and economic burden on patients and the healthcare system.

Clinical Outcomes, Resource Utilization, and Treatment Over the Disease Course of Symptomatic Obstructive Hypertrophic Cardiomyopathy in the United States.

We sought to describe the clinical outcomes, resource utilization, and treatment options for patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) over the course of their disease. Adults with obstructive HCM who were symptomatic were identified from the IBM MarketScan Commercial and Medicare supplemental database (January 2009 to March 2019). The index date was the initial obstructive HCM diagnosis date. Patients were required to have ≥12-month continuous eligibility before and after the index date. Incidence rates (IRs) and cumulative risk of cardiovascular events, healthcare resource utilization, and pharmacotherapy were assessed after index and compared with matched controls. Among 4,617 eligible patients with obstructive HCM, 2,917 (63.2%, mean age 60, 47.2% women) were symptomatic at index date. The most common cardiovascular events were atrial fibrillation/flutter (IR:1.421 per person-year [PPY], heart failure (IR: 0.895 PPY), and dyspnea (IR:0.797 PPY). Patients incurred higher resource use with frequent tests and monitoring, hospitalizations (0.454 PPY), and emergency room visits (0.611 PPY). The use of pharmacotherapy increased from 61.2% in the 6-month preindex period to 83.9% in the 6-month postindex period and remained stable after diagnosis. These events ranged from 3 to over 60-fold higher compared with controls, with the largest difference observed in arrhythmic events. The majority of patients were symptomatic at the time of obstructive HCM diagnosis, resulting in significantly increased cardiovascular complications and frequent disease monitoring after diagnosis versus controls. In conclusion, healthcare resource utilization was substantial, and these findings suggest a higher clinical and economic burden over the disease course among patients with symptomatic obstructive HCM, despite current treatment.

Validation of the Kansas City Cardiomyopathy Questionnaire in Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: The primary goal for treating patients with obstructive hypertrophic cardiomyopathy (oHCM) is to improve their symptoms, function, and quality of life. Although the Kansas City Cardiomyopathy Questionnaire (KCCQ) is a valid, reliable, and sensitive measure for other etiologies of heart failure, its appropriateness for patients with oHCM is unknown. OBJECTIVES: The purpose of this study was to establish the interpretability, validity, reliability, and responsiveness of the KCCQ in patients with oHCM. METHODS: Cognitive debriefing of the KCCQ was performed in 26 patients with oHCM. The validity, reliability, responsiveness, and interpretability of the KCCQ were tested in 196 participants from the EXPLORER-HCM trial by comparing each scale with relevant comparators, describing the internal reliability and the mean change in stable patients, and comparing the mean change in patients who reported different degrees of clinical change using a patient-reported global impression of change (PGIC). RESULTS: All KCCQ domains demonstrated strong correlations with external standards of symptoms, function, social limitation, and quality of life, including a recently designed instrument measuring symptoms not captured by the KCCQ (P < 0.0001 for all). Mean changes in stable patients were nonsignificant, ranging from 0.21 to 2.3 points (P > 0.30 for all), with high intraclass correlation coefficients. The mean changes in patients with small, moderate, and large clinical changes were consistent with the 5-, 10-, and 20-point mean differences observed in other etiologies of heart failure. CONCLUSIONS: The KCCQ is well understood by patients with oHCM and has strong evidence of good psychometric performance. It can not only serve as a relevant endpoint in clinical trials of oHCM therapy, but may also prove useful in the clinical care of patients with oHCM. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [EXPLORER-HCM]; NCT03470545).

