CredibleMeds.org_ What does it offer?

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Available online at www.sciencedirect.com

www.elsevier.com/locate/tcm

CredibleMeds.org: What does it offer? Raymond L. Woosley, MD, PhDa,b,n, Kristin Black, BAb, C. William Heise, MDa, and Klaus Romero, MS, MDc a

Division of Clinical Data Analytics and Decision Support, Department of Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ b AZCERT, Oro Valley, AZ c Critical Path Institute, Tucson, AZ

abstra ct Since the 1990s, when numerous non-cardiac drugs were first recognized to have the potential to prolong the QT interval and cause torsades de pointes (TdP), clinicians, drug regulators, drug developers, and clinical investigators have become aware of the complexities of assessing evidence and determining TdP causality for the many drugs being marketed or under development. To facilitate better understanding, the Arizona Center for Education and Research on Therapeutics, known as AZCERT, has developed the CredibleMeds.org website which includes QTdrugs, a listing of over 220 drugs placed in four risk categories based on their association with QT prolongation and TdP. Since the site was launched in 1999, it has become the single and most reliable source of information of its kind for patients, healthcare providers, and research scientists. Over 96,000 registered users rely on the QTdrugs database as their primary resource to inform their medication use, their prescribing or their clinical research into the impact of QT-prolonging drugs and druginduced arrhythmias. The QTdrugs lists are increasingly used as the basis for clinical decision support systems in healthcare and for metrics of prescribing quality by healthcare insurers. A free smartphone app and an application program interface enable rapid and mobile access to the lists. Also, the CredibleMeds website offers numerous educational resources for patients, educators and healthcare providers that foster the safe use of medications. Key words: QT prolongation, QT interval, Torsades de pointes, Sudden death, Arrhythmia. & 2017 Elsevier Inc. All rights reserved.

Introduction The CredibleMeds.org website is a unique resource for anyone seeking reliable information regarding the many drugs known to prolong the QT interval and cause the potentially lethal arrhythmia, torsades de pointes (TdP) [1]. In the 16 years since its launch, the website has grown from a simple list of drugs that cause TdP to a valuable clinical and research resource for patients, healthcare providers, and research scientists. The website was created by AZCERT, one of a network of 14 federally funded Centers for Education and Research on Therapeutics (CERTs) created to improve health outcomes from therapeutics [2,3]. Initially based at the

The authors have indicated there are no conflicts of interest. ⁎ Corresponding author. E-mail address: [email protected] (R.L. Woosley). http://dx.doi.org/10.1016/j.tcm.2017.07.010 1050-1738/& 2017 Elsevier Inc. All rights reserved.

University of Arizona, AZCERT has focused on identifying drugs and drug-drug interactions that are responsible for QT prolongation and TdP. In 2012, AZCERT transitioned from a university-based program to a free-standing non-profit 501(c) 3 corporation, now funded by the US Food and Drug Administration, research grants, and charitable contributions. AZCERT and its CredibleMeds website are recognized as the singular international resource for reliable, up to date, and independent information on medications, especially those associated with QT prolongation and/or TdP [1]. To prevent real or perceived bias in assessing QT or TdP causality for drugs, AZCERT does not accept funding from companies that have a commercial interest in medications.

