Karen A. Hicks

2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards)

This document was approved by the American Heart Association Science A College of Cardiology Board of Trustees on November 12, 2014. The American College of Cardiology requests that this document be cited a Fonarow GC, Jacobs JP, Jaff MR, Lichtman JH, Limacher MC, Mahaffey KW elements and definitions for cardiovascular endpoint events in clinical trials: Task Force on Clinical Data Standards (Writing Committee to Develop Cardi This article has been copublished in Circulation. Copies: This document is available on the World Wide Web sites of the Association (my.americanheart.org). For copies of this document, please con reprints@elsevier.com. Permissions: Multiple copies, modification, alteration, enhancement, and permission of the American College of Cardiology. Requests may be compl author-agreement/obtaining-permission). Marian C. Limacher, MD, FACC, FAHA Kenneth W. Mahaffey, MD, FACC Roxana Mehran, MD, FACC, FAHA Steven E. Nissen, MD, MACC, FAHA Eric E. Smith, MD, MPH, FAHA Shari L. Targum, MD, FACC*

Bleeding Academic Research Consortium Consensus Report The Food and Drug Administration Perspective

The Center for Drug Evaluation and Research (CDER) of the Food and Drug Administration (FDA) is responsible for ensuring the safety and effectiveness of human drug products. CDER recognizes the value of therapeutic agents and encourages innovation in their development. CDER tries to ensure that approved drugs are accompanied by labeling that describes the benefits and risks of the drugs and provides good directions for use. Article see p 2736 CDER has a continuing interest in ensuring the quality of clinical trials, both because better trials will produce results that are reliable, and because they will be more efficient, ie, more likely to show a useful effect when there is one. One important way to improve the quality and efficiency of clinical trials and to enable consideration of multiple trials is through the development of standardized end point definitions. The Bleeding Academic Research Consortium (BARC) is an example of such efforts. An independent group, BARC includes members of academic research organizations, cardiovascular professional societies, pharmaceutical and cardiovascular device manufacturers, the National Institutes of Health, and the FDA (CDER and Center for Devices and Radiological Health). The FDA participated in a 1-day meeting in February …

Troponin measurements during drug development--considerations for monitoring and management of potential cardiotoxicity: an educational collaboration among the Cardiac Safety Research Consortium, the Duke Clinical Research Institute, and the US Food and Drug Administration.

Drug-induced cardiac toxicity is a recognized challenge in development and implementation of pharmacotherapy. Appropriate biomarkers are needed to detect these abnormalities early in development and to manage the risk of potentially cardiotoxic drugs or biologic agents. Circulating cardiac troponin (cTn) is the most widely used biomarker for detection of myocardial injury. Although most commonly used to detect myonecrosis in the setting of ischemia, cTns are also elevated with other acute and chronic disease processes, including heart failure, renal failure, sepsis, pulmonary embolic disease, and many others. High-sensitivity assays for both cTnI and cTnT are now available that achieve acceptable imprecision (coefficient of variation <10%) at the 99th percentile of a normal reference population. Even more sensitive assays are being developed that detect cTn in ranges that are near the level of normal cellular turnover (apoptosis). These properties of cTn and the continuing evolution of highly sensitive assays position cTn as a potentially uniquely informative marker for early detection of cardiac toxicity. This article summarizes collaborative discussions among key stakeholders in the Cardiac Safety Research Consortium about the use of cTn monitoring in drug development.

Cardiac imaging approaches to evaluate drug-induced myocardial dysfunction

The ability to make informed benefit-risk assessments for potentially cardiotoxic new compounds is of considerable interest and importance at the public health, drug development, and individual patient levels. Cardiac imaging approaches in the evaluation of drug-induced myocardial dysfunction will likely play an increasing role. However, the optimal choice of myocardial imaging modality and the recommended frequency of monitoring are undefined. These decisions are complicated by the array of imaging techniques, which have varying sensitivities, specificities, availabilities, local expertise, safety, and costs, and by the variable time-course of tissue damage, functional myocardial depression, or recovery of function. This White Paper summarizes scientific discussions of members of the Cardiac Safety Research Consortium on the main factors to consider when selecting nonclinical and clinical cardiac function imaging techniques in drug development. We focus on 3 commonly used imaging modalities in the evaluation of cardiac function: echocardiography, magnetic resonance imaging, and radionuclide (nuclear) imaging and highlight areas for future research.

