Female "Paradox" in Atrial Fibrillation-Role of Left Truncation Due to Competing Risks.

Area of Science:

• Cardiology
• Epidemiology
• Biostatistics

Background:

• Female sex is a controversial stroke risk factor in atrial fibrillation (AF), increasing risk in specific demographics despite male predominance in cardiovascular diseases.
• The underlying mechanism for this paradoxical association remains unclear, prompting investigation into non-causal explanations.

Purpose of the Study:

• To investigate the hypothesis that the sex difference in stroke risk among atrial fibrillation patients is non-causally generated by left truncation due to competing risks (CR).
• To explore how competing risks, like coronary artery disease, can create spurious associations between female sex and stroke incidence in AF populations.

Main Methods:

• Utilized statistical simulations to model the hazards of stroke and competing risks (CR) with correlated heterogeneous risk.
• Modeled a left-truncated atrial fibrillation population, assuming some individuals died from CR before AF diagnosis.
• Calculated the hazard ratio for female sex in the simulated left-truncated population.

Main Results:

• Female sex emerged as a risk factor for stroke in the simulated left-truncated AF population, even without a causal role.
• The observed hazard ratio was attenuated in younger populations, those without left truncation, and in scenarios with low CR and high stroke incidence.
• Findings align with real-world observations of female sex as a risk factor in specific AF patient subgroups.

Conclusions:

• Left truncation due to correlated competing risks can generate spurious risk factors, explaining the paradoxical association of female sex with stroke in atrial fibrillation.
• This statistical artifact, rather than a direct causal link, may underlie the observed increased stroke risk in women with AF.
• Highlights the importance of considering competing risks and potential biases like left truncation in epidemiological studies.