Atrial fibrillation (AF) is a cardiac arrhythmia that manifests as irregular heartbeat. According to the U.S. Centers for Disease Control, AF affected approximately 2.66 million people in the United States in 2010, and the numbers are expected to increase over time. AF is the most common arrhythmia in the US, and its prevalence increases with aging. Patients with AF are at increased risk of having blood clots, stroke, and heart failure. More than 30% of strokes in individuals over the age of 75 years are due to AF, presumably due to thromboembolism from the left atrial appendage (LAA). Oral anticoagulation therapy with warfarin or more recently approved novel anticoagulants are the standard of care to reduce risks of blood clots and stroke. Emerging new technologies in stroke prevention have been undergoing development rapidly. One new technology is the percutaneous LAA closure (or occlusion) device. The LAA is a small pouch, often shaped like a windsock, which connects and empties into the left atrium, the top chamber of the left side of the heart. This structure is prone to form and collect blood clots, in particular in patients with AF. When a blood clot travels from the LAA to the systemic blood circulation and travels to the brain, it may result in stroke. The percutaneous LAA closure device is a novel technology that closes the LAA via percutaneous vascular access, and thus prevents blood clots from entering the systemic circulation and reduces stroke risk. It is recognized that there are sex-specific differences in the pathophysiology of stroke and AF. Moreover, women (particularly elderly women) often have more challenging vascular anatomies (e.g. smaller blood vessels and heart sizes) for percutaneous procedures vs. men, and more often have higher rates of surgical complications. It is unknown whether these sex differences impact the effectiveness and safety of this new LAA closure device for stroke prevention. Our goal is to answer this question by pooling and analyzing both pre-market and post-market data available at the FDA on this type of device via an in-depth statistical analysis. This study will help us better understand sex difference in stroke prevention and increase the assurance the safety and effectiveness of the LAA closure device in women.
Evaluation of thromboembolic events following C1-inhibitor therapy
- Paul Buehler, PharmD, PhD/CBER
Hereditary angioedema (HAE) is a rare potentially life threatening disorder associated with a deficiency of functional C1-esterase inhibitor (C1INH), and it is more severe and frequent in female population than in men. Until recently, there was no HAE-targeted therapy available in the United States, and only fresh-frozen plasma or attenuated androgens were used to provide some relief during acute attacks. Since 2008, DHRR/CBER approved three C1INH products for replacement therapy in patients with HAE for the treatment of acute attacks and for prophylaxis. According to the available database and recent publications, C1INH therapy in HAE patients is associated with a risk of thromboembolic events. Thrombosis also has been predominantly reported in women and appears to depend on hormonal status. This project will focus on the evaluation of a risk of thromboembolic events due to C1INH administration at supraphysiological levels and elucidation of possible underlying mechanisms. Secondly, to assure safety and effectiveness of C1INH treatment in case of recently proposed concomitant administration of C1INH and pharmaceutical heparins, this project will focus on the evaluation of the C1INH potentiation by heparin and the impact of various compositions and conditions on possible thrombotic events. The proposed studies, both in vitro and in animal models, are essential for the development of reliable biomarkers to evaluate and predict thromboembolic events in women during C1INH therapies, as well as for elucidating the mechanisms for possible enhancement of currently available C1INH therapies by pharmaceutical heparins and its impact on a risk of thrombosis.
Developing biomarkers for trastuzumab-induced cardiotoxicity - Wen Jin Wu, MD, PhD/CDER
Trastuzumab (also known as Herceptin®) is a humanized monoclonal antibody directed against extracellular domain of human epidermal growth factor receptor 2 (HER2) and is approved for the treatment of breast cancers that are HER2-positive. Trastuzumab provides considerable therapeutic benefits in HER2-positive breast cancers and improves disease free and overall survival after adjuvant chemotherapy. However, trastuzumab treatment is also associated with cardiac dysfunction. There are no clinically approved biomarkers that can be used to predict the cardiac dysfunction induced by trastuzumab. Furthermore, several large clinical trials have shown that cardiomyopathy induced by trastuzumab maybe potentially irreversible in some patients. Therefore, it is important to develop biomarkers and sensitive and specific testing methods that could be used to detect cardiotoxicity induced by trastuzumab. Using echocardiography, we recently found that trastuzumab significantly reduced left ventricular performance in mice. Importantly, this trastuzumab-induced cardiac dysfunction was associated with elevated level of cardiac myosin light chain 1 (cMLC-1) in mice sera, suggesting that cMLC1 could be a potential biomarker for trastuzumab-induced cardiotoxicity. The goal of this study is to further investigate the mechanisms of trastuzumab-induced cardiotoxicity and to collaborate with clinical investigators at Massachusetts General Hospital (MGH), Harvard University to validate the potential biomarker that we identified based on our preclinical studies. This proposed collaborative study may yield biomarkers that could be used to predict trastuzumab-induced cardiac dysfunction and to help define the risks and the benefits of trastuzumab treatment.