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What CredibleMeds.org offers AZCERT curates and posts on the CredibleMeds website list of drugs based on their risk of TdP. The “QTdrugs” list includes all drugs that can affect the QT interval in humans and therefore have some risk of TdP. This list includes three subcategories of drugs, that is, those with Known Risk of TdP, those with Possible Risk of TdP, and those with Conditional Risk of TdP. The website also posts another list, drugs to avoid in patients with congenital long QT syndrome (CLQTS), which includes all of the drugs on the QTdrugs list plus additional drugs that have a special risk for CLQTS patients because of their adrenergic effects [4]. Most search engines when queried with “QTdrugs,” “torsades.org,” or “AZCERT” quickly direct visitors to the CredibleMeds.org home page where they can easily search the QTdrugs lists for specific drugs of interest. If any of the 250,000 visitors each year wish to download and/or print the complete lists of drugs, the site requires that they register so that they can be notified by e-mail when the lists have been revised. This is considered necessary for the safe use of the lists due to the fact that the lists are revised every 4–8 weeks. The home page for the website presents visitors with three main portals shown in Fig. 1. All three portals offer access to the QTdrugs lists, but each has additional information that is tailored for specific types of visitors, either “For Everyone,” “For Healthcare Providers,” or “For Research Scientists.” For each audience, the first link on the navigation bar is to “QTdrugs Lists (registration required).”

For Everyone: QTdrugs lists (registration required) Under a contract with the U.S. Food and Drug Administration's Safe Use Initiative, AZCERT curates and posts on the CredibleMeds website lists of drugs that are associated with TdP and/or QT prolongation, commonly referred to as the QTdrugs lists [4]. The continually updated lists are currently

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accessed by over 96,000 registered visitors from 193 countries. Fifty six percentage of the registrants are healthcare providers, 39% are other individuals, and 5% are research scientists. A survey of visitors found that 95% had a positive impression of the website [5]. To expand and facilitate the use of the most up to date version of QTdrugs, AZCERT has developed and released an application program interface (API) that enables health information technology systems to have online open-source access to the lists. Also, this API connects the QTdrugs Lists to CredibleMeds® smartphone apps that are available free from the major mobile application providers (iOS version at the App Store®, Android version at Google Play®, or Windows 360 version at Microsoft Mobile®). The apps include information about the QTdrugs list and the list of Drugs to Avoid in CLQTS and the user can search each list for drugs of interest and display each drug's generic name, common brand names, TdP risk category and route given. In addition, for each drug, a link is provided to search the National Library of Medicine for relevant citations.

AZCERT's scientific review of drugs Medications are evaluated for their association with druginduced QT prolongation or TdP by a Scientific Review Committee with three physician members (R.L.W., C.W.H., and K.R.). The committee's decisions and recommendations for placement of drugs into TdP risk categories are reviewed by an International Advisory Board of 39 recognized authorities on drug safety and cardiovascular medicine (https:// www.crediblemeds.org/research-scientists/advisory-board/). AZCERT developed the process for Adverse Drug Event Causality Analysis (ADECA™), described on the website and in peer-reviewed publications, to evaluate drugs for their risk of causing QT prolongation and TdP [4,6]. Because the available evidence frequently has limitations and gaps, and is often of variable quality, AZCERT uses this systematic, indepth analysis of all available data to assess causality. Since

Fig. 1 – The three major portals for visitors to CredibleMeds.org (For Everyone, For Healthcare Providers, and For Research Scientists) and the navigation bars that are available for each page.

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the lists were first compiled and posted on the internet in 1999, over 135 new drugs have been added and many have been moved among categories or removed because of new evidence. Beginning in 2012, AZCERT expanded the lists to include drugs marketed outside the United States, especially in Europe, Japan and Canada. Twenty five drugs marketed outside the United States have been added to the lists and designated as non-US drugs. The risk categorization process begins when new or suspect drugs are brought to the attention of AZCERT scientists, usually in 1 of the 3 ways shown at the top of Fig. 2. The AZCERT Scientific Review Committee assesses the ability of each drug to prolong QT and/or cause TdP by analyzing the available laboratory and clinical evidence and applying the Bradford Hill criteria for causality (i.e., the conditions necessary to provide adequate evidence of a causal relationship between incidence and a consequence) [7]. The analysis includes a thorough review of published research (PubMed search results using standardized search terms) and all adverse events reported to the FDA's Adverse Event Reporting System (FAERS), and uses the empirical Bayesian data-mining statistical software developed for the FDA (Empirica Signal Software, Oracle Health Sciences, Redwood Shores, California) [8]. CredibleMeds places drugs in one of four categories of TdP risk. Drugs with “Known Risk of TdP” are those found to have conclusive evidence that they cause TdP in some patients, even when administered as recommended in the drug's FDAapproved label. Drugs that prolong the QT interval during

