Longitudinal Management of Cardiovascular Risk Factors Among Postpartum Women.

Background: Pregnancy-related cardiovascular (CV) conditions, including hypertensive disorders of pregnancy (HDP) and gestational diabetes (GDM), are associated with increased long-term CV risk. Methods: This retrospective cohort study defined the prevalence of HDP and GDM within a large, academic health system in the southeast United States between 2012 and 2015 and described health care utilization and routine CV screening up to 1-year following delivery among those with pregnancy-related CV conditions. Rates of follow-up visits and blood pressure, hemoglobin A1c (HbA1c), and lipid screening in the first postpartum year were compared by provider type and pregnancy-related CV condition. Results: Of the 6027 deliveries included, 20% were complicated by HDP and/or GDM. Rates of pre-pregnancy CV risk factors were high, with a significantly higher proportion of pre-pregnancy obesity among women with HDP than in normal pregnancies. Those with both HDP/GDM had the highest rates of follow-up by 1-year postpartum, yet only half of those with any pregnancy-related CV condition had any follow-up visit after 12 weeks. Although most (70%) of those with HDP had postpartum blood pressure screening, less than one-third of those with GDM had a repeat HbA1c by 12 months. Overall, postpartum lipid screening was rare (<20%). Conclusion: There is a high burden of pregnancy-related CV conditions in a large U.S. academic health system. Although overall rates of follow-up in the early postpartum period were high, gaps in longitudinal follow-up exist. Low rates of CV risk factor follow-up at 1 year indicate a missed opportunity for early CV prevention.

Strategies for enhancing the representation of women in clinical trials: an evidence map.

BACKGROUND: Equitable sex- and gender-based representation in clinical trials is an essential step to ensuring evidence-based care for women. While multi-institutional actions have led to significant improvements in the inclusion of women in trials, inequity persists in areas like sex-neutral cancers and cardiovascular disease. We sought to identify strategies described or evaluated to boost the inclusion of women in clinical trials. METHODS: We used evidence mapping methodology to examine the breadth of relevant literature. We developed an a priori protocol and followed reporting guidance from the Preferred Reporting Items for Systematic Reviews and Meta-Analysis where applicable. We searched MEDLINE® (via PubMed) and EMBASE (via Elsevier) databases from inception through April 4, 2023, and used standardized procedures incorporating duplication and data verification. We included articles that described strategies to improve the recruitment and retention of women in clinical trials. RESULTS: We identified 122 articles describing recruitment and retention strategies for 136 trials (377,595 women). Only one article distinguished between the sex and gender identity of participants, and none defined their use of the terms such as "women" or "female". The majority of articles (95%) described recruitment for only women, and 64% were conducted in the USA. Ninety-two articles (75%) described strategies in the context of sex-specific conditions (e.g., gynecologic diagnosis). The majority of included articles evaluated a behavioral intervention (52%), with 23% evaluating pharmacologic interventions and 4% invasive interventions. The most common trial phase for reported strategies was during outreach to potential participants (116 articles), followed by intervention delivery (76), enrollment (40), outcomes assessment (21), analysis and interpretation (3), and dissemination (4). We describe specific types of strategies within each of these phases. CONCLUSIONS: Most of the existing literature describing strategies to improve the inclusion of women draws from trials for sex-specific conditions and is largely related to outreach to potential participants. There is little information about how and if studies have attempted to proportionally increase the inclusion of women in trials with both men and women or those focused on invasive and pharmacologic interventions. Future work in this area should focus on how to increase the participation of women in mixed-sex studies and on those areas with remaining inequities in trial participation.

Connected health in US, EU, and China: opportunities to accelerate regulation of connected health technologies to optimize their role in medicines development.

Connected health technology is playing an increasingly important role in healthcare. The power, complexity, functionality, and accessibility of connected health technologies are increasing rapidly, showing promise for improved and more equitable healthcare outcomes. They are integral to the lifecycle of medical products, from discovery and development to manufacturing and ultimately to the patient. The spectrum of integration between medical products and digital technologies ranges from non-drug specific solutions for supporting adherence or patient monitoring, which may or may not require regulatory approval, to digital therapeutics and software-containing combination products, which make claims supported by clinical evidence. The exponential increase and rapid evolution of connected health technologies - and the accompanying possibilities for innovative healthcare interventions, delivery systems, and clinical trial designs - pose new and complicated regulatory challenges. Currently, connected health may involve the use of regulated medical devices, including software as a medical device, or consumer products, such as wearables or apps, that fall under regulatory discretion. In this paper we examine how connected health technologies intersect with the development and lifecycle of medical products, how they are impacted by existing regulatory frameworks in the US, EU, and China, and propose future focus areas of activity.

