Patient case: 19-year-old female with long QT syndrome; genetic feature: KCNH2

Clinical trial: Genetics of QT Prolongation With Antiarrhythmics

Summary: To assess the ability of common genetic variants in aggregate to predict drug-induced QT prolongation in patients being loaded with dofetilide or sotalol, and validate the feasibility of using a smartphone device for measuring QT interval.

Detailed description: Drug-induced long QT syndrome (LQTS), and the subsequent fatal arrhythmia torsade de pointes (TdP), is a major concern with use of a number of medications. Prolongation of the QT interval is the most common cause of withdrawal of medications already on the market, and despite the relatively rarity with non-cardiovascular drugs, the public health impact is magnified by the fact that drug-induced TdP can occur with medications used for benign conditions, such as allergic rhinitis. The QT interval is heritable, and a number of common genetic variants have been associated with QT interval in large population studies.
  Dofetilide is a commonly used anti-arrhythmic medication known to be associated with drug-induced LQTS to such a degree that the Federal Drug Administration requires a mandatory 3 day hospitalization with initiation to screen for QT prolongation. Sotalol is also a commonly-used anti-arrhythmic medication that is associated with drug-induced LQTS and requires a 3 day hospitalization for initiation, although it does not have an FDA-specified initiation protocol like dofetilide. Although certain clinical predictors have been associated with prolongation of QT with dofetilide or sotalol, there is limited information about genetic predictors of QT prolongation. As identification of such genetic predictors could help to identify potentially toxic responses in this and other medications, we plan to examine genetic predictors of QT interval on the QT prolongation with dofetilide or sotalol. In addition, to assess the feasibility (and safety) of using genetic-guided outpatient initiation, we plan to study the accuracy of the AliveCor device for measuring QT interval in select patients.
  STUDY OVERVIEW: This study is a multi-center study attempting to identify genetic and other factors that influence QT interval response to dofetilide or sotalol. One of the goals of this study is to determine whether genetics might identify individuals at low enough genetic risk for QT prolongation that outpatient initiation might be feasible. As an additional safety measure of this approach might include ambulatory QT measurements, we would also like to test the accuracy of a smart phone-based device for measuring QT interval called the AliveCor device. The dofetilide or sotalol use will be solely determined by clinical staff independent of the research study based on standard clinical care. The research components of this study include only the additional collection of blood for genetic analysis, collection of subject data on a CRF and copies of electrocardiograms performed as part of routine clinical care. This study will be performed at Harvard hospitals including MGH, BWH, BIDMC, all of which are eligible for participation in ceded review (MGH = primary). Other hospitals that may participate include West Roxbury VA; local IRB approval will be sought at each of these centers as they do not participate in the Harvard ceded review process. Data will be collected at each individual hospital by co-investigators/site PIs and stored locally according to IRB requirements. Copies of CRFs, ECGs and blood samples for genetic analysis will be forwarded to MGH, which will serve as a coordinating and analysis center (as well as a recruiting center). Data will be encoded where possible; however, due to the impracticality of removing patient identifiers from certain data types, such as medication lists and ECGs, some data containing patient information will be transported and stored at MGH. Dr. Newton-Cheh will serve as overall study PI.
  The investigators propose to conduct a research study to examine known and explore potentially unknown genetic predictors of QT response in patients being admitted for dofetilide or sotalol initiation as part of their routine clinical care. Any patient being admitted to a participating institution for the purpose of dofetilide or sotalol initiation will be eligible. Patients must be able to understand the risks of genetic testing, and be willing to undergo a venipuncture for blood collection for genotyping. Exclusion criteria include inability to provide informed consent. The investigators had planned to enroll a goal of 500 study participants total across all participating centers, although due to lower than expected enrollment with dofetilide alone, the investigators have included sotalol as well to improve statistical power.
  Patients will be identified by investigators based on planned admission for dofetilide or sotalol initiation, and following explanation of the study by co-investigator, will be asked about study participation and informed consent will be obtained. Investigators will complete a data collection form for each patient, which will include contact information, demographic information, clinical information, family history and pedigree, and all electrocardiography information available (tracings, reports). Those individuals who agree to undergo AliveCor testing will be educated in how to use the device, and a clean quality tracing will be obtained, recorded, processed, and sent via email to the study investigation email (QTstudies@partners.org). The time and date of the recording will be recorded on the case report form, to allow linking with the transmission. No identifying patient information will be entered onto the AliveCor application, and thus no identifying information will be sent over the internet, or transmitted to the AliveCor company. No information about mental illness will be collected. Patients will then undergo venipuncture, and four 5mL blood samples (tubes) will be collected for genotyping. Patients will also be consented for future re-contact about additional data, information, or samples needed for analysis.

Eligibility: Inclusion Criteria:
  -  All patients admitted for dovetailed or sotalol initiation for clinical purposes.
  Exclusion Criteria:
  -  Inability to provide informed consent
  -  Inability to provide blood samples for DNA testing (anemia, coagulopathy)

Relevance to patient case: not relevant