Introduction: Challenging the Conventional Wisdom of Electrocardiography
For decades, the QT interval—a measure of the time between the start of the Q wave and the end of the T wave representing ventricular depolarization and repolarization—has served as a vital sentinel in cardiovascular medicine. In the general population, a prolonged corrected QT (QTc) interval is a well-established harbinger of adverse outcomes, including sudden cardiac death, ventricular arrhythmias, and incident ischemic stroke. However, the dynamics of secondary prevention often differ from primary prevention.
Recent data from a secondary analysis of the Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial suggest a provocative reversal of this relationship. In patients with cryptogenic stroke and evidence of atrial cardiopathy, a prolonged QTc interval was not a risk factor for recurrence but was instead associated with a significantly lower risk of subsequent stroke. This finding challenges our understanding of electrocardiographic markers and necessitates a deeper look into the unique pathophysiology of atrial cardiopathy.
Highlight
- In the ARCADIA trial population, prolonged cohort-specific QTc was associated with an 84% reduction in the risk of recurrent stroke compared to normal QTc (HR 0.16; 95% CI 0.04–0.64).
- The inverse association remained consistent across multiple QT correction formulae, including Framingham, Hodges, Bazett, and Fridericia.
- These results contrast sharply with general population studies, suggesting that QTc may have distinct prognostic implications in the specific context of established atrial cardiopathy and recent cryptogenic stroke.
Background: The Burden of Cryptogenic Stroke and Atrial Cardiopathy
Approximately one-quarter of all ischemic strokes are classified as cryptogenic, meaning no definitive cause is identified after standard diagnostic evaluation. A significant subset of these patients exhibits “atrial cardiopathy”—a structural, functional, or electrical remodeling of the left atrium that can predispose to thromboembolism even in the absence of clinically detectable atrial fibrillation (AF).
While the QT interval primarily reflects ventricular activity, it is influenced by systemic autonomic tone, electrolyte balances, and underlying myocardial health, all of which are relevant to stroke risk. In primary prevention cohorts, such as the ARIC (Atherosclerosis Risk in Communities) study, QTc prolongation is linked to a higher risk of first-time stroke. The ARCADIA investigators sought to determine if this risk profile holds true for recurrent events in a high-risk population with pre-existing atrial disease.
Study Design and Methodology
The ARCADIA trial was a multicenter, randomized, double-blind clinical trial conducted across North America from 2018 to 2023. It compared apixaban to aspirin for the prevention of recurrent stroke in patients with cryptogenic stroke and evidence of atrial cardiopathy (defined by specific ECG criteria, biomarkers, or left atrial enlargement).
In this specific secondary analysis, researchers evaluated 881 patients. To ensure the accuracy of the QT measurements, the team excluded patients with missing ECG data or those with a prolonged QRS duration (≥120 ms), as intraventricular conduction delays can artificially lengthen the QT interval.
The primary exposure was the post-stroke QTc interval, corrected using a cohort-specific formula to minimize bias, as well as several standard formulae (Framingham, Hodges, Bazett, and Fridericia). The primary outcome was the recurrence of any stroke type. Multivariable Cox proportional hazards models were employed to adjust for potential confounders, including age, sex, hypertension, diabetes, and baseline stroke severity.
Key Findings: A Surprising Protective Association
Among the 881 patients analyzed, 139 (15.8%) were identified as having a prolonged cohort-specific QTc. During a mean follow-up period of 1.8 years, 62 patients experienced a recurrent stroke, resulting in an annualized rate of 3.9% per year.
Statistical Significance of the Inverse Relationship
The results were unexpected. After adjusting for multivariable factors, each standard deviation (SD) increase in cohort-specific QTc was associated with a decreased risk of recurrent stroke (Hazard Ratio [HR] 0.72; 95% CI 0.54 to 0.95). When comparing those with prolonged QTc directly against those with normal QTc, the reduction in risk was even more pronounced, with an HR of 0.16 (95% CI 0.04 to 0.64).
Consistency Across Models
One of the strengths of this analysis was the robustness of the data across different correction methods. Whether using the Framingham or the Fridericia formula, the direction and significance of the association remained stable. Furthermore, the researchers accounted for the timing of the baseline ECG relative to the index stroke, the duration of the QRS complex, and the development of incident atrial fibrillation during the trial. None of these factors altered the fundamental finding: prolonged QTc was linked to fewer recurrent strokes.
Expert Commentary: Mechanistic Insights and the “Survivor Bias”
The stark contrast between these findings and those from the general population requires careful interpretation. Several hypotheses may explain this “QTc paradox” in the context of atrial cardiopathy.
1. Phenotypic Differences in Atrial Cardiopathy
It is possible that in patients who have already suffered a cryptogenic stroke, a prolonged QTc represents a specific electrophysiological phenotype. If the index stroke was driven primarily by atrial structural changes rather than ventricular or systemic autonomic instability, the QTc might not serve as a marker of embolic risk in the same way it does for a first-time event.
2. Autonomic Modulation
Stroke often causes a massive disruption of the autonomic nervous system, which in turn affects the QT interval. It is conceivable that the QTc measured in the subacute phase of stroke reflects a specific state of neuro-cardiac interaction that is markers of a lower-risk profile for recurrence in this specific ARCADIA cohort.
3. Selection and Survivorship Bias
Patients enrolled in ARCADIA had to survive an initial stroke and meet specific criteria for atrial cardiopathy. This “selection” may have filtered out individuals in whom QTc prolongation is truly malignant. In those who remained and were eligible for the trial, the prolonged QTc might be a surrogate for a different, less aggressive underlying pathology.
4. Competing Risks
While the study adjusted for the competing risk of death, it is always a consideration in elderly stroke populations. However, since the findings remained significant after this adjustment, it suggests the protective association against stroke is likely independent of overall mortality.
Conclusion: Redefining Risk Stratification
The ARCADIA secondary analysis provides a critical reminder that clinical markers can have different meanings depending on the population to which they are applied. For patients with recent cryptogenic stroke and atrial cardiopathy, a prolonged QTc interval should not currently be viewed as a sign of increased recurrence risk; if anything, the reverse may be true.
If these findings are confirmed in broader, independent cohorts, they could significantly impact how clinicians use the ECG for risk stratification. Rather than a one-size-fits-all marker of cardiovascular danger, the QTc interval may need to be interpreted through the lens of the patient’s specific stroke history and the presence of underlying atrial disease.
Funding and Clinical Trial Information
The ARCADIA trial was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH). Study medication was provided by the Bristol-Myers Squibb/Pfizer Alliance.
Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.
References
1. Boursiquot BC, Elias A, Kamel H, et al. Prolonged QT interval and risk of recurrent stroke in the Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial. Heart. 2026; Epub ahead of print. PMID: 41720625.
2. Kamel H, Longstreth WT Jr, Tirschwell DL, et al. The Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) Trial: Methods and Baseline Characteristics. J Stroke Cerebrovasc Dis. 2019;28(11):104309.
3. Soliman EZ, Howard G, Cushman M, et al. Prolongation of QTc and risk of stroke: The REasons for Geographic And Racial Differences in Stroke (REGARDS) study. J Am Coll Cardiol. 2012;59(16):1460-1467.