Establishing a core dossier for multiple regulatory submissions: a case study in the Latin America region.

The Latin America region comprises several countries that do not follow harmonized regulatory requirements for drug product (DP) marketing authorization applications (MAA), resulting in customized registration dossiers for each country. Here, we established a core dossier for multiple MAA in the Latin America region by examining the similarities between regulatory requirements and reconciling their potential discrepancies through discussions among all national regulatory representatives. The core dossier was used in the submission of a new small molecule, NME1, to nine markets. Assessment of the process included the time to submission; the timing, number, and complexity of questions received; and timing of final national regulatory agencies (NRA) evaluation decisions. The core dossier resulted in an accelerated submission timeline for most markets and earlier receipt of NRA queries from some markets, compared with projections. One round of queries of a low or medium complexity was received from all agencies. The receipt of final NRA evaluation decisions was also accelerated in most markets, compared with the best-case approval timeframes. The core dossier approach was also evaluated against the standard submission of a similar small molecule, NME2. In contrast to the core dossier submission of NME1, a second round of questions, and high-complexity questions were received from two markets for NME2. In conclusion, a core dossier has the potential to simplify the regulatory process for both reviewers and applicants in regions that do not share harmonized regulatory requirements, with a consequential acceleration of DP approvals.

Racial Differences in Nontraditional Risk Factors Associated with Cardiovascular Conditions in Pregnancy Among U.S. Women Veterans.

Background: Pregnancy-related cardiovascular (CV) conditions are important predictors of future cardiovascular disease (CVD). Nontraditional factors, such as depression and chronic stress, have been associated with CVD, but their role in pregnancy-related CVD conditions (pCVD) remains unknown. To determine the association between nontraditional factors and CV conditions in pregnancy, and to explore if this risk varies by race. Methods: Using data from a prospective study of pregnant women within the veterans affairs health system (COMFORT study), we described the prevalence of nontraditional factors (e.g., depression, post-traumatic stress disorder [PTSD], chronic stress) and used logistic regression to determine the association between nontraditional factors and pregnancy-related CV conditions (pre-eclampsia/eclampsia, gestational hypertension, gestation diabetes, or preterm delivery). Analyses were then stratified by race. Results: Among 706 enrollees, 26% had pregnancy-related CV conditions. These women had significantly higher rates of depression (62% vs. 45%, p < 0.01), anxiety (50% vs. 37%, p = 0.01), PTSD (44% vs. 29%, p < 0.01), and high stress levels before pregnancy (22% vs. 16%, p = 0.05) compared with women with normal pregnancies. Overall, these factors were not associated with increased adjusted odds of pCVD. Overall, Black women had disproportionately higher rates of prepregnancy hypertension compared with White women (22% vs. 6%, p < 0.01). Conclusions: Women Veterans with pCVD are a high-risk group for future CVD, with disproportionately high rates of depression, anxiety, PTSD, and chronic stress. Racial disparities exist in pregnancy-related CV risk factors, which may further compound existing racial disparities in CVD among women Veterans.

Management of cardiovascular risk factors during pregnancy.

Cardiovascular (CV) risk factors are rising among women of reproductive age. Obesity, hyperlipidaemia, diabetes, and hypertension are associated with adverse pregnancy outcomes and increased CV disease (CVD) risk following pregnancy. Pre-conception counselling and longitudinal postpartum follow-up with ongoing CV risk factor screening are critical for early CVD prevention, though significant racial/ethnic disparities in access to care result in significant gaps. This review summarises the recommended management of CV risk factors during and after pregnancy. For obesity, prevention of excessive weight gain is critical. Except in rare cases, lipid-lowering therapies for women with hyperlipidaemia should be stopped before pregnancy. Women with diabetes in pregnancy should maintain tight glucose control, with hemolgobin A1c (HbA1c) <6.5% to prevent congenital abnormalities. Hypertensive disorders of pregnancy are associated with high maternal and neonatal morbidity and require long-term follow-up to prevent future CVD. Finally, this review highlights the lack of clinical trials informing optimal treatment strategies of CV risk factors during and after pregnancy. Further research is needed to better understand how to improve long-term CV health among this high-risk population.

Analysis of the Regulatory Science Applied to a Single Portfolio of Eight Biosimilar Product Approvals by Four Key Regulatory Authorities.