Sex and racial difference in prosthetic aortic valve selection and risk factors for patient outcome—an observational study of Medicare beneficiaries - Dongyi Du, MD, PhD/CDRH
Calcium and material characterization in women using dual-energy CT: Phase II - Nicholas Petrick, PhD/CDRH
Cardiovascular disease is the leading cause of death for American women and women have higher cardiovascular mortality rates compared with men. Large numbers of cardiovascular events occur in asymptomatic people who do not belong to high risk groups. Risk-based markers, such as coronary artery calcium score, have been suggested as methods for identifying candidates for primary prevention of coronary artery disease (CAD) through risk-factor modification. The calcium score, related to the amount of calcium found in coronary vessels, is used as a summary measure of coronary health, with higher scores indicating higher risk of CAD. Women have smaller, faster beating hearts, smaller arteries, and different anatomy than men. While research in standardizing CT quantification of coronary calcium has been carried out, little has been done to 1) address gender differences, 2) develop methods for systematically quantifying measurement error or 3) validate the performance of calcium scoring and plaque material characterization in dual-energy CT. In Phase I (OWH funded 2014-15), we are evaluating the accuracy and precision of calcium scoring in single- and dual-energy CT scans through static phantom studies. Our initial results show that vessel size and gender-based anatomy are significant factors that strongly influence calcium scoring. In Phase II, we propose to investigate how quantitative coronary calcium scoring and plaque material characterization are affected by gender difference and CT acquisition techniques with a special focus on measuring and optimizing performance of dual-energy CT in women. We will build on our initial static phantom studies by developing a dynamic motion controller that allows the impact of heart motion to be accounted for. We are also proposing a substantial expansion to evaluate the potential of dual-energy CT for characterizing the material composition of coronary plaques and in particular to validate how well dual-energy CT can differentiate hard from soft plaques. While the phantoms developed are specific to coronary vessel measurements, the general approaches and validation methods developed will generalize to the assessment of technical performance for other quantitative imaging biomarkers.
Cardiovascular Risk of Testosterone Treatment in Women (Special Funding) - Lai-Ming Lee, PhD/CDER
A variety of testosterone products are used off-label for the treatment of female sexual dysfunction (FSD). Due to the chronic nature of FSD, these products are anticipated to be used as long-term therapy in women. Therefore, assessment of cardiovascular risk will be an important factor in the risk/benefit determination. The Framingham General Cardiovascular Risk Score predicts the 10-year risk of all cardiovascular events including coronary heart disease, stroke, transient ischemic attacks, and heart failure. The variables used in the formula are age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein, use of hypertension medication, smoking status, and history of diabetes. We hypothesize that the Framingham General Cardiovascular Risk Score will be useful in estimating cardiovascular risk of drug products in Phase 3 trials. We will use available data to determine the utility of the Framingham General Risk Score to estimate the cardiovascular risk in women exposed to drug products with a likelihood of a cardiovascular signal. If successful, this formula would be applied to androgens and androgen-like products being evaluated for the treatment of female sexual dysfunctions in women.
Optimization of an in silico cardiac cell model for predicting sex differences in drug-induced proarrhythmia risk (Special Funding) - Wendy Wu, PhD/CDER
Capturing Sex-Specific Data in Regulatory Submissions and National Vascular Quality Initiative Registry - Danica Marinac-Dabic, MD, PhD/CDRH
Addressing the unmet medical needs for cardioprotection in women receiving chemotherapy - Ashutosh Rao, PhD/CDER (Supplementary funds)
The FDA regulates several oncology agents, including anthracyclines, monoclonal antibodies and cytokines that are known to induce oxidative damage and cardiac dysfunction. Younger women appear to be sensitive to cardiac dysfunction from chronic exposure to chemotherapy. Taken together with the fact that heart disease is the number one killer of women in the US, cardioprotection in women remains an unmet medical need. This project designed and validated a preclinical model for testing of both anticancer potential and cardiac safety, where spontaneously hypertensive rats (SHRs) were implanted with a syngeneic breast cancer cell line (SST-2). Using this model the project identified an inverse correlation between cardiac stress and circulating reproductive hormone levels using doxorubicin for proof-of-principle studies. This study is currently investigating reproductive hormone supplementation with doxorubicin for potential chemoprotection. The project is leveraging the SHR/SST-2 preclinical model to investigate a mechanistic link between hormone levels, oxidative stress, and cardiac health in females, as a means to provide critical, missing information on the mechanism behind female cardiac sensitivity. The results of this study may potentially enable the development of personalized therapies that can provide a mechanistically-sound treatment window to maximize anticancer activity while minimizing cardiotoxicity in women receiving chemotherapy.
