QT-related Drug Interactions: Building Evidence and Assessing Risk

Monday, January 14, 2019

Daniel S. Streetman, PharmD, MS

Drug-induced prolongation of the QT interval – or the time it takes for heart ventricles to depolarize and repolarize – is of substantial concern to healthcare providers. An abnormally prolonged QT interval may increase the risk for development of a malignant ventricular arrhythmia, such as Torsades de Pointes (TdP). Combined use of drugs that prolong the corrected QT interval (QTc) may further increase the risk for serious toxicities, but evidence about the risks with such combinations is limited.

The drug information team at Wolters Kluwer recognized the inherent risk in drug-induced QTc interval prolongation and felt there was a lack of actionable material on the topic designed for the point of care. We embarked on a project in 2018 to identify the drugs most likely to produce a potentially clinically-significant degree of QTc interval prolongation and provide within our solutions accessible, useful information and evidence on the associated risk.

Where We Started

As previously stated, evidence about the risks to QT interval prolongation posed by various drug combinations is limited. This is what we knew prior to our project:

  • Use of multiple QT-prolonging drugs increased the risk of QT prolongation in two different risk models in a 2013 study and a 2017 study
  • At least one other study has identified the use of more than one QT-prolonging drug as the most common risk factor among patients with QT prolongation
  • In contrast, two 2017 studies report only a limited increase in QT prolongation with concurrent use of more than one QT-prolonging drug, and the magnitude of risk depends on the specific drugs. This evidence comes from three reports, two by Meid, et al, and one by Vandael, et al
  • In a 2009 report, 49 patients had an electronic medical record QT-related drug interaction alert that was overridden, and based on a pre- and post-alert ECG, 17 (35%) experienced more than a 30 ms QT interval increase

Many drugs have been associated with QT interval prolongation. In March of 2013, a review of  205 drugs by the U.S. Food and Drug Administration (FDA) found that 46 (22%) of these agents prolonged the QT interval according to the results of thorough QT studies. As of November 2018, one online resource that categorizes drugs according to their TdP risks listed 223 drugs as having a known, possible, or conditional risk of causing TdP.

What We Did

Drug information specialists worked to identify those drugs most likely to produce a potentially clinically-significant degree of QTc interval prolongation, and thus most likely to cause TdP or other serious adverse outcomes. Additionally, we attempted to distinguish medications that are more likely from those less likely to increase the risk of QTc interval prolongation or TdP to a significant degree.

Assessments of risk were performed using published data, to the extent possible, and drugs were not included solely based on pharmacologic or therapeutic class, in vitro or animal data, drug label warnings, or grouping in other published listings of QT-prolongation or TdP risk groups:

  1. A search of the published literature was performed for all drugs with a suspected association with QT interval prolongation or an increased risk of TdP.
  2. Data regarding QT interval prolongation and TdP risk were collected, reviewed, and summarized.
  3. Data from these reviews were used to place individual drugs into high or moderate risk categories or to exclude them from either specific risk grouping.
  4. Initial groupings, along with the summary of data supporting that grouping, were then reviewed by a group of seven expert clinical content specialists.
  5. Drugs for which there was less than complete agreement on how they should be classified were discussed by the group until consensus on most appropriate grouping was achieved.

Interaction Risk Categories

Specific criteria are used to define two primary risk categories:

  • High risk QT-prolonging agents
  • Moderate risk QT-prolonging agents

Drugs are included in these groups only if there is a consensus that they meet these criteria, which are outlined below. Drugs for which there are some drug interaction/ adverse event concerns related to a possible QT-prolonging effect or TdP risk, but insufficient evidence to be included in one of these primary risk groups, are included in an "indeterminate risk" group that allows for some communication of label warnings and information about possible risks concerning their use with drugs that have a more substantiated risk of QT prolongation or TdP.