Longitudinal Psychometric Analysis of the Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) Using Outcomes from the Phase III EXPLORER-HCM Trial.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) symptoms include shortness of breath (SOB), fatigue, chest pain, palpitations, dizziness, and fainting. The HCM Symptom Questionnaire (HCMSQ), the only patient-reported outcome instrument designed to specifically measure HCM symptoms, yields four domain scores (SOB, tiredness, cardiovascular symptoms, syncope) and a total score. We evaluated the longitudinal psychometric properties of the HCMSQ using baseline to week 30 data from the phase III EXPLORER-HCM trial (NCT03470545). METHODS: Test-retest reliability was assessed via intraclass correlation of patients with stable Patient Global Impression of Change (PGIC) and Patient Global Impression of Severity (PGIS) responses. Sensitivity to change was assessed via Spearman correlations with the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) and the EuroQoL visual analogue scale (EQ VAS), and via one-way ANOVA comparing change groups defined on clinical (New York Heart Association [NYHA] class, left ventricular outflow tract [LVOT] gradient, peak oxygen consumption [pVO2]) and patient-reported (PGIS, PGIC) variables. Meaningful change thresholds were established via PGIC/PGIS. RESULTS: All HCMSQ scores showed strong evidence of test-retest reliability (intraclass correlation coefficient > 0.70). Sensitivity to change was demonstrated with mostly strong/moderate correlations with KCCQ-23 and EQ VAS, and significant differences (p ≤ 0.05) in PGIS, PGIC, pVO2, and NYHA (except tiredness domain) change categories, but not LVOT gradient. Clinically meaningful score reductions were ≥1 point for tiredness and cardiovascular symptoms domains, ≥ 2.5 points for SOB domain, and ≥2 points for total score. CONCLUSIONS: Results suggest that HCMSQ is fit for purpose in capturing HCM symptoms and may provide evidence of treatment benefit from the patients' perspectives.

Treatment Changes, Healthcare Resource Utilization, and Costs Among Patients with Symptomatic Obstructive Hypertrophic Cardiomyopathy: A Claims Database Study.

INTRODUCTION: There is limited evidence on therapies for obstructive hypertrophic cardiomyopathy (HCM), and data regarding treatment patterns and cost are scarce. This study assessed treatment patterns and economic outcomes in patients with symptomatic obstructive HCM. METHODS: Adults with symptomatic obstructive HCM as per study design and treated with pharmacotherapies [beta blockers (BBs), calcium channel blockers (CCBs), BB + CCB, or disopyramide] or procedures (septal reduction therapy, heart transplantation, implantable cardioverter-defibrillator, and pacemaker implantation) were identified from the IBM® MarketScan® Commercial and Medicare Supplemental database (January 2009-March 2019). Patients had 12-month continuous eligibility before and after (study period) treatment initiation (index treatment). Healthcare resource utilization (HRU), costs, and treatment changes were assessed. RESULTS: Of the 4883 patients included in the analysis, 85% received pharmacotherapies (BB 52.5%; CCB 11.7%; BB + CCB 17.7%; disopyramide 2.4%) and 15.7% underwent procedures. During the study period, 38, 34, and 100% of all patients had ≥ 1 inpatient stay, emergency room (ER) visit, and outpatient visit, respectively; mean total healthcare costs were US$53,053. Patients undergoing procedures had the highest HRU and costs across groups. Among patients receiving pharmacotherapies, HRU was lowest with BBs and highest with disopyramide. Treatment changes were observed in 43.8% of patients receiving pharmacotherapies. CONCLUSIONS: Patients experienced high rates of treatment changes, and the economic burden associated with symptomatic obstructive HCM increased as therapy escalated. More effective therapies are needed to stabilize or decrease the economic burden of obstructive HCM.

Assessing health-related quality-of-life in patients with symptomatic obstructive hypertrophic cardiomyopathy: EQ-5D-based utilities in the EXPLORER-HCM trial.

