Do QT-Prolonging Drugs Cause Major Adverse Cardiac Events in Hospitalized Adults? (QTP-MACE)

Do 'Known' QT-prolonging Medications Cause Major Adverse Cardiac Events in Hospitalized Adults? The QTP-MACE Study

There are 28 non-cardiology medications from multiple families costing more than $13 billion annually in Canada, categorized as 'Known' QT-prolonging medications (QTPmeds) based on very low levels of evidence. The association between many commonly used medications listed as known QTPmeds and actual major adverse cardiac events (MACE) is weak. Meanwhile, QTPmeds-related warnings are ubiquitous in every healthcare setting, triggering 'hard stop' disruption millions of times per day to front line clinicians. Poor quality medication safety alerts are increasingly recognized as a source of inferior patient care and provider burnout which detracts from healthcare sustainability.

In this study, anonymized hospital electronic medical record data from more than 990,000 adult patients across Ontario will be used to compare patients who experience MACE with those who do not, measuring their real-time exposure to QT-prolonging drugs. Additionally, machine-learning techniques will also be used to find which patient or treatment factors best predict risk.

The objectives of this study are to 1) Investigate whether exposure to one or more 'Known' QTPmed is associated with an increased risk of MACE after adjusting for confounders; and 2) Identify predictors and their relative importance for QTPmeds-associated MACE.

In summary, QT-prolonging medications have the potential to cause very serious adverse events, including death. However, it is not sufficiently clear which patients under which circumstances suffer events, or when is QT prolongation a useful surrogate marker for harm. Meanwhile, ubiquitous medication alerts related to QT-prolonging medications are at best imprecise and at worst, misleading, costly and potentially dangerous. Now that data resources are available with the data elements, structure and sample size required to rigorously assess this association, this study will address this question to improve patient safety, provider satisfaction and the cost-effectiveness of care.

Study Overview

• Status: Recruiting
• Conditions: Syncope; Ventricular Arrhythmias; Torsades de Pointes; MACE; Medication Safety; Acquired Long QT

Detailed Description

This study's investigators have formed the largest hospital electronic medical record (EMR) research network in Canada to be able to address this important patient safety issue. The team's combined use of the Ontario GEMINI network and Epic-Dovetale EMR data has huge power because of the nearly 1 million patients, the rich data including medication exposure, outcomes and risk factor determination that is not available elsewhere, and the development of data structure that allows for future international collaborations.

The investigators plan a nested case-control analysis using the Epic-Dovetale EMR and the GEMINI hospital electronic medical record (EMR) data repository (N > 990,000 eligible adult patients) comparing patients with a MACE to those without a MACE and their relative exposure to one or more Known QTPmed during a hospitalization. In addition, the investigators will do time-varying estimates of the risk of MACE for those patients with periods of Known QTPmed exposure and non-exposure during the same hospitalization. The MACE primary outcome is a QTP-relevant composite of death, non-fatal cardiac arrest, ventricular arrhythmias, and syncope. A second analysis will use machine learning algorithms to predict QTPmeds-associated MACE and determine the relative importance of each predictor.

This project will not only improve patient safety dramatically by improving the accuracy of QTPmeds-related alerts, it will also improve productivity and work satisfaction for thousands of healthcare providers internationally. In addition, the continued expansion and improvement of the largest Canadian hospital EMR research data platform is a huge new opportunity for future high-quality research.

• Study Type: Observational
• Enrollment (Estimated): 990000

Contacts and Locations

• Study Contact: Name: Anne M Holbrook, MD,PharmD,MSc,FRCPC; Phone Number: 35269 905-522-1155; Email: cptres@mcmaster.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 1Y3
      • Recruiting
      • St. Joseph's Healthcare Hamilton
      • Contact: Anne M Holbrook; Phone Number: 35269 905-522-1155; Email: cptres@mcmaster.ca
    • Toronto, Ontario, Canada, M5B 1T8
      • Recruiting
      • GEMINI
      • Contact: Amol Verma; Phone Number: 416-360-4000; Email: amol.verma@mail.utoronto.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

This is a retrospective observational study using de-identified electronic-medical-record data from St. Joseph's Healthcare Hamilton and GEMINI hospitals; no direct participant enrollment or consent is required.

Description

Inclusion Criteria:

• Adult patients 18 years of age or older
• Admitted to St. Joseph's Healthcare Hamilton or GEMINI hospitals between December 2017 and March 2025

Exclusion Criteria:

• Patients <18 years old
• Outpatient encounters

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Exposed (Known QTPmeds); Exposed to a known QTP medication
Unexposed (no known QTP meds); No exposure to a known QTP medication

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of major adverse cardiac events (MACE)	Time to first MACE during hospitalization, defined as incidence of any of the following: Mortality, non-fatal cardiac arrest, ventricular arrythmia including torsades de pointes, and syncope	From first exposure to the end of hospitalization, which would typically be up to 4 weeks follow-up.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Mortality	In-hospital death	From first exposure to the end of hospitalization, which would typically be up to 4 weeks follow-up.
Non-fatal cardiac arrest	Cardiac arrest based on diagnosis or Code Blue or resuscitation with CPR where the patient survives	From first exposure to the end of hospitalization, which would typically be up to 4 weeks follow-up.
Ventricular arrhythmias	Includes Ventricular fibrillation or tachycardia or torsades de pointes	From first exposure to the end of hospitalization, which would typically be up to 4 weeks follow-up.
Syncope	Syncopal event based on diagnosis - brief loss of consciousness	From first exposure to the end of hospitalization, which would typically be up to 4 weeks follow-up.

Collaborators and Investigators

• Sponsor: St. Joseph's Healthcare Hamilton
• Collaborators: Canadian Institutes of Health Research (CIHR); McMaster University
• Investigators: Principal Investigator: Anne M Holbrook, St. Joseph's Healthcare Hamilton

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: December 6, 2025
• First Submitted That Met QC Criteria: January 24, 2026
• First Posted (Actual): January 28, 2026

Study Record Updates

• Last Update Posted (Actual): January 28, 2026
• Last Update Submitted That Met QC Criteria: January 24, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Ventricular arrhythmia; Long QT syndrome; Torsades de pointes; Medication safety; QT interval prolongation; Major adverse cardiac events
• Additional Relevant MeSH Terms: Cardiac Conduction System Disease; Neurologic Manifestations; Nervous System Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Neurobehavioral Manifestations; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Consciousness Disorders; Unconsciousness; Tachycardia, Ventricular; Tachycardia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Cardiovascular Diseases; Long QT Syndrome; Syncope; Torsades de Pointes
• Other Study ID Numbers: CIHR grant # PJT-197768

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: It is not permitted for datasets from Epic-Dovetale and GEMINI to be shared openly as they contain sensitive patient health information. This is based on the data governance policies of the Epic-Dovetale and GEMINI research network as well as its research ethics board-approved study protocols. The data can only be accessed in the secure Epic-Dovetale and GEMINI research environment. Summary analyses will be shareable.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No