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routine clinical use, but do not at this time have conclusive evidence of TdP causality, are classified as having a “Possible Risk of TdP.” Beginning in 2004, the “Conditional Risk” category was added and includes drugs for which there is a risk of TdP, but only under certain specific conditions, such as overdose, hypokalemia, hypomagnesemia, bradycardia, or the result of drug-drug interactions. In addition, this category includes drugs that are associated with TdP due to their ability to generate the conditions that enable another drug to induce TdP (e.g., loop diuretic agents or metabolic inhibitors of a QT-prolonging drug). The fourth category is for those drugs with Special Risk for CLQTS patients. The lists of drugs in these categories include additional information about each drug (see below) and a link to PubMed that provides the users with a list of research publications that result from the following search query: drug name and (QT or Torsad⁎). If the visitor enters a drug name that is misspelled, they receive suggestions of drugs with similar spelling. If a drug is entered that has been reviewed by AZCERT but not placed on one of the four lists, visitors are informed of such with the caveat “Since the available evidence may be incomplete, this should not be construed as evidence that the drug is free of risk of QT prolongation or torsades de pointes.” The process for evaluating drugs and all of the decisions made by the Scientific Review Committee regarding the drugs to be included on lists are reviewed and overseen by an International Advisory Board of clinical and pharmacological experts. The board's advice is also sought whenever

Fig. 2 – Schematic for the ADECA process for causality analysis of drug safety. Drugs from one or more of the three primary sources (cases, the medical literature, or new or revised drug labeling for marketed drugs) are evaluated for their risk of QT prolongation, TdP, or both. The Bradford Hill criteria [7] are used to analyze all available evidence and construct a summary report that is reviewed by the CredibleMeds.org team and, in some cases, referred to the Advisory Board for consideration. On the basis of this analysis, an iterative process is used to decide whether the drug should be placed on one of the three lists: drugs with Known Risk of TdP; drugs with Possible Risk of TdP; or drugs with Conditional Risk of TdP. All drugs on these lists are monitored continuously for new evidence that could result in a change in their TdP risk classification. FDA ¼ Food and Drug Administration; TdP ¼ torsades de pointes. (Adapted with permission from Woosley et al. [6].)

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Fig. 3 – The number of drugs in each of the four categories of TdP risk posted on the CredibleMeds website from 1999– 2017. The graph displays the changing number of drugs in each of the four categories of TdP risk from the initial postings at www.CredibleMeds.org in 1999 until June 2017. The number of drugs on the list of drugs with Known Risk of TdP at any point in time is shown as a green line. The number of drugs with Possible Risk of TdP is shown in red. The number of drugs with Conditional Risk of TdP (i.e., associated with TdP under certain conditions) is shown in orange. The number of drugs on the list of Drugs to Avoid in patients with congenital long QT Syndrome (CLQTS) is shown in blue. The latter list includes all of the drugs listed in the other three risk categories plus other drugs that do not prolong QT per se (e.g., adrenergic drugs) but have actions known to place some CLQTS patients at risk. CLQTS ¼ congenital long QT syndrome; TdP ¼ torsades de pointes. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