AIMS: To assess the effects of mavacamten on health-related quality-of-life (HRQoL) in symptomatic obstructive hypertrophic cardiomyopathy (HCM) and estimate health utilities by New York Heart Association (NYHA) functional class. MATERIALS AND METHODS: Patients with symptomatic obstructive HCM were randomized to 30 weeks of mavacamten or to placebo treatment, with or without beta-blocker or calcium channel blocker monotherapy, in EXPLORER-HCM (ClinicalTrials.gov identifier: NCT03470545). Health utility was measured using the EuroQoL 5-dimension 5-level (EQ-5D-5L) index score with the US value set. The 30-week changes in EQ-5D-5L index score and EuroQoL visual analog scale (EQ-VAS) score were compared between the two arms using linear regression, and the proportions of patients with a meaningful improvement were compared using logistic regression. The meaningful change thresholds were estimated using both distribution- and anchor-based approaches. Mean utilities by NYHA class were estimated for each arm using a generalized estimating equation. RESULTS: Compared with placebo (N = 89), patients receiving mavacamten (N = 96) had significantly greater 30-week improvement in EQ-5D-5L index score (mavacamten = 0.084; placebo = 0.009; adjusted difference = 0.073 [95% confidence interval = 0.027-0.118]) and EQ-VAS score (mavacamten = 8.5; placebo = 0.7; adjusted difference = 7.5 [95% confidence interval = 1.8-13.2]), and a significantly higher proportion of these patients showed meaningful improvement in EQ-5D-5L index score and EQ-VAS score. Both outcomes were correlated with the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS) and HCM Symptom Questionnaire Shortness-of-Breath (HCMSQ SoB) subscore, two patient-reported anchor variables. Additionally, mean utilities significantly decreased with higher NYHA functional class (values for NYHA class I, II, and III/IV - mavacamten = 0.950, 0.866, and 0.708; placebo = 0.952, 0.850, and 0.704). CONCLUSIONS: Compared with placebo, mavacamten significantly improved EQ-5D-5L index score and EQ-VAS score - and thus HRQoL - among patients with symptomatic obstructive HCM. Patients with a higher NYHA functional class had a lower health utility value.

Projecting the Long-term Clinical Value of Mavacamten for the Treatment of Obstructive Hypertrophic Cardiomyopathy in the United States: An Assessment of Net Health Benefit.

PURPOSE: The aim of the study was to project the long-term net health benefits of mavacamten for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM) in the United States. METHODS: A Markov model with 4 mutually exclusive health states (New York Heart Association [NYHA] functional classes I, II, and III/IV and death) was developed to project the life-years (LYs) and quality-adjusted life-years (QALYs) over a lifetime horizon for patients with symptomatic obstructive HCM receiving mavacamten with or without ß-blocker (BB) or calcium channel blocker (CCB) monotherapy or placebo with or without BB or CCB monotherapy. The model simulated a patient cohort with a starting age of 59 years and 41% women. Transition probabilities across NYHA functional classes were estimated using data from the Phase III Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy (EXPLORER-HCM) and the EXPLORER long-term extension (EXPLORER-LTE) cohort from the Long-term Safety Extension Study of Mavacamten in Adults who Have Completed MAVERICK-HCM or EXPLORER-HCM (MAVA-LTE) trial and were extrapolated after week 30. The mortality risks of NYHA functional class I were assumed to be the age- and sex-specific mortality risks of the US general population. The mortality risks for NYHA class II and III/IV were estimated using those for class I in conjunction with the relative mortality risks derived using patients with obstructive HCM from a large real-world registry. Health state utilities for each treatment were estimated from EXPLORER-HCM. Both LYs and QALYs were aggregated over a lifetime for each treatment arm, discounted at 3% annually, and compared between the 2 arms. Sensitivity analyses were conducted to evaluate the robustness of the model findings. FINDINGS: Over a lifetime, treatment with mavacamten with or without BB or CCB monotherapy was associated with 3.67 incremental LYs compared with placebo with or without BB or CCB monotherapy (13.00 vs 9.33 LYs). Compared with individuals in the placebo group, patients in the mavacamten group were projected to spend 6.17 additional LYs in NYHA functional class I and 0.04 and 2.46 fewer LYs in NYHA functional classes II and III/IV, respectively. With utilities incorporated, mavacamten with or without BB or CCB monotherapy was associated with 4.17 additional QALYs compared with placebo with or without BB or CCB monotherapy (11.74 vs 7.57 QALYs). In the sensitivity analyses, incremental benefits ranged from 1.55 to 6.21 LYs and from 2.48 to 6.19 QALYs across the scenarios. IMPLICATIONS: This model projected substantial net health benefits associated with mavacamten for symptomatic obstructive HCM owing to improved patient survival and quality of life. The projected QALY gain underscored the likely long-term clinical value of mavacamten in symptomatic obstructive HCM.

Clinical and economic burden of obstructive hypertrophic cardiomyopathy in the United States.