Highest Risk Criteria

Drugs are placed in the “QT-prolonging agents (highest risk)” group if there is published evidence showing any of the following:

  • A mean increase in QTc of >60 ms, or an upper bound of a 90%, or 95% confidence interval of >60 ms
  • >10% of patients with an increase in QTc >60 ms, an absolute QTc >500 ms, or TdP in any given study or analysis
  • >10 published or reported individual cases of an increased QTc >60 ms, an absolute QTc >500 ms, or TdP together with evidence from a case-control or cohort study showing a statistically significant increase in the risk for significant QT prolongation, TdP, or sudden cardiac death/ventricular arrhythmia (SCD/VA)

When we refer to “individual cases,” we include those described in a case report or case series, those described in aggregate (e.g., as in a database review), or individuals that are part of a larger clinical trial. As possible, each individual's risk for QTc prolongation should be assessed using the QTc interval prolongation risk score, and cases in which the individual is deemed to have a moderate or high risk of developing significant QTc prolongation (score of ≥7, corresponding to a ≥34% risk) should not be counted. Similarly, cases involving substantial overdoses or patients with long QT syndrome (LQTS) should not be counted.

Also included in the “highest risk” group are all class IA and class III antiarrhythmics and all drugs removed from the U.S. market due, at least in part, to QT prolongation or TdP concerns.

Moderate Risk Criteria

Drugs are placed in the “QT-prolonging agents (moderate risk)” group if there is published evidence showing any of the following:

  • A mean increase in QTc of >20 ms, or an upper bound of a 90%, or 95% confidence interval of >20 ms
  • >25% of patients with an increase in QTc of >20 ms or an increase to a QTc of >460 ms in any given study or analysis
  • ≥10 reported cases of a QTc increase of >60 ms, an absolute QTc of >500 ms, or TdP. Individual cases should be evaluated in the same manner described above for “highest risk” drugs

Drugs for which there is evidence from a database review suggesting a possible or likely risk of significant QTc prolongation or TdP, and for which there is some other signal of QTc- or TdP-related concern (e.g., report or referencing of cases in published reports or labeling; signals from case-control, cohort, or other studies; etc.), are also included in the “moderate risk” group.

How Does This Compare with Other Approaches?

The approach in the Wolters Kluwer project represents a substantial change from how drugs with a risk for QT interval prolongation were previously classified in our Lexicomp drug interactions and Medi-Span Drug Therapy Monitoring System (DTMS) databases. While our drug interaction groupings have always been informed by published data, avoidance recommendations or black box warnings in drug labeling previously played a bigger role in groupings, even if specific data regarding such risk was absent. This new approach classifies drugs according to the evidence of their risk, while still ensuring that all appropriate drug interaction warnings are included.

A full comparison of this approach to outside groups’ classification of QT-related risks is beyond the scope of this article; however, a brief comparison to one such resource does illustrate some important similarities and differences. A November 2018 comparison of the new Lexicomp interactions and Medi-Span DTMS groupings with the CredibleMeds torsadogenic risk groupings found that 87.5% of the new “highest risk” group and 94% of the new “moderate risk” drugs were included in the CredibleMeds database. Most of the grouped drugs not in the CredibleMeds listings are non-U.S. drugs or are newly-approved U.S. products.

One other notable difference is the size of the groupings. As of this review, the “highest risk” and “moderate risk” groups included 24 and 50 drugs, respectively. In comparison, the CredibleMeds included 223 drugs among its Known Risk, Conditional Risk, and Possible Risk groups.

The complete list of drugs included in our high and moderate risk groups is available for review in this online appendix.

Content Availability

Content reflective of these new QT-specific interaction groupings became available to Lexicomp users in late October 2018. These changes are being implemented more gradually in the Medi-Span DTMS database, with the initial changes released in October 2018 and final implementation anticipated to take place during the first quarter of 2019.

Dr. Daniel S. Streetman is the manager of referential content in the Metabolism, Interactions, & Genomics group with Clinical Effectiveness at Wolters Kluwer, Health. He completed a research fellowship in clinical pharmacology, with an emphasis in pharmacogenomics, at Bassett Healthcare in Cooperstown, NY, and was a clinical faculty member at the University of Michigan for several years prior to joining Wolters Kluwer. Dr. Streetman continues to maintain an academic relationship with several schools, lecturing on pharmacogenomics and other topics.

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