Shari Targum

Acute Heart Failure Syndromes Current State and Framework for Future Research

Acute heart failure syndromes (AHFS) poses unique diagnostic and management challenges. This syndrome has recently received attention from researchers, clinicians, regulatory agencies, and the pharmaceutical industry. However, there is no consensus on its definition, epidemiology, pathophysiology, appropriate therapeutic options, and directions for future research. This document is the result of the First and Second International Workshop on Acute Heart Failure Syndrome that took place in May 2004 and April 2005. At these workshops, a selected group of physician scientists, epidemiologists, clinicians, regulatory and governmental funding agencies, and industry representatives from North and South America and Europe convened to develop a platform for future investigative approaches and management of AHFS. Subsequently, emergency physicians, who play a pivotal role in the early management of AHFS, contributed to this document. AHFS is defined as gradual or rapid change in heart failure (HF) signs and symptoms resulting in a need for urgent therapy. These symptoms are primarily the result of severe pulmonary congestion due to elevated left ventricular (LV) filling pressures (with or without low cardiac output). AHFS can occur in patients with preserved or reduced ejection fraction (EF). Concurrent cardiovascular conditions such as coronary heart disease (CHD), hypertension, valvular heart disease, atrial arrhythmias, and/or noncardiac conditions (including renal dysfunction, diabetes, anemia) are often present and may precipitate or contribute to the pathophysiology of this syndrome.1–3 HF hospitalizations have risen steadily, with >1 million in 2004 in the United States4; a similar number has been reported in Europe. In the United States, it is estimated that these hospitalizations account for >75% of the 46 billion dollars spent each year on the care of HF patients.4 Although much has been accomplished in the management of chronic HF, the absence of evidence-based clinical practice guidelines for AHFS is striking in comparison to …

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*

Contemporary Cardiac Issues in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder diagnosed in childhood. It affects ≈1 in every 5000 live male births (≈20 000 new cases worldwide each year).1,2 This results in a US prevalence of 1.3 to 1.8 per 10 000 males 5 to 24 years of age. DMD is caused by mutations in the gene encoding the dystrophin protein. The loss of dystrophin results in a cascade of events leading to progressive loss of muscle function. Without supportive care, young men with DMD typically die in their late teens and early 20s. Historically, the most common cause of death has been respiratory failure. However, with improved respiratory support, an increasingly important source of morbidity and mortality is cardiomyopathy leading to heart failure and arrhythmias.3,4 There are important differences in DMD cardiomyopathy compared with other types of pediatric dilated cardiomyopathy.5 DMD cardiomyopathy is similar to the cardiomyopathy seen in some forms of limb girdle muscular dystrophy and congenital muscular dystrophy. In particular, a shared cardiomyopathic process is seen in those disorders in which the primary mutation alters components that directly or indirectly interact with dystrophin. There is less left ventricular (LV) enlargement at diagnosis in DMD. Only 30% of boys with DMD have cardiac symptoms at diagnosis (far fewer than other dilated cardiomyopathy). DMD cardiomyopathy is less often treated at the time of diagnosis. However, treatment rates have increased over time. Finally, there is a higher mortality for DMD cardiomyopathy than for other dilated cardiomyopathies. The DMD Care Considerations published in 2010 addressed cardiac care recommendations based on minimal surveillance standards with echocardiography.6,7 However, echocardiography has known limitations in DMD patients.8 Since the 2010 publication of the DMD Care Considerations,6,7 there have been significant advances in the understanding …

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.

Quantitative Understanding of QTc Prolongation and Gender as Risk Factors for Torsade de Pointes

Several risk factors for development of a potentially fatal ventricular arrhythmia, torsade de pointes, have been observed, including female gender. However, in most investigations, only few torsade events were included and/or rarely were postdose heart rate corrected QT (QTc) measurements included, as a surrogate of drug exposure. We developed a multivariate logistic regression model using data from 22,214 patients (33% women) with 84 torsade events (56% women) to evaluate the relationship between risk factors for torsade using data from four anti‐arrhythmic drug development programs. Before model development, we evaluated different QT/QTc postdose metrics (average, maximum, etc.) to determine which QT metric should be included into the model. The developed multivariate model showed that, after accounting for known risk factors for torsade and postdose QTc, that female gender remained a significant risk factor for torsade.

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).

Is Randomization to Placebo Safe? Risk in Placebo-Controlled Angina Trials: Angina Risk Meta-Analysis

Objective: It was the aim of this study to document the risks of symptomatic patients with angina in placebo-controlled, anti-anginal drug development trials in which symptom-limited exercise testing was used as the primary endpoint. Patients and Methods: The original case report forms submitted to the United States Food and Drug Administration in support of approval of new or supplemental new drug applications between 1973 and 2001 were identified and subjected to a by-patient meta-analysis, utilizing both a maximum likelihood analysis and classical Mantel-Haenszel methods. Results: There were 63 placebo-controlled, clinical trials that randomized 10,865 patients, with 1,047 patient-years of observation time. The trials involved 21 different chemical entities from 4 different drug classes. The relative risk (RR) for withdrawal (placebo compared to drug-treated patients) was not increased [RR = 0.92, 95% confidence interval (CI) 0.78–1.08; p = 0.28]. Of interest, a RR of 0.54 (95% CI 0.26–1.04; p < 0.068) for irreversible harm (a combination of cerebrovascular accidents, myocardial infarction and death) and a RR of 0.89 (95% CI 0.61–1.30; p = 0.56) for serious cardiovascular events (myocardial infarction, congestive heart failure, cerebrovascular accidents) both non-statistically significantly favored being randomized to placebo. Conclusions: For the development of current or future drugs for the treatment of angina, there is no obvious contraindication to the use of placebo controls and exercise tolerance testing.

Drug Approval Process for Acute Heart Failure Syndrome in the United States

The history of drug approval that targets the heart failure (HF) population has been subject to the advancements that have been made in the field of HF. A better understanding of the pathophysiology of the HF syndrome, with its complexity and an ever-growing number of patients, has led to an evolution in thinking at the Food and Drug Administration (FDA) Division of Cardiovascular and Renal Products. Once thought of as a terminal disorder without much hope even of palliation, heart failure therapies have emerged as powerful agents that can impact mortality and morbidity and may alter the course of the disease. The therapeutic choices through the years have targeted the concepts that were “in vogue” in each era. As an example, when inotropic derangement was thought to be the primary cause of HF, several inotropic therapies emerged and were approved based on a small amount of data.1 As the neurohormonal hypothesis was tested, drugs were targeted to this important axis, and the mortality and morbidity improved.