AIMS: Obstructive hypertrophic cardiomyopathy (oHCM) is a disease of the cardiomyocyte in which dynamic left ventricular outflow track obstruction may lead to heart failure, valvular disease, and sudden death. Little is known about healthcare resource utilization (HRU) and costs associated with oHCM. This study investigated the clinical and economic burden of oHCM in patients with or without symptoms associated with oHCM. METHODS: We used the US IBM MarketScan Commercial and Medicare Supplemental database to identify patients with oHCM (January 2009-March 2019). Control patients without cardiomyopathy were matched to each patient with oHCM based on age, sex, region, and index year (3:1 ratio). One-year HRU and cost data were compared between all oHCM, symptomatic oHCM, and asymptomatic oHCM subgroups, and their respective controls. RESULTS: Among 11,401 eligible patients with oHCM (mean age 57 years, 42% female), 5,667 (50%) were symptomatic (23% chest pain, 57% dyspnea, 29% fatigue, 17% syncope). oHCM was associated with significant increases in all-cause hospitalizations, hospital days, outpatient visits, and total healthcare costs (mean ± standard deviation: $26,929 ± 77,720 vs. $6,808 ± 25,712, p<.001) compared with matched controls. These differences were driven mainly by the clinical and economic burden of symptomatic oHCM, which was associated with significant increases in 1-year hospitalization rates (38.0 vs. 6.9%), hospital days (3.7 ± 9.9 vs. 0.4 ± 3.0), and total healthcare costs ($43,586 ± 103,756 vs. $6,768 ± 27,618; all p<.001). Adjustment for comorbidities had minimal impact on these differences. LIMITATIONS: The use of claims data relies on International Classification of Diseases (ICD-9 and ICD-10) diagnosis codes, which might be inaccurate. Only commercially insured patients were included. CONCLUSION: In a real-world population, oHCM was associated with substantial increases in HRU and incremental costs of ∼$20,000/year when compared with matched controls-a difference that increased to ∼$35,000/year among symptomatic patients. Further studies are warranted to understand the potential impact of specific therapies on HRU and the economic burden of oHCM.

PLAIN LANGUAGE SUMMARYObstructive hypertrophic cardiomyopathy (oHCM) is a medical condition in which the heart muscle becomes abnormally thick and can cause partial blockage of blood flow out of the heart. Some patients experience symptoms (such as shortness of breath, chest pain, and fatigue) from this condition while others do not. Little is known about the healthcare resource utilization (HRU) and costs associated with oHCM, and if there are any differences between patients with oHCM who experience symptoms versus those who are asymptomatic. Therefore, we performed a study to investigate the clinical and economic burden of oHCM in patients with or without symptoms associated with oHCM. Based on insurance claims data, ∼50% of all patients with diagnosed oHCM are symptomatic. Symptomatic patients experience nearly 8 times as many hospitalizations and cost the healthcare system >$35,000 per year more than matched controls. In contrast, asymptomatic patients with oHCM have a much smaller difference in HRU and costs (∼$3,600/year) compared with matched controls. The results of this study suggest that effective therapies for oHCM may provide economic value, even if the impact of therapy is limited solely to the relief of symptoms.