conflicting evidence must be resolved or when any board member expresses concern about a recommendation made by the Scientific Review Committee. Medications on all four lists are continuously monitored for new evidence and, in recent years, the lists have been revised every 4–8 weeks. Fig. 3 shows how the number of drugs on each list has changed since they were first launched in 1999. Currently, 57 medications are on the list of drugs known to cause TdP (including nine removed from the U.S. market, but which are still available in some countries). Another 92 are on the list with Possible Risk of TdP and 43 are on the Conditional Risk list. Two hundred and twenty-four medications are on the list of Drugs to Avoid by patients with CLQTS. Fig. 4 shows the broad range of therapeutic areas for the drugs on the QTdrugs lists and demonstrates the breadth of potential impact on medical practices. CredibleMeds has become an invaluable tool for the clinical management of patients affected by CLQTS [9]. Established arrhythmia centers caring for these patients refer them to the CredibleMeds website so they or a family member can print an updated list of drugs to avoid [9]. Since many healthcare professionals, from general practitioners to cardiologists, are unaware of the QT-prolonging potential of many cardiac and non-cardiac drugs [10,11], the lists have become an essential resource in the management of patients with channelopathies. Visitors to CredibleMeds.org have several options to access or download the information in the QTdrugs list. Each list can be copy/pasted or printed as a table that includes each drug's generic name, common brand names, drug class, therapeutic

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Fig. 4 – Spectrum of therapeutic areas for drugs listed at www.CredibleMeds.org with Known Risk of TdP, Possible Risk of TdP, or Conditional Risk of TdP. The x-axis displays the number of drugs that were in each of the therapeutic categories listed on the y-axis as of July 2016. Each drug was placed in the therapeutic category in which it has demonstrated predominant clinical efficacy. ADHD ¼ attention deficit hyperactivity disorder; Misc. ¼ miscellaneous; TdP ¼ torsades de pointes.

use, TdP risk category and route of administration. The complete tables of information can also be converted to a PDF or Excel File and printed. The user can also print a shorter 2–3 page PDF in English or Spanish that lists only the drug names (generic and brand) and each drug's risk category. In the last year, these PDFs have been downloaded and printed 32,000 times with 15% of those in Spanish. This shorter format for QTdrugs is available as a “Combined List” of all drugs in the Known, Possible and Conditional risk categories or as the longer list of all Drugs to Avoid for patients with CLQTS.

Additional resources for specific types of visitors For Everyone: Create “My Medicines” online lists To address one of the most challenging aspects of therapeutics, AZCERT has created an online repository for patients to create and maintain a list of the medicines they are taking. The user is prompted to remember to include hormones, vitamins, non-prescription medicines and dietary supplements. When creating the medicines list, the program informs the user if any drug they enter is in one of the four TdP risk categories and it will subsequently inform the user by e-mail if one of the drugs they are taking has been newly added to the lists. The lists can be printed or directly e-mailed for delivery to the patient's pharmacist or physician.

For Everyone: Educational tools Several links are on a navigation bar to take the visitor to (1) educational papers written for the lay public, (2) a guide for

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Fig. 5 – Logic diagram for clinical decision support to reduce the risk of drug-induced torsades de pointes (TdP). safe medication use, (3) a drug interaction advisory on the 25 major drug-drug interactions, (4) useful links to other reliable sources of information on medicines, and (5) a list of scientific peer-reviewed articles published by AZCERT scientists.

that is, they are found in one of the main three TdP risk categories, Known Risk, Possible Risk, and Conditional Risk. These include anti-cancer drugs, anti-nausea medicines, anti-depressants, and anesthetics. Similar tables are being developed for neuropsychiatry and internal medicine.

For Everyone: Virtual medicine cabinet For Research Scientists The Virtual Medicine Cabinet is an educational tool designed as a cartoon representation of a medicine cabinet filled with the non-prescription medicines that are commonly found in the home. By clicking on any of the products in the cabinet, the user sees a pop-up that alerts them to potentially dangerous drug interactions relevant to these non-prescription drugs.

