Background: We hypothesized that the change in stroke risk profile between baseline and follow-up may be a better predictor of ischemic stroke than the baseline stroke risk determination using the CHA2DS2-VASc score ((congestive heart failure, hypertension, age ≥75 years (doubled), diabetes, stroke/transient ischemic attack/thromboembolism (doubled), vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque), age 65–75 years, sex category (female))). Methods: We collected information for all patients treated with atrial fibrillation (AF) in French hospitals between 2010 and 2019. We studied 608,108 patients with AF who did not have risk factors of the CHA2DS2-VASc score (except for age and sex). The predictive accuracies of baseline and follow-up CHA2DS2-VASc scores, as well as the ‘Delta CHA2DS2-VASc’ (i.e., change/difference between the baseline and follow-up CHA2DS2-VASc scores) for prediction of ischemic stroke were studied. Results: The mean CHA2DS2-VASc score at baseline was 1.7, and increased to 2.4 during follow-up of 2.2 ± 2.4 years, (median (interquartile range: IQR) 1.2 (0.1–3.8) years), resulting in a mean Delta CHA2DS2-VASc score of 0.7. Among 20,082 patients suffering ischemic stroke during follow-up, 67.1% had a Delta CHA2DS2-VASc score ≥1 while they were only 40.4% in patients without ischemic stroke. The follow-up CHA2DS2-VASc score and Delta CHA2DS2-VASc score were predictors of ischemic stroke (C-index 0.670, 95% confidence interval (CI) 0.666–0.673 and 0.637, 95%CI 0.633–0.640) and they performed better than baseline CHA2DS2-VASc score (C-index 0.612, 95%CI 0.608–0.615, p < 0.0001). Conclusions: Stroke risk was non-static, and many AF patients had ≥1 new stroke risk factor(s) before ischemic stroke occurred. The follow-up CHA2DS2-VASc score and its change (i.e., ‘Delta CHA2DS2-VASc’) were better predictors of ischemic stroke than relying on the baseline CHA2DS2-VASc score.