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Improving symptoms is a primary treatment goal in patients with obstructive hypertrophic cardiomyopathy. Currently available pharmacological options for hypertrophic cardiomyopathy are not disease-specific and are often inadequate or poorly tolerated. We aimed to assess the effect of mavacamten, a first-in-class cardiac myosin inhibitor, on patients' health status-ie, symptoms, physical and social function, and quality of life. METHODS: We did a health status analysis of EXPLORER-HCM, a phase 3, double-blind, randomised, placebo-controlled trial. The study took place at 68 clinical cardiovascular centres in 13 countries. Adult patients (≥18 years) with symptomatic obstructive hypertrophic cardiomyopathy (gradient ≥50 mm Hg and New York Heart Association class II-III) were randomly assigned (1:1) to mavacamten or placebo for 30 weeks, followed by an 8-week washout period. Both patients and staff were masked to study treatment. The primary outcome for this secondary analysis was the Kansas City Cardiomyopathy Questionnaire (KCCQ), a well validated disease-specific measure of patients' health status. It was administered at baseline and weeks 6, 12, 18, 30 (end of treatment), and 38 (end of study). Changes from baseline to week 30 in KCCQ overall summary (OS) score and all subscales were analysed using mixed model repeated measures. This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned. Of 123 patients randomly assigned to mavacamten, 92 (75%) completed the KCCQ at baseline and week 30 and of the 128 patients randomly assigned to placebo 88 (69%) completed the KCCQ at baseline and week 30. At 30 weeks, the change in KCCQ-OS score was greater with mavacamten than placebo (mean score 14·9 [SD 15·8] vs 5·4 [13·7]; difference +9·1 [95% CI 5·5-12·8]; p<0·0001), with similar benefits across all KCCQ subscales. The proportion of patients with a very large change (KCCQ-OS ≥20 points) was 36% (33 of 92) in the mavacamten group versus 15% (13 of 88) in the placebo group, with an estimated absolute difference of 21% (95% CI 8·8-33·4) and number needed to treat of five (95% CI 3-11). These gains returned to baseline after treatment was stopped. INTERPRETATION: Mavacamten markedly improved the health status of patients with symptomatic obstructive hypertrophic cardiomyopathy compared with placebo, with a low number needed to treat for marked improvement. Given that the primary goals of treatment are to improve symptoms, physical and social function, and quality of life, mavacamten represents a new potential strategy for achieving these goals. FUNDING: MyoKardia, a Bristol Myers Squibb company.

MOdified NARanjo Causality Scale for ICSRs (MONARCSi): A Decision Support Tool for Safety Scientists.

INTRODUCTION: Within the field of Pharmacovigilance, the most common approaches for assessing causality between a report of a drug and a corresponding adverse event are clinical judgment, probabilistic methods and algorithms. Although multiple methods using these three approaches have been proposed, there is currently no universally accepted method for assessing drug-event causality in ICSRs and variability in drug-event causality assessments is well documented. OBJECTIVE: This study describes the development and validation of an Individual Case Safety Report (ICSR) Causality Decision Support Tool to assist Safety Professionals (SPs) performing causality assessments. METHODS: Roche developed this model with nine drug-event pair features capturing important aspects of Naranjo's scoring system, selected Bradford-Hill criteria, and internal Roche safety practices. Each of the features was weighted based on individual safety professional (n = 65) assessments of the importance of that feature when assessing causality, using an ordinal weighting scale (0 = no importance, 4 = very high importance). The mean and associated standard deviation for each feature weight was calculated and were used as inputs to a fitted logistic equation, which calculated the probability of a causal relationship between the drug and adverse event. Model training, validation, and testing were conducted by comparing MONARCSi causality classifications to previous company causality assessments for 978 randomly selected, clinical trial drug-event pairs based on their respective features and weights. RESULTS: The final model test, a two-by-two comparison of the results, showed substantial agreement (Gwet Kappa = 0.77) between MONARCSi and Roche safety professionals' assessments of causality, using global introspection. The model exhibited moderate sensitivity (65%) and high specificity (93%), high positive and negative predictive values (79 and 88%, respectively), and an F1 score of 71%. CONCLUSION: Analysis suggests that the MONARCSi model could potentially be a useful decision support tool to assist pharmacovigilance safety professionals when evaluating drug-event causality in a consistent and documentable manner.

Evolution of Drug Development: Integrating the Patient Perspective Into Early Research.

Soaring drug development costs, increasingly stringent regulatory requirements, and demanding market access environments have necessitated that pharmaceutical companies examine their research processes in order to provide novel and meaningful solutions for patients. In this paper, we describe an initiative that aims to incorporate a better appreciation of the exam room experience of both patients and practitioners into the drug development pathway from the earliest point of research. Focusing on 4 core pillars-medical value, patient need, scientific rationale, and market environment-an integrated analytic process is undertaken so as to facilitate early identification of ideal target populations and criteria that will need to be met for successful entry into the treatment continuum. Collaborative interactions with other specialist roles within the organization are also described. It is argued that understanding the unmet medical need and the risks and opportunities inherent in different development scenarios can help direct early research so as to encourage truly transformative health care solutions.

Sorting Through the Safety Data Haystack: Using Machine Learning to Identify Individual Case Safety Reports in Social-Digital Media.

