In 916 patients with coronary heart disease who had no known AF at baseline, we found that the CHADS2 score was strongly predictive of ischemic stroke/TIA. Compared to participants with low CHADS2 scores (0-1), those with intermediate CHADS2 scores (2-3) had an over 2-fold increased rate of stroke and those with high CHADS2 scores (4-6) had a 4-fold increased rate of stroke. The event rate in non-AF CHD patients with high CHADS2 scores (5-6) was comparable to the rate in AF patients with moderate CHADS2 scores (1-2), a population known to derive benefit from stroke prevention therapies such as anticoagulation.15
This association remained independent after adjustment for a wide range of covariates. Moreover, model discrimination in this non-AF cohort (c-statistic = 0.65) was similar to that which has been observed in external contemporary AF cohorts (c-statistic = 0.56-0.62).23
These findings indicate the CHADS2 score may also be useful for risk stratification of patients without known AF. Notably, the discrimination of other, more complex risk stratification schemes (CHA2
-VASc, Framingham) were no better than CHADS2 in this population (c-statistic = 0.63-0.64).
Several potential mechanisms may explain these findings. First, patients with high CHADS2 scores may have a higher risk of developing atrial arrhythmias, which mediates the relationship with stroke outcomes. The strongest support for this comes from the cryptogenic stroke literature. In a study of patients monitored for arrhythmia after suffering an ischemic stroke, higher CHADS2 scores were noted in patients subsequently found to have occult AF. This association was particularly strong in patients with CHD. These investigators suggested using the CHADS2 criteria “backwards” to identify a subset of patients with cryptogenic stroke who may benefit from prolonged event monitoring.24
A similar investigation of hypertensive patients admitted for ischemic stroke demonstrated a higher prevalence of CHF, diabetes, CHD, and advanced age in patients found to have silent AF than those in whom monitoring did not reveal AF.25
Alternatively, the CHADS2 risk factors themselves may increase the risk of stroke or stroke subtypes, independent of cardiac rhythm. In AF, substantial evidence supports induction of a prothrombotic state, endothelial dysfunction, and blood stasis as underlying mechanisms of thrombus formation and stroke.26
However, even in the absence of AF, patients with heart failure27
have elevated markers of hypercoagulability and endothelial dysfunction. A recent study demonstrated similar levels of platelet activation in both AF and non-AF patients with cardiovascular comorbidities, suggesting that platelet activation in AF may be due to underlying cardiovascular disease rather than AF itself.30
Finally, the CHADS2 risk factors may directly contribute to left atrial (LA) remodeling, a process characterized by dilatation and mechanical dysfunction of the left atrium.31
These factors may result in blood stasis and confer an increased risk of thromboembolism independent of rhythm.32
Atrial structural remodeling can be accompanied by wall stretch and electrical remodeling resulting in atrial arrhythmias, with AF being the most common.31,33,34
Diabetes, heart failure, hypertension, and CHD have all been associated with LA remodeling.35-37
The CHADS2 risk factors may therefore contribute to stroke risk via LA remodeling, either by chamber dilatation producing blood stasis, by induction of AF, or both.
Further investigation is warranted to gain a better understanding of the underlying mechanism, as such knowledge may inform more directed screening or stroke prevention efforts. Our findings of comparable stroke risk in non-AF patients with high CHADS2 scores (5-6) and AF patients with moderate CHADS2 scores (1-2) raise the question of whether high risk, non-AF patients may benefit from stroke prevention therapies such as anticoagulation, either due to a greater risk of silent AF or rhythm-independent mechanisms of thromboembolism in this population.
The 2011 AHA/ASA guidelines for prevention of primary and recurrent stroke recommend risk factor modification of hyperlipidemia, hypertension, and diabetes.38,39
For patients with CHD or prior stroke/TIA, the guidelines recommend antiplatelet therapy. Notably, there were stroke events in our cohort despite the fact that the majority of subjects were receiving antiplatelet therapies (84%) and statins (65%) and had achieved excellent risk factor control (low density lipoprotein: 105+/−33 mg/dL, systolic blood pressure: 133 +/−21 mmHg, hemoglobin A1c: 6.0 +/−1.2%). Although stroke prevention guidelines state that opportunistic pulse screening followed by EKG to assess for AF in patients ≥65 may be useful, this limited ascertainment may be insensitive for sufficient detection of paroxysmal AF. 39, 40
There are several notable limitations of our study. This study was performed in a cohort of predominantly male patients with stable CHD, which may limit generalizability. The observational nature of the study cannot eliminate the possibility of residual confounding. However, the CHADS2 score remained strongly and independently predictive of stroke/TIA after adjustment for potential confounding variables; more extensive adjustment did not change point estimates or widen confidence intervals. Notably, approximately 6.2% of participants in the study were receiving antiarrhythmic agents, with greater use in those with high CHADS2 scores. If prescribed for atrial rather than ventricular arrhythmias, those with high CHADS2 scores may have had a higher rate of paroxysmal AF at baseline. Adjustment for antiarrhythmic drug use demonstrated no change in point estimates.
Finally, because our criterion for exclusion of subjects with AF was the baseline EKG, it is possible that individuals with known paroxysmal AF who were in sinus rhythm at the time of the baseline EKG could have been misclassified as non-AF participants and included in the analyses. It is also possible that participants without known AF but who had AF on the baseline study EKG could have been misclassified and excluded. However, for paroxysmal AF, any method of AF ascertainment other than continuous EKG monitoring would be subject to similar misclassification.