For Healthcare Providers: Rx tools—Flockhart's table This link takes the visitor to several educational articles and tools important to prescribers. Downloadable monographs developed by AZCERT in collaboration with the American Medical Association are available on topics such as Pharmacogenetics and Warfarin Genetic Testing. A PowerPoint® slide presentation on Preventable Adverse Drug-Drug Interactions, developed in collaboration with the FDA, has been downloaded over 50,000 times. Articles on drug-induced long QT, short QT syndrome and methadone drug interactions are available. A link is provided to Indiana University's Clinically Relevant Table of Cytochrome P450 Drug-Drug Interactions that was developed by Dr. David Flockhart, a founding member of the AZCERT Board of Directors. Flockhart's table is an internationally recognized resource to help clinicians understand and prevent adverse drug-drug interactions [12]. There is also a link to Frequently Asked Questions (FAQs) about the CredibleMeds website that are relevant to the interests of prescribers.

For Healthcare Providers: OncoSupport for oncology prescribing This link in the navigation bar takes the visitor to a table that lists the QTdrugs commonly prescribed by oncologists,

This portal includes a link that takes researchers to a full description of the ADECA process that is used by the Scientific Review Committee to evaluate evidence while considering drugs for the QTdrugs Lists. There are links to web pages that include brief bios of the members of the Scientific Review Committee and the Advisory Board. Another link takes visitors to a list of over 90 peer-reviewed publications that have resulted from the research and educational programs in AZCERT. This portal also includes summaries of scientific articles that have used the QTdrugs lists in cardiovascular epidemiology research and in development of clinical decision support systems. These articles have examined the incidence of drug-induced TdP and increased mortality in patients with excessive QT prolongation in large populations such as in the national health systems for Germany [13,14], Belgium [15], Sweden [16], and Denmark [17]. Also, the Pharmacy Quality Alliance identified the CredibleMeds list of drugs with Known Risk of TdP as those that should be used when screening for serious drug-drug interactions (DDIs). Screening for DDIs with these drugs was accepted by the Centers for Medicare and Medicaid Services (CMS) as a metric for measuring the quality of healthcare delivery [18].

Role of CredibleMeds in clinical decision support systems The overall goal of the CredibleMeds website is to foster and support efforts to prevent TdP. Consensus papers have defined what actions are required for prevention of TdP but successful implementation requires that physicians be able

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to manage massive amounts of information about the drugs and about their patients [19]. This has prompted scientists to develop Clinical Decision Support Systems (CDSS) to help physicians and other members of the health care team to reach optimal medical and therapeutic decisions that minimize the risk of TdP. Using the QTdrugs lists, investigators at the Mayo Clinic [20] and the University of Indiana [21] developed CDSS that issue alerts to warn prescribers of potential harm from a therapeutic choice. These programs have been shown to improve prescribing and reduce the risk of QT prolongation in hospitalized patients [21,22]. Unfortunately, the beneficial impact of these CDSS has been diminished because physicians and pharmacists override or ignore 75–95% of the alerts [20,21,23,24]. To improve the acceptance of alerts and the effectiveness of CDSS overall, an national panel of experts has recommended that CDSS should strive to provide patient-specific, clinically relevant and essential information at the time when a decision is being made, without overwhelming the decision-makers with alerts perceived to be annoying or irrelevant [23]. In order to move away from the use of alerts that only signal prescribing errors, the concept of “medical autopilots” that send prescribers patient-specific advisories has been suggested as a preferred approach for CDSS [25]. Such a program in now in place in hospitals affiliated with the University of Arizona. The system monitors each patient's electronic medical record (EMR) and sends advisories to guide prescribers toward decisions that are expected to result in maximum clinical benefit and minimal risk of TdP. Fig. 5 shows the decision support logic and examples of the types of advisories that are tailored to the risk profile of the patient. Hopefully, in the near future, a CDSS with these characteristics will be shown to prevent TdP and improve patient outcomes by incorporating the QTdrugs lists and all of the clinical and genomic risk factors that we know can contribute to a person's risk of TdP. Finally, the CredibleMeds website has several mechanisms for visitors to send questions or advice on how the website can better support the needs of patients, healthcare providers and research scientists. Such feedback is welcomed and all questions receive a personal response.

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