INTRODUCTION: There is increasing interest in social digital media (SDM) as a data source for pharmacovigilance activities; however, SDM is considered a low information content data source for safety data. Given that pharmacovigilance itself operates in a high-noise, lower-validity environment without objective 'gold standards' beyond process definitions, the introduction of large volumes of SDM into the pharmacovigilance workflow has the potential to exacerbate issues with limited manual resources to perform adverse event identification and processing. Recent advances in medical informatics have resulted in methods for developing programs which can assist human experts in the detection of valid individual case safety reports (ICSRs) within SDM. OBJECTIVE: In this study, we developed rule-based and machine learning (ML) models for classifying ICSRs from SDM and compared their performance with that of human pharmacovigilance experts. METHODS: We used a random sampling from a collection of 311,189 SDM posts that mentioned Roche products and brands in combination with common medical and scientific terms sourced from Twitter, Tumblr, Facebook, and a spectrum of news media blogs to develop and evaluate three iterations of an automated ICSR classifier. The ICSR classifier models consisted of sub-components to annotate the relevant ICSR elements and a component to make the final decision on the validity of the ICSR. Agreement with human pharmacovigilance experts was chosen as the preferred performance metric and was evaluated by calculating the Gwet AC1 statistic (gKappa). The best performing model was tested against the Roche global pharmacovigilance expert using a blind dataset and put through a time test of the full 311,189-post dataset. RESULTS: During this effort, the initial strict rule-based approach to ICSR classification resulted in a model with an accuracy of 65% and a gKappa of 46%. Adding an ML-based adverse event annotator improved the accuracy to 74% and gKappa to 60%. This was further improved by the addition of an additional ML ICSR detector. On a blind test set of 2500 posts, the final model demonstrated a gKappa of 78% and an accuracy of 83%. In the time test, it took the final model 48 h to complete a task that would have taken an estimated 44,000 h for human experts to perform. CONCLUSION: The results of this study indicate that an effective and scalable solution to the challenge of ICSR detection in SDM includes a workflow using an automated ML classifier to identify likely ICSRs for further human SME review.

Mental health leadership and patient access to care: a public-private initiative in South Africa.

BACKGROUND: Mental health leadership is a critical component of patient access to care. More specifically, the ability of mental health professionals to articulate the needs of patients, formulate strategies and engage meaningfully at the appropriate level in pursuit of resources. This is not a skill set routinely taught to mental health professionals. METHODS: A public-private mental health leadership initiative, emanating from a patient access to care programme, was developed with the aim of building leadership capacity within the South African public mental health sector. The express aim was to equip health care professionals with the requisite skills to more effectively advocate for their patients. The initiative involved participants from various sites within South Africa. Inclusion was based on the proposal of an ongoing "project", i.e. a clinician-initiated service development with a multidisciplinary focus. The projects were varied in nature but all involved identification of and a plan for addressing an aspect of the participants' daily professional work which negatively impacted on patient care due to unmet needs. Six such projects were included and involved 15 participants, comprising personnel from psychiatry, psychology, occupational therapy and nursing. Each project group was formally mentored as part of the initiative, with mentors being senior professionals with expertise in psychiatry, public health and nursing. The programme design thus provided a unique practical dimension in which skills and learnings were applied to the projects with numerous and diverse outcomes. RESULTS: Benefits were noted by participants but extended beyond the individuals to the health institutions in which they worked and the patients that they served. Participants acquired both the skills and the confidence which enabled them to sustain the changes that they themselves had initiated in their institutions. The initiative gave impetus to the inclusion of public mental health as part of the curriculum for specialist training. CONCLUSIONS: Despite the significant adverse social and economic costs of mental illness, psychiatric and related services receive a low level of priority within the health care system. Ensuring that mental health receives the recognition and the resources it deserves requires that mental health care professionals become effective advocates through mental health leadership.

A survey on the treatment of atrial fibrillation in South Africa.

