Changes in stroke risk by freedom-from-stroke time in simulated populations with atrial fibrillation: Freedom-from-event effect when event itself is a risk factor

<div><p>The risk of atrial fibrillation (AF)-related stroke is usually assessed by calculating the CHA₂DS₂-VASc score, the components of which are various risk factors, including prior stroke. Although prior stroke is considered the strongest risk factor, the associated risk is actually inferred. Nevertheless, it implies a “freedom-from-event effect” (FEE)—the longer a patient is stroke-free, the lower the stroke risk. Although dynamic prognostication has been applied to cancer, the FEE has been ignored in AF, probably because of methodological difficulties. We conducted a simulation study to evaluate the FEE in the risk of AF-related stroke. We modeled various populations of AF patients and simulated the development of stroke assuming a nonhomogeneous Poisson process, where the hazard depends on age, comorbidities, and individual variability. Parameters were set so that the model respects the CHA₂DS₂-VASc scoring scheme and reproduces the 1-year CHA₂DS₂-VASc score-wise stroke risk and relative risk conferred by real-world risk factors. We tracked stroke risk over 0 to 15 years of freedom-from-stroke time (FST), both prospective FST (pFST), which begins at the time of diagnosis and continues to the future, and retrospective FST (rFST), which begins at the present and looks backward to the time of diagnosis. The pFST counterbalanced the increase in stroke risk conferred by aging; in patients with a CHA₂DS₂-VASc score of 1, the pFST offset 62% of the age-conferred risk increase. The rFST reduced the stroke risk; in patients with a CHA₂DS₂-VASc score of 2 and without prior stroke, an rFST of 6.8 years reduced the stroke risk to the midpoint between CHA₂DS₂-VASc scores 1 and 2. The study results suggest that the FEE should be considered in evaluating stroke risk in patients with AF. The FEE may be important in other recurrent diseases for which a prior event is a risk factor for a future event.</p></div

CHA₂DS₂-VASc-wise stroke risks along the pFST.

<p>Line graphs showing stroke risk along a pFST of up to 15 years per initial CHA₂DS₂-VASc-score for patients (A) without prior stroke and (B) with prior stroke. Stroke risk is the probability of stroke occurring during the following year.</p

Stroke risks along the pFST.

<p>Line graphs showing stroke risk along a pFST of up to 15 years in patient populations representing (A) all combinations of risk factors, including 0–5 comorbidities, (B, C) presence or absence of prior stroke, and (D–F) age (categorized as <65, 65–75, or ≥75 years). Stroke risk is the probability of stroke occurring during the following year. Solid lines denote absence of prior stroke, and dashed lines denote presence of prior stroke. Green denotes age <65 years; blue denotes age 65–75 years; red denotes age ≥75 years. Note that 16 common CHA₂DS₂-VASc score-wise trajectories resulted.</p

Adjusted CHA₂DS₂-VASc scores (adjCVSs) of patients without prior stroke over the rFST.

<p>Line graph showing adjCVSs plotted against an rFST of up to 15 years per CHA2DS2-VASc score. For patients with an rFST of 0, the adjCVS is simply the CHA2DS2-VASc score.</p

Stroke risk in the simulated populations in comparison to stroke risk in a real-world population.

<p>Dot plots of stroke risk in 36 patient populations representing (A) all combinations of risk factors, including 0–5 comorbidities, (B, C) presence or absence of prior stroke, and (D–F) age (categorized as <65, 65–75, or ≥75 years) arranged according to CHA₂DS₂-VASc scores. Stroke risk is the probability of stroke occurring within 1 year following the diagnosis of AF. Rectangles (▢) denote absence of prior stroke, and triangles (▵) denote presence of prior stroke. Green denotes age <65 years; blue denotes age 65–75 years; red denotes age ≥75 years. Superimposed are the 1-year stroke risks observed in the Danish cohort [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194307#pone.0194307.ref016" target="_blank">16</a>] with point estimates (dots) and their 95% confidence intervals (error bars).</p

CHA₂DS₂-VASc-wise stroke risks over the rFST.

<p>Line graphs showing stroke risk over an rFST of up to 15 years per CHA₂DS₂-VASc score for patients (A) without prior stroke and (B) with prior stroke. Stroke risk is the probability of stroke occurring during the following year.</p

Adjusted CHA₂DS₂-VASc scores (adjCVSs) of patients without prior stroke plotted along a 15-year pFST.

<p>Adjusted CHA₂DS₂-VASc scores (adjCVSs) of patients without prior stroke plotted along a 15-year pFST.</p

Relative risks (RRs) of stroke by aging, comorbidities, and prior stroke in our model and from previously reported meta-analyses.

<p>Relative risks (RRs) of stroke by aging, comorbidities, and prior stroke in our model and from previously reported meta-analyses.</p