Slow uptake of biosimilars in some regions is often attributed to a lack of knowledge combined with concerns about safety and efficacy. To alleviate physician and patient apprehensions, regulatory reviews from four major regulatory authorities (RAs) (European Medicines Agency, US Food and Drug Administration, Health Canada, and Japan Pharmaceuticals and Medical Devices Authority) across a portfolio of eight biosimilars were analyzed to provide insight into RA review focus and approach. RA queries were evaluated in an unbiased and systematic manner by major classification (Chemistry, Manufacturing and Controls [CMC], nonclinical, clinical or regulatory) and then via detailed sub-classification. There was a consistent, predominant focus on CMC from all RAs. The review focus based on sub-classification of clinical and regulatory queries was influenced by molecular complexity, with significant differences between categories (monoclonal antibody or protein) in the distribution of query topics; specifically, bioanalytical (p = 0.023), comparative safety and efficacy (p = 0.023), and statutory (including the justification of extrapolation) (p = 0.00033). Each biosimilar had a distinct distribution of clinical query topics, tailored to product-specific data. This analysis elucidated areas of heightened RA interest, and validated their application of regulatory science in the evaluation of biosimilar safety and efficacy.

High Burden of Cardiac Disease in Pregnancy at a National Referral Hospital in Western Kenya.

Background: Cardiac disease is a leading cause of non-obstetric maternal death worldwide, but little is known about its burden in sub-Saharan Africa. Objectives and Methods: We conducted a retrospective case-control study of pregnant women admitted to a national referral hospital in western Kenya between 2011-2016. Its purpose was to define the burden and spectrum of cardiac disease in pregnancy and assess the utility of the CARPREG I and modified WHO (mWHO) clinical risk prediction tools in this population. Results: Of the 97 cases of cardiac disease in pregnancy, rheumatic heart disease (RHD) was the most common cause (75%), with over half complicated by severe mitral stenosis or pulmonary hypertension. Despite high rates of severe disease and nearly universal antenatal care, late diagnosis of cardiac disease was common, with one third (38%) of all cases newly diagnosed after 28 weeks gestational age and 17% diagnosed after delivery. Maternal mortality was 10-fold higher among cases than controls. Cases had significantly more cardiac (56% vs. 0.4%) and neonatal adverse events (61% vs. 27%) compared to controls (p < 0.001). Observed rates of adverse cardiac events were higher than predicted by both CARPREG I and mWHO risk scores, with high cardiac event rates despite low or intermediate risk scores. Conclusions: Cardiac disease is associated with significant maternal and neonatal morbidity and mortality among pregnant women in western Kenya. Existing clinical tools used to predict risk underestimate adverse cardiac events in pregnancy and may be of limited utility given the unique spectrum and severity of disease in this population.

Prevalence and Management of Adult Obesity in a Large U.S. Academic Health System.

INTRODUCTION: Both medication and surgical interventions can be used to treat obesity, yet their use and effectiveness in routine clinical practice are not clear. This study sought to characterize the prevalence and management of patients with obesity within a large U.S. academic medical center. METHODS: All patients aged ≥18 years who were seen in a primary care clinic within the Duke Health System between 2013 and 2016 were included. Patients were categorized according to baseline BMI as underweight or normal weight (<25 kg/m2), overweight (25-29.9 kg/m2), Class I obesity (30-34.9 kg/m2), Class II obesity (35-39.9 kg/m2), and Class III obesity (≥40 kg/m2). Baseline characteristics and use of weight loss medication were assessed by BMI category. Predicted change in BMI was modeled over 3 years. All data were analyzed between 2017 and 2018. RESULTS: Of the 173,462 included patients, most were overweight (32%) or obese (40%). Overall, <1% (n=295) of obese patients were prescribed medication for weight loss or underwent bariatric surgery within the 3-year study period. Most patients had no change in BMI class (70%) at 3 years. CONCLUSIONS: Despite a high prevalence of obesity within primary care clinics of a large, U.S. academic health center, the use of pharmacologic and surgical therapies was low, and most patients had no weight change over 3 years. This highlights the significant need for improvement in obesity care at a health system level.

Building a Better Approach for the Benefit of Patients: 10 Pillars to Strengthen Regulatory Review Systems Globally.

In the current pharmaceutical regulatory environment, patients continue to benefit from great advances in medical care. Sophisticated regulatory review systems have also evolved to ensure that safe and effective medicines are approved. However, these systems are not optimized in all countries. Gaps in individual regulatory agency capabilities together with duplication in non-value added national regulatory requirements, particularly in low- and middle-income countries (LMICs), can slow down regulatory approvals and therefore impede patient access to new medicines. These gaps exist despite the achievements in both regulatory convergence and harmonization of technical requirements by bodies such as the International Conference on Harmonization (ICH). There is a pressing need to strengthen regulatory review systems in emerging market economies as highlighted by the World Health Organization (WHO). These diverse challenges may seem overwhelming to individual national regulators, in part because of the sheer number of initiatives by multiple stakeholders, combined with a lack of information on concise practical actionable measures that can have a positive impact on review efficiency. This commentary presents 10 pillars that we believe represent the key hallmarks of strong regulatory review systems. Leveraging our internal company expertise at the global, regional, and country level across our entire product portfolio (both innovative and generic), we selected features proven to work in leading regulatory agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), which are also relevant for other regulatory authorities, especially in LMICs.