BACKGROUND: The burden of cardiovascular disease is expected to escalate in developing countries. However, studies and guidelines concerning atrial fibrillation (AF) are restricted to the developed world. OBJECTIVES: To assess the treatment modalities of AF in South Africa. METHODS: A cross-sectional, observational, multicentre, national registry of the treatment of 302 patients with AF was conducted from February 2010 to March 2011. Specific drug use for rate or rhythm control, as well as drug use for stroke prevention, was surveyed. Events during the 12 months prior to the survey were also characterised, including non-drug treatments, resource utilisation and complications. RESULTS: The single most prevalent clinical characteristic was hypertension (65.9%). Rhythm control was being pursued in 109 patients (36.1%) with class Ic and class III antiarrhythmic agents, while rate control, mainly with beta-blockers, was pursued in the remainder of the patients. Concomitant use of other cardiovascular drugs was high, and 75.2% of patients were on warfarin for stroke prevention. There was a high burden of AF-related morbidity during the preceding year, with 32.5% reporting a history of heart failure, 8.3% a stroke and 5.3% a transient ischaemic attack. Therapeutic success, as defined by either the presence of sinus rhythm or rate-controlled AF, was achieved in 86.8% as judged clinically by the treating physician, but in only 70.2% according to the electrocardiogram criterion of heart rate ≤80 bpm. CONCLUSION: There were no striking differences from previously reported registries worldwide. The lack of application of strict rate control criteria is highlighted.

Prevalence of and risk factors for diabetic macular edema in the United States.

IMPORTANCE: Diabetic macular edema (DME) is a leading cause of vision loss in persons with diabetes mellitus. Although there are national estimates for the prevalence of diabetic retinopathy and its risk factors among persons with diabetes, to our knowledge, no comparable estimates are available for DME specifically. OBJECTIVES: To estimate the prevalence of DME in the US population and to identify associated risk factors. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional analysis of 1038 participants aged 40 years or older with diabetes and valid fundus photographs in the 2005 to 2008 National Health and Nutrition Examination Survey. MAIN OUTCOMES AND MEASURES: The overall prevalence of DME and its prevalence according to age, race/ethnicity, and sex. RESULTS: Of the 1038 persons with diabetes analyzed for this study, 55 had DME, for an overall weighted prevalence of 3.8% (95% CI, 2.7%-4.9%) or approximately 746, 000 persons in the US 2010 population aged 40 years or older. We identified no differences in the prevalence of DME by age or sex. Multivariable logistic regression analysis showed that the odds of having DME were higher for non-Hispanic blacks than for non-Hispanic whites (odds ratio [OR], 2.64; 95% CI, 1.19-5.84; P = .02). Elevated levels of glycosylated hemoglobin A1c (OR, 1.47; 95% CI, 1.26-1.71 for each 1%; P < .001) and longer duration of diabetes (OR, 8.51; 95% CI, 3.70-19.54 for ≥ 10 vs <10 years; P < .001) were also associated with DME prevalence. CONCLUSIONS AND RELEVANCE: These results suggest a greater burden of DME among non-Hispanic blacks, individuals with high levels of hemoglobin A1c, and those with longer duration of diabetes. Given recent treatment advances in reducing vision loss and preserving vision in persons with DME, it is imperative that all persons with diabetes receive early screening; this recommendation is even more important for those at higher risk for DME.

Underuse of the health care system by persons with diabetes mellitus and diabetic macular edema in the United States.

IMPORTANCE: Thickening of the center of the retina, diabetic macular edema (DME), is the most common cause of visual loss due to diabetes mellitus. Treatment of DME has improved dramatically, and the prompt diagnosis of DME and referral of these patients have become more critical. Nonetheless, awareness of and care for DME in the US population is uncharacterized. OBJECTIVE: To characterize eye care and awareness of eye disease among persons with DME in the general US population. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of data from participants in the 2005 to 2008 National Health and Nutrition Examination Survey 40 years or older with diabetes mellitus and fundus photographs. MAIN OUTCOMES AND MEASURES: Among persons with DME, (1) awareness that diabetes has affected their eyes; (2) report on the last time they visited a diabetes specialist; (3) report on their last eye examination with pupil dilation; and (4) prevalence of visual impairment. RESULTS: In 2010, only 44.7% (95% CI, 27.0%-62.4%) of US adults 40 years or older with DME reported being told by a physician that diabetes had affected their eyes or that they had retinopathy; 46.7% (95% CI, 27.5%-66.0%), that they had visited a diabetes nurse educator, dietician, or nutritionist for their diabetes mellitus more than 1 year ago or never; and 59.7% (95% CI, 43.5%-75.9%), that they had received an eye examination with pupil dilation in the last year. Among persons with DME, 28.7% (95% CI, 12.7%-44.7%) were visually impaired (defined as visual acuity worse than 20/40 in the eye with DME) based on visual acuity at the initial examination and 16.0% (95% CI, 2.5%-29.4%) based on best-corrected visual acuity. CONCLUSIONS AND RELEVANCE: Many persons with diabetes mellitus in the United States are not getting care that can prevent visual impairment and blindness. Strategies to increase awareness are warranted, especially given the recent availability of improved therapies for DME.