Assessing Sex Differences in the Risk of Cardiovascular Disease and Mortality per Increment in Systolic Blood Pressure: A Systematic Review and Meta-Analysis of Follow-Up Studies in the United States

In the United States (US), cardiovascular (CV) disease accounts for nearly 20% of national health care expenses. Since costs are expected to increase with the aging population, informative research is necessary to address the growing burden of CV disease and sex-related differences in diagnosis, treatment, and outcomes. Hypertension is a major risk factor for CV disease and mortality. To evaluate whether there are sex-related differences in the effect of systolic blood pressure (SBP) on the risk of CV disease and mortality, we performed a systematic review and meta-analysis. We conducted a comprehensive search using PubMed and Google Scholar to identify US-based studies published prior to 31 December, 2015. We identified eight publications for CV disease risk, which provided 9 female and 8 male effect size (ES) observations. We also identified twelve publications for CV mortality, which provided 10 female and 18 male ES estimates. Our meta-analysis estimated that the pooled ES for increased risk of CV disease per 10 mmHg increment in SBP was 25% for women (95% Confidence Interval (CI): 1.18, 1.32) and 15% for men (95% CI: 1.11, 1.19). The pooled increase in CV mortality per 10 mm Hg SBP increment was similar for both women and men (Women: 1.16; 95% CI: 1.10, 1.23; Men: 1.17; 95% CI: 1.12, 1.22). After adjusting for age and baseline SBP, the results demonstrated that the risk of CV disease per 10 mm Hg SBP increment for women was 1.1-fold higher than men (P<0.01; 95% CI: 1.04, 1.17). Heterogeneity was moderate but significant. There was no significant sex difference in CV mortality.

2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards).

This document was approved by the American Heart Association Science A College of Cardiology Board of Trustees on November 12, 2014. The American College of Cardiology requests that this document be cited a Fonarow GC, Jacobs JP, Jaff MR, Lichtman JH, Limacher MC, Mahaffey KW elements and definitions for cardiovascular endpoint events in clinical trials: Task Force on Clinical Data Standards (Writing Committee to Develop Cardi This article has been copublished in Circulation. Copies: This document is available on the World Wide Web sites of the Association (my.americanheart.org). For copies of this document, please con reprints@elsevier.com. Permissions: Multiple copies, modification, alteration, enhancement, and permission of the American College of Cardiology. Requests may be compl author-agreement/obtaining-permission).

Circulating Cardiac Troponins as Specific Biomarkers of Myocardial Damage: Clinical Considerations

Cardiac troponin (cTn) is one of the most widely used biomarkers in clinical care and biomedical research. Compared to the MB fraction of creatine kinase (CK-MB), cTn is the preferred biomarker for detecting myocardial necrosis because of its high myocardial tissue specificity and high clinical sensitivity. Although an elevated cTn value reflects injury leading to myocardial necrosis, the underlying mechanism may be difficult to ascertain. Such mechanisms may be ischemic, nonischemic, or analytical in origin and can only be determined by considering the clinical context in which the measurement is made.

The Devil Is Always in the Details

M yocardial infarction (MI) is a commonly used endpoint in clinical trials evaluating the efficacy and safety of cardiovascular drugs and devices. Periprocedural MIs (PMIs), also known as type 4a MIs, contribute to the MI endpoint and can account for a substantial number of events. In the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitionWith Prasugrel–Thrombolysis InMyocardial Infarction 38) study, for example, approximately 40% of MIs occurred periprocedurally (1). How a PMI is defined influences the number of MI events that may be adjudicated by a clinical events committee (CEC).