Clinical and geographic patterns of rheumatic heart disease in outpatients attending cardiology clinic in western Kenya.

INTRODUCTION: Rheumatic heart disease (RHD) remains a leading cause of cardiovascular mortality in sub-Saharan Africa. Identifying high risk populations and geographic patterns of disease is crucial to developing RHD prevention and screening strategies in endemic areas. OBJECTIVES: To identify clinical and geographical trends in RHD throughout western Kenya METHODS: We conducted a retrospective chart review of all patients <50years old attending adult cardiology clinic at a national referral hospital in western Kenya. Demographic information, residential location and cardiac history were collected. We mapped the spatial distribution of cardiac disease rates and analyzed the effect of distance from the hospital on RHD status. RESULTS: Two-thirds (64%) of cardiology clinic patients <50years old (n=906) had RHD. RHD patients were younger (26 vs. 33years, p<0.001) and more often female (69% vs. 59%, p=0.001) than non-RHD patients. Global clustering of disease rates existed within 200km of the hospital with significant clustering of the RHD and non-RHD rate difference surrounding the hospital (Moran's I: 0.3, p=0.001). There was an interaction between ethnicity and distance from the hospital such that the odds of RHD decreased with further distance for Nilotes, but the odds of RHD increased with further distance for non-Nilotes CONCLUSION: Most adult cardiology patients treated at a national referral hospital in western Kenya have RHD. Young people and females are commonly affected. Ethnicity and distance to the hospital interdependently affect the odds of RHD. Future studies in this area should consider the impact of ethnic predisposition to RHD.

The Causes of HIV-Associated Cardiomyopathy: A Tale of Two Worlds.

Antiretroviral therapy (ART) has transformed the clinical profile of human immunodeficiency virus (HIV) from an acute infection with a high mortality into a treatable, chronic disease. As a result, the clinical sequelae of HIV infection are changing as patients live longer. HIV-associated cardiomyopathy (HIVAC) is a stage IV, HIV-defining illness and remains a significant cause of morbidity and mortality among HIV-infected individuals despite ART. Causes and clinical manifestations of HIVAC depend on the degree of host immunosuppression. Myocarditis from direct HIV toxicity, opportunistic infections, and nutritional deficiencies are implicated in causing HIVAC when HIV viral replication is unchecked, whereas cardiac autoimmunity, chronic inflammation, and ART cardiotoxicity contribute to HIVAC in individuals with suppressed viral loads. The initiation of ART has dramatically changed the clinical manifestation of HIVAC in high income countries from one of severe, left ventricular systolic dysfunction to a pattern of subclinical cardiac dysfunction characterized by abnormal diastolic function and strain. In low and middle income countries, however, HIVAC is the most common HIV-associated cardiovascular disease. Clear diagnostic and treatment guidelines for HIVAC are currently lacking but should be prioritized given the global burden of HIVAC.

Human Immunodeficiency Virus and Heart Failure in Low- and Middle-Income Countries.

Successful combination therapy for human immunodeficiency virus (HIV) has transformed this disease from a short-lived infection with high mortality to a chronic disease associated with increasing life expectancy. This is true for high- as well as low- and middle-income countries. As a result of this increased life expectancy, people living with HIV are now at risk of developing other chronic diseases associated with aging. Heart failure has been common among people living with HIV in the eras of pre- and post- availability of antiretroviral therapy; however, our current understanding of the pathogenesis and approaches to management have not been systematically addressed. HIV may cause heart failure through direct (e.g., viral replication, mitochondrial dysfunction, cardiac autoimmunity, autonomic dysfunction) and indirect (e.g., opportunistic infections, antiretroviral therapy, alcohol abuse, micronutrient deficiency, tobacco use) pathways. In low- and middle-income countries, 2 large observational studies have recently reported clinical characteristics and outcomes in these patients. HIV-associated heart failure remains a common cardiac diagnosis in people living with heart failure, yet a unifying set of diagnostic criteria is lacking. Treatment patterns for heart failure fall short of society guidelines. Although there may be promise in cardiac glycosides for treating heart failure in people living with HIV, clinical studies are needed to validate in vitro findings. Owing to the burden of HIV in low- and middle-income countries and the concurrent rise of traditional cardiovascular risk factors, strategic and concerted efforts in this area are likely to impact the care of people living with HIV around the globe.