Driving ability reported by neovascular age-related macular degeneration patients after treatment with ranibizumab.

OBJECTIVES: To determine the impact of ranibizumab on driving status, driving ability perception, and having 20/40 vision or better in patients with choroidal neovascularization resulting from age-related macular degeneration (AMD). DESIGN: Phase III, multicenter, randomized clinical trials (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration [MARINA] and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration [ANCHOR]). PARTICIPANTS: One thousand one hundred twenty-six patients with choroidal neovascularization resulting from AMD. METHODS: Participants were assigned randomly to sham (n=238), 0.3-mg ranibizumab monthly injections (n=238), or 0.5-mg ranibizumab monthly injections (n=240) for 24 months (MARINA), or were randomized to verteporfin photodynamic therapy (PDT; n=143), 0.3-mg ranibizumab monthly injections (n=140), or 0.5-mg ranibizumab monthly injections (n=140) for 24 months (ANCHOR). MAIN OUTCOME MEASURES: Self-reported driving status and driving ability perception were assessed as exploratory outcomes at baseline through 24 months after baseline using the 25-item National Eye Institute Visual Function Questionnaire. Best-corrected visual acuity in each eye was assessed monthly through 24 months. RESULTS: At baseline, 68.6% of patients in the MARINA trial and 62.7% of patients in the ANCHOR trial reported driving. Among patients driving at baseline in the MARINA trial 2 years after randomization, 67.2% (95% confidence interval [CI], 59.2-75.2) of sham patients and 78.4% (95% CI, 71.8-85.0) of 0.5-mg patients reported that they were still driving. Among patients driving at baseline in the ANCHOR trial at 2 years after randomization, 71.6% (95% CI, 60.8-82.4) of PDT patients and 91.4% (95% CI, 85.3-97.5) of 0.5-mg patients were still driving. Also in the ANCHOR trial, ranibizumab-treated patients who were not driving at baseline seemed more likely to drive by months 12 and 24 than PDT patients. Perception of driving ability was correlated with improvement in visual acuity (VA) in the better-seeing eye at 12 and 24 months (R2=0.17 and R2=0.20 at 12 and 24 months, respectively [P<0.001], in the MARINA trial; R2=0.13 and R2=0.14, respectively [P<0.001], in the ANCHOR trial). Visual acuity in one or both eyes 2 years after randomization was more likely to be 20/40 or better in the ranibizumab-treated groups. CONCLUSIONS: These results suggest that patients with neovascular AMD treated with ranibizumab are more likely to report driving ability and have vision of at least 20/40 than patients given sham treatment or PDT. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Rotigotine effects on early morning motor function and sleep in Parkinson's disease: a double-blind, randomized, placebo-controlled study (RECOVER).

In a multinational, double-blind, placebo-controlled trial (NCT00474058), 287 subjects with Parkinson's disease (PD) and unsatisfactory early-morning motor symptom control were randomized 2:1 to receive rotigotine (2-16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1-8 weeks with subsequent dose maintenance for 4 weeks. Early-morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's Disease Sleep Scale (PDSS-2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by -7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by -3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS-2 total score had decreased by -5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by -1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: -3.55 [95% confidence interval (CI) -5.37, -1.73]; P = 0.0002) and PDSS-2 (treatment difference: -4.26 [95% CI -6.08, -2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty-four-hour transdermal delivery of rotigotine to PD patients with early-morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances.