Drug Risk Update

Website publishes risk categories for QT-prolonging drugs

In 1999, as the result of growing recognition of the potential for noncardiac drugs such as terfenadine or cisapride to cause QT prolongation and torsades de pointes ventricular arrhythmias, the federal Agency for Healthcare Research and Quality awarded a grant to the Georgetown University Center for Education and Research on Therapeutics to conduct research and develop methods to accurately and more rapidly determine which drugs have the potential to induce torsades de pointes and to make its findings freely available to the medical community and the public. In 2001, the center moved to the University of Arizona and, in 2012, it became a freestanding nonprofit foundation known as the Arizona CERT, or AZCERT.

Under a contract with the FDA’s Safe Use Initiative, AZCERT conducts its research and educational programs to improve the safe use of medicines. AZCERT is best known for its web-based categorical listing of drugs based on their risk of causing QT prolongation and/or torsades de pointes (TdP). The lists, also known as the QTdrugs lists, are made available on the CredibleMeds.org website to more than 80,000 registered users from 193 countries. In the last year, more than 702,000 visitors have accessed and/or downloaded the lists of drugs.

Raymond L. Woosley, MD, PhD
Raymond L. Woosley

The lists are also recognized as research tools and have been cited by dozens of teams of researchers who have used the lists in their epidemiologic research on drug-induced QT prolongation, TdP and sudden cardiac death. Numerous large health care systems now use the drug lists as the basis for clinical decision-support logic and have them incorporated in electronic medical records systems to prevent drug-induced QT prolongation and TdP. To facilitate access to the lists for online systems, AZCERT has recently developed an open-source application program interface for health information technology software.

AZCERT method to evaluate risk

To more reliably identify drugs that have the ability to cause QT prolongation and/or TdP, AZCERT has developed a process (see Figure 1). The process, termed Adverse Drug Event Causality Analysis (ADECA), has been summarized in scientific publications and is described in detail on the CredibleMeds.org website. ADECA utilizes the time-tested Bradford-Hill criteria to assess laboratory and clinical evidence and identify causal relationships between specific drugs and QT prolongation or TdP.

Because the evidence for a drug’s TdP risk is often incomplete, the process places drugs into one of three categories that have differing levels of certainty — known TdP risk, possible risk and conditional risk. As evidence is likely to evolve or change over time, the ADECA process includes the continued gathering and analysis of any newly emerging evidence. When justified by new evidence, assignments of drugs to these categories are changed or removed. The types of evidence required for placement of a drug in any of these categories are shown in the Figure 2.

Drugs with “known risk for TdP” are those found to have conclusive evidence that, when administered as recommended in the drug’s FDA-approved label, they have been found to cause TdP. Drugs found to prolong the QT interval but which lack convincing evidence of TdP are classified as having a “possible risk for TdP.” Beginning in 2006, the “conditional risk” category was added and includes drugs found to have a risk for TdP, but only under certain specific conditions, such as overdose, hypokalemia, hypomagnesemia, bradycardia or when there is an interaction with other drug(s). This category also includes drugs that are associated with TdP because they have pharmacologic actions that create conditions which enable other drugs to cause TdP (eg, loop diuretic agents or metabolic inhibitors of QT-prolonging drugs).

Figure. Schematic of Adverse Drug Event Causality Analysis method to assign drugs to categories of risk for QT prolongation and torsades de pointes.
Figure 1. Schematic of Adverse Drug Event Causality Analysis method to assign drugs to categories of risk for QT prolongation and torsades de pointes.

Figures: Adapted from information provided by Raymond L. Woosley, MD, PhD; printed with permission.

Figure 2. Categories of risk and evidence required for drugs that prolong the QT interval and/or cause TdP.
Figure 2. Categories of risk and evidence required for drugs that prolong the QT interval and/or cause TdP. Abbreviations: FAERS = FDA’s Adverse Event Reporting System. WHO = World Health Organization Adverse Event Reporting System. TQT=Thorough QT study for regulatory purposes.

The CredibleMeds.org website posts the lists of drugs in these three categories and a fourth list of drugs that should be avoided if possible by patients with congenital long QT syndrome. This list includes all drugs in the three risk categories of QT-prolonging drugs plus others with adrenergic actions that could place some patients with long QT syndrome at high risk for sudden death. The process for evaluating drugs and decisions regarding their category of risk are overseen by an interventional advisory board of clinical and pharmacological experts. Medications on all four lists are continuously monitored for new evidence and, in recent years, the lists have been revised every 4 to 6 weeks. Currently, 55 medications are on the list of drugs known to cause TdP (including nine removed from the U.S. market, but which may still be available in some countries). Another 84 QT-prolonging drugs are on the list with possible risk for TdP, and 41 are on the list with conditional TdP risk.

Since the lists were first posted in 2000, more than 130 new drugs have been added, and many have been removed or moved among categories. Beginning in 2012, drugs marketed outside the United States, especially in Europe and Canada, are reviewed, and many have been included in the lists and designated as such.

Open access to the QTdrugs lists

Cardiologists and other health care providers are encouraged to use the lists as references in their practices or as research tools. The lists are available at www.QTdrugs.org or www.CredibleMeds.org and can be searched by brand or generic name, sorted according to drug class or therapeutic use, downloaded and/or printed. Because the lists are updated frequently and because use of an outdated list could potentially result in harm to patients, the CredibleMeds.org website requires users who wish to download the lists to register so they can be notified by email when the lists are changed. The lists and the other content on the website are copyrighted, but permission to reproduce the lists can be obtained.

Disclosure: Woosley reports no relevant financial disclosures.

Editor’s Note: This is a new column that will be printed regularly in Cardiology Today. This column is intended to inform readers of up-to-date topics within the area of arrhythmia disorders.

In 1999, as the result of growing recognition of the potential for noncardiac drugs such as terfenadine or cisapride to cause QT prolongation and torsades de pointes ventricular arrhythmias, the federal Agency for Healthcare Research and Quality awarded a grant to the Georgetown University Center for Education and Research on Therapeutics to conduct research and develop methods to accurately and more rapidly determine which drugs have the potential to induce torsades de pointes and to make its findings freely available to the medical community and the public. In 2001, the center moved to the University of Arizona and, in 2012, it became a freestanding nonprofit foundation known as the Arizona CERT, or AZCERT.

Under a contract with the FDA’s Safe Use Initiative, AZCERT conducts its research and educational programs to improve the safe use of medicines. AZCERT is best known for its web-based categorical listing of drugs based on their risk of causing QT prolongation and/or torsades de pointes (TdP). The lists, also known as the QTdrugs lists, are made available on the CredibleMeds.org website to more than 80,000 registered users from 193 countries. In the last year, more than 702,000 visitors have accessed and/or downloaded the lists of drugs.

Raymond L. Woosley, MD, PhD
Raymond L. Woosley

The lists are also recognized as research tools and have been cited by dozens of teams of researchers who have used the lists in their epidemiologic research on drug-induced QT prolongation, TdP and sudden cardiac death. Numerous large health care systems now use the drug lists as the basis for clinical decision-support logic and have them incorporated in electronic medical records systems to prevent drug-induced QT prolongation and TdP. To facilitate access to the lists for online systems, AZCERT has recently developed an open-source application program interface for health information technology software.

AZCERT method to evaluate risk

To more reliably identify drugs that have the ability to cause QT prolongation and/or TdP, AZCERT has developed a process (see Figure 1). The process, termed Adverse Drug Event Causality Analysis (ADECA), has been summarized in scientific publications and is described in detail on the CredibleMeds.org website. ADECA utilizes the time-tested Bradford-Hill criteria to assess laboratory and clinical evidence and identify causal relationships between specific drugs and QT prolongation or TdP.

Because the evidence for a drug’s TdP risk is often incomplete, the process places drugs into one of three categories that have differing levels of certainty — known TdP risk, possible risk and conditional risk. As evidence is likely to evolve or change over time, the ADECA process includes the continued gathering and analysis of any newly emerging evidence. When justified by new evidence, assignments of drugs to these categories are changed or removed. The types of evidence required for placement of a drug in any of these categories are shown in the Figure 2.

Drugs with “known risk for TdP” are those found to have conclusive evidence that, when administered as recommended in the drug’s FDA-approved label, they have been found to cause TdP. Drugs found to prolong the QT interval but which lack convincing evidence of TdP are classified as having a “possible risk for TdP.” Beginning in 2006, the “conditional risk” category was added and includes drugs found to have a risk for TdP, but only under certain specific conditions, such as overdose, hypokalemia, hypomagnesemia, bradycardia or when there is an interaction with other drug(s). This category also includes drugs that are associated with TdP because they have pharmacologic actions that create conditions which enable other drugs to cause TdP (eg, loop diuretic agents or metabolic inhibitors of QT-prolonging drugs).

Figure. Schematic of Adverse Drug Event Causality Analysis method to assign drugs to categories of risk for QT prolongation and torsades de pointes.
Figure 1. Schematic of Adverse Drug Event Causality Analysis method to assign drugs to categories of risk for QT prolongation and torsades de pointes.

Figures: Adapted from information provided by Raymond L. Woosley, MD, PhD; printed with permission.

Figure 2. Categories of risk and evidence required for drugs that prolong the QT interval and/or cause TdP.
Figure 2. Categories of risk and evidence required for drugs that prolong the QT interval and/or cause TdP. Abbreviations: FAERS = FDA’s Adverse Event Reporting System. WHO = World Health Organization Adverse Event Reporting System. TQT=Thorough QT study for regulatory purposes.

The CredibleMeds.org website posts the lists of drugs in these three categories and a fourth list of drugs that should be avoided if possible by patients with congenital long QT syndrome. This list includes all drugs in the three risk categories of QT-prolonging drugs plus others with adrenergic actions that could place some patients with long QT syndrome at high risk for sudden death. The process for evaluating drugs and decisions regarding their category of risk are overseen by an interventional advisory board of clinical and pharmacological experts. Medications on all four lists are continuously monitored for new evidence and, in recent years, the lists have been revised every 4 to 6 weeks. Currently, 55 medications are on the list of drugs known to cause TdP (including nine removed from the U.S. market, but which may still be available in some countries). Another 84 QT-prolonging drugs are on the list with possible risk for TdP, and 41 are on the list with conditional TdP risk.

Since the lists were first posted in 2000, more than 130 new drugs have been added, and many have been removed or moved among categories. Beginning in 2012, drugs marketed outside the United States, especially in Europe and Canada, are reviewed, and many have been included in the lists and designated as such.

Open access to the QTdrugs lists

Cardiologists and other health care providers are encouraged to use the lists as references in their practices or as research tools. The lists are available at www.QTdrugs.org or www.CredibleMeds.org and can be searched by brand or generic name, sorted according to drug class or therapeutic use, downloaded and/or printed. Because the lists are updated frequently and because use of an outdated list could potentially result in harm to patients, the CredibleMeds.org website requires users who wish to download the lists to register so they can be notified by email when the lists are changed. The lists and the other content on the website are copyrighted, but permission to reproduce the lists can be obtained.

Disclosure: Woosley reports no relevant financial disclosures.

Editor’s Note: This is a new column that will be printed regularly in Cardiology Today. This column is intended to inform readers of up-to-date topics within the area of arrhythmia disorders.