The diagrams below illustrate the QT list decision process using the example of methadone, a drug only recently found to cause Torsades de Pointes, despite decades of use.
We are now aware that some drugs, including those in previously unsuspected drug classes, have the ability to cause death by inducing a rare cardiac arrhythmia, Torsades de Pointes (TdP) (https://arizonacert.org/consumers/ask-expert.htm). Part of the mission of the Arizona CERT is to identify drugs that cause arrhythmias, to understand the mechanisms behind this adverse event and to develop tools to prevent drug-induced arrhythmia. The Lists of drugs that can cause prolonged QT and TdP was created to fulfill this mission. We have developed a method of examining drugs that is multifaceted; we feel it is very important to provide information about the potential risk of drugs in such a way that providers and patients can make informed decisions about the benefits and risks of drugs.
There are several ways that questions about the safety of specific drugs come to our attention. We look at drugs after being alerted to an event submitted to our International Registry of Drug Induced Arrhythmia (https://arizonacert.org/medical-pros/clinical-overview.htm). We are also prompted by cases reported in the medical literature. We examine the labels of newly approved drugs and any changes that are made to existing labels. Finally, we receive requests for information about the safety of drugs from providers, pharmacists, nurses, and consumers. We then use QSCAN®, a commercially available program designed to facilitate searching the Food and Drug Administration’s (FDA) publicly-available database for adverse drug event reports. We look to see if there are more reports of TdP and prolonged QT than would be expected in association with the drug. We examine at the medical literature to see if there are cases, randomized trials, and any laboratory or clinical testing that would suggest a pharmacological basis of drug-induced TdP, e.g the ability of a drug to block a potassium channel in cardiac muscle cells. We take into account not only the quantity of reports in the literature, but the quality as well, including the expertise of the authors, the journal it is published in, and the quality of experimental design.
Ideally, we then can move into clinical and pharmacologic analyses. We would examine in our laboratory whether the drug can block the human cardiac potassium channel. We could also conduct a clinical trial to see if taking the drug in usual dosages causes prolongation of the QT interval on the ECG. Drugs that are known to cause TdP do so primarily in rare cases and it is thought that it is due to either a drug interaction or an accumulation of other factors known to be implicated in TdP, such as low serum potassium levels, female sex and/or congenital causes. In most people, taking the drug will only cause their QT interval on the ECG to prolong slightly. Therefore, it is appropriate to test drugs on healthy adults in controlled clinical environments.
A tool that is proving to be of value is looking at events in large databases, such as those of medications and hospitalizations for patients who are insured by health maintenance organizations. We think that with the addition of medication coverage for those with Medicare, we might have an important new resource for examining drug safety.
Finally, we complete a summary analysis. We have a panel at the University of Arizona Health Sciences Center that includes a cardiac electrophysiologist, a clinical pharmacist, a nurse/epidemiologist, and two physician/clinical pharmacologists that review the information and decide whether the drug should be included on the list. They also decide, based on the criteria described with our lists (https://arizonacert.org/medical-pros/drug-lists/drug-lists.htm), what lists the drugs should go on. When the lists were first compiled, they were sent to the larger scientific advisory committee for comment and suggestions (https://arizonacert.org/advisory-committee.htm). Periodically, we again ask the panel about specific drugs and for input about the content of the drug lists.
Arizona Center for Education and Research on Therapeutics
The Critical Path Institute
Tucson, Arizona and Rockville, Maryland
Funded in part by Agency for Healthcare Research and Quality grant 1 U18 HS10385-01
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