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.
Novel therapeutic approaches to prevent drug-induced torsade de pointes - Norman Stockbridge, MD, PhD, CDER
Fourteen drugs have been removed from the market worldwide because they cause an abnormal heart rhythm that leads to sudden death and up to 70% of the cases occur in women. The exact reason for this higher rate in women is unknown, but it may be because (1) women are exposed to higher drug levels due to smaller body size, (2) women break down the drugs and transport the drugs to the heart differently or (3) women’s hearts are inherently more susceptible to drugs that cause abnormal heart rhythms.
This project will perform a clinical study where an equal number of women and men will receive multiple drugs that affect different ion channels in the heart. This project will take blood samples to measure the amount of drug in the blood and record electrocardiograms (“EKG”) to assess the effect of the drugs on the ion channels of the heart. This project will also combine drugs to determine if the potentially harmful effects of one drug can be prevented by the beneficial effects of a second drug. This work will examine the reasons for why women and men respond differently to drugs and why women are at higher risk for some types of abnormal heart rhythms caused by drugs. In addition, the project will determine if drug-induced abnormal heart rhythms may be able to be prevented by combining drugs. Together, this will ensure the safer use of drugs in women.
Publications from this project:
-Vicente J, Simlund J, Johannesen L, Sundh F, Florian J, Ugander M, Wagner GS, Woosley RL, Strauss DG. Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk. J Electrocardiol. 2015 Jul-Aug;48(4):533-8.
-Vicente J, Johannesen L, Mason JW, Pueyo E, Stockbridge N, Strauss DG. Sex differences in drug-induced changes in ventricular repolarization. J Electrocardiol. 2015 Aug 4. pii: S0022-0736(15)00226-5. doi: 10.1016/j.jelectrocard.2015.08.004.
Develop animal and cellular models to investigate the mechanisms of cardiotoxicity induced by trastuzumab, trastuzumab/pertuzumab, and ado-trastuzumab emtansine to support post-marketing surveillance of these antibody-based HER2-targeted therapies, and characterize novel serum biomarker of cardiotoxicity induced by trastuzumab, trastuzumab/pertuzumab, and ado-trastuzumab emtansine - Wen Jin Wu, MD, PhD, CDER
Breast cancer is one of the most common cancers diagnosed in the U.S. women. Trastuzumab (Herceptin®) is a humanized monoclonal antibody that binds to a cell surface protein called human epidermal growth factor receptor 2 (HER2) and is approved for the treatment of HER2-positive breast cancer. HER2 is a member of HER family receptors, involved in the development and progression of human breast cancer. HER2-positive breast cancers tend to be more aggressive than other types of breast cancer. Clinical studies have found that trastuzumab is associated with sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline-containing chemotherapy regimens. The mechanisms by which trastuzumab induces cardiac damage remain unclear. Currently there are no approved biomarkers that can be used to predict the occurrence of cardiac damage induced by trastuzumab. Recently, pertuzumab and ado-trastuzumab emtansine, both of which are also directed against HER2, have been approved for the treatment of HER2-positive breast cancer. This study focuses on identification of biomarkers for the detection of cardiac damage induced by trastuzumab, pertuzumab and ado-trastuzumab emtansine. Information obtained from this study may enhance post-marketing surveillance of cardiac adverse effects associated with use of antibody-based HER2-targeted therapies.
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.
Blood pressure threshold for cardiovascular disease risk: an assessment of sex-based criterion - Ching-Wei Chang, NCTR
Cardiovascular disease (CVD) is the leading cause of death for both women and men in the United States. Blood pressure is one of the seven metrics used by the American Heart Association to assess cardiovascular health, and hypertension (uncontrolled elevated BP) is considered a primary risk factor for CVD. Under current blood pressure (BP) guidelines for assessing hypertension, the prevalence of hypertension is higher in men than in women and averaged BP is generally higher in men, yet women tend to have worse outcomes after a cardiovascular disease event. Due to these inconsistencies, it is reasonable to explore whether current BP guidelines for hypertension should be modified to reflect sex-difference. The proposed study will present a systematic review of published literature and analyze summarized data from existing studies to examine whether BP guidelines for cardiovascular disease risk should vary by sex. Consequently, if warranted, new BP guidelines for hypertension will be determined to appropriately reflect differences between women and men. The results of the proposed study may play a critical role in determining whether women will benefit from sex-specific hypertension guidelines. Thus, findings from this study will enable improvements in antihypertensive treatment and management practices for women.
Sex differences in drug-induced QT prolongation and torsade de pointes: establishing an in vitro model for high-throughput scre ening and risk assessment of torsadogenic drugs - Li Pang, MD, NCTR
Numerous drugs have the potential adverse effect of prolonging the QT interval, a marker for torsade de pointes (TdP), which can cause the heart to stop beating. Women are at a much higher risk than men for experiencing drug-induced TdP. As sex hormones are believed to play an important role in determining why women are more susceptible to drug-induced TdP, this study will establish a model to simulate sex differences in drug-induced QT prolongation and TdP by evaluating drug effects on human heart cells from men and women treated with sex hormones. This project will test the model for high-throughput screening and risk assessment of QT prolonging drugs. The innovative model established in this study will 1) strengthen FDA’s ability to detect and rapidly analyze cardiac safety problems that are associated with new drug approval; 2) aid pharmaceutical companies in identifying compounds that may do more harm to women before costly clinical trials are conducted; and 3) provide valuable information to physicians for potential TdP risk of many QT prolonging drugs and guide them in prescribing those drugs to different subgroups of patients, particularly women versus men.
Abdominal Aortic, Aneurysms: analysis of patient Characteristics and Anatomy Related to EVAR treatment and outcomes-AAA CARE - Tina Morrison PhD/CDRH