Individual patient-data meta-analysis and post-market analysis as a method for improving data quality in demographic subgroups (Support for implementation of FDASIA Section 907 Action Plan) - Daniel Canos, PhD, MPH/CDRH
Women have been underrepresented in clinical trials for medical devices and cardiovascular devices in particular. Therefore, the results of these trials primarily reflect outcomes in men. Directly addressing the FDASIA 907 Action Plan priorities of improving the quality and public availability of demographic subgroup data this project combines clinical trial data submitted to the FDA as part of pre-market approval applications. This allows for the analysis of sex-differences in medical devices, hereby leveraging existing clinical data and improving methodology for performing sex-specific analysis as individual clinical trials are often underpowered to detect potential sex-differences. Furthermore, this project pools pre-market and post-market data to assess sex-differences in real-world use thereby strengthening the system to make better use of data once medical products are available on the market. By combining already existing pre-market clinical trial data and assessing post-market real-world performance, this study will be able to quickly evaluate device performance in demographic subgroups. Next to recommendations for future individual-patient data meta-analyses as a result of this project, this will also lead to rapid implementation into the regulatory review process and guidance documents, better clinical trial designs, and improve women’s health supporting multiple FDASIA priorities and action items.
Ensuring accessible supply of safe and effective drugs: Quantifying women-specific pro-arrhythmia risk of drug therapies (OWH Women's Health Cardiovascular Research Fellowship) - David Strauss, MD/PhD/CDER
Prolongation of the heart rate corrected QT (QTc) interval by drugs has been used as a surrogate for developing Torsade de Pointes (Torsade), a cardiac arrhythmia that can cause sudden cardiac death. Women are disproportionally affected by pro-arrhythmic effects of certain drugs compared to men. While some studies have suggested that women have greater drug-induced QTc prolongation compared to men, recent work has found that there is no sex difference in QTc prolongation for certain drugs. This indicates that QTc prolongation is likely not the best marker for actual Torsade risk and does not explain sex-differences in Torsade risk on its own. Instead of evaluating the effects of drug-induced QTc prolongation, this project will quantify real-world sex-specific risk of Torsade using multiple pre-market and post-market databases. The data will be used to develop Torsade risk models based on multiple predictors in women and men separately.
Calcium and material characterization in women using dual-energy computed tomography - Nicholas Petrick, PhD, CDRH
Large numbers of cardiovascular events occur in asymptomatic people who do not have a high level of risk in terms of multivariable risk scores. Novel risk markers (e.g., CT coronary calcium scoring) have been suggested as additional ways to identify patients for primary prevention of coronary artery disease (CAD). The calcium score is a summary measure of coronary health with higher scores indicating higher risk of CAD. Women have smaller, faster beating hearts and smaller arteries than men increasing the error in calcium scoring in women. Little research has been conducted to address gender differences or to develop methods for quantifying calcium score measurement error. In addition, little work has been done validating the performance of calcium scoring in dual-energy CT scans. Dual-energy CT has the ability to differentiate tissues and may reduce x-ray dose. This research project will investigate how quantitative coronary calcium scoring is affected by CT acquisition techniques with a special focus on quantifying and comparing the accuracy and precision of single- and dual-energy CT in women. The project will identify gender differences in calcium scoring and determine how CT acquisitions can be optimized to both minimize measurement error and the x-ray dose to the patient.
Publications from this project:
- Li Q, Liu S, Kyle J Myers KJ, et al. Calcium scoring with dual-energy CT in men and women: an anthropomorphic phantom study. Proc. SPIE 9783, Medical Imaging 2016: Physics of Medical Imaging, 978346 (March 30, 2016); doi:10.1117/12.2216105.
- Li Q, Liu S, Kyle J Myers KJ, et al. Impact of Reconstruction Algorithms and Gender-Associated Anatomy on Coronary Calcium Scoring with CT: An Anthropomorphic Phantom Study. Academic Radiology, December 2016; 23 (12):1470-1479.
Abdominal Aortic, Aneurysms: analysis of patient Characteristics and Anatomy Related to EVAR treatment and outcomes-AAA CARE - Tina Morrison PhD/CDRH
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