Other Risk Factors, Risk Modifiers and the Role of Biomarkers
In addition to the risk factors included in current risk stratification schemes, several other risk factors have been recognised. These include a family history of stroke, the presence of chronic kidney disease, atrial high-rate episodes (AHRE) and atrial tachyarrhythmia (AT)/AF burden.
Chronic kidney disease is a major cardiovascular risk factor, which is particularly common among elderly people. 61 However, whether it does in fact independently raise the risk for ischaemic stroke is poorly understood. Among 13,535 adults with AF, chronic kidney disease raised the risk of thromboembolism in AF independently of other known risk factors. The presence of proteinuria has also been shown to reflect an increased thromboembolic risk in patients with normal or
moderately impaired renal function. The duration of AF was previously not considered as a risk factor for stroke in AF patients due to the ambiguity of clinical symptoms.
However, the diagnostic features of atrial-based pacemakers are now sufficiently advanced to supply information on the presence and duration of atrial arrhythmias. Three key studies have assessed the consequences related to these arrhythmias. In a study to evaluate the relationship between daily AT burden from implantable device diagnostics and stroke risk (The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk [TRENDS]), the overall rate of ischaemic events was low in this cohort of more than 2,400 patients (1.3 % per year). Patients with atrial rate >175 bpm, lasting >20 seconds, for <5.5
hours on a single day during a 30-day period experienced a clinical thromboembolism rate of 1.1 % per year, while the event rate among those with a high AT/AF burden was 2.4 % per year. After
statistical adjustment for stroke risk factors and antithrombotic therapy, a high AT/AF burden <5.5 hours per day over 30 days was associated with a risk of thromboembolism similar to that of patients
entirely free of AT/AF, while the risk doubled among patients with AT/AF during >5.5 hours per day. However, compared with zero burden, the difference in HR for the groups with low and high AT/AF burdens was not statistically significant.
In preliminary results presented at the American Heart Association Scientific Sessions 2010 of the Asymptomatic atrial fibrillation and stroke evaluation in pacemaker patients and the atrial fibrillation reduction atrial pacing trial (ASSERT), episodes of device-detected atrial tachycardia greater than six minutes were found in 261 of 2,580 pacemaker patients, with hypertension but no history of AF over almost three years of follow-up. These arrhythmias were associated with a 2.5-fold increase in risk of ischaemic stroke and systemic embolism. Among the patients with a CHADS2 score of ≥2, device-detected ATs increased the absolute risk of stroke to 2.1 % per year. Among pacemaker patients without any prior history of atrial arrhythmias, 35 % of all strokes and systemic emboli were preceded by device-detected ATs.
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A study contributing further information comparing the duration of AF with the risk of stroke found that in patients without atrial arrhythmias, the risk of stroke was 1.2 % per year. If at least five minutes of atrial arrhythmias were detected, the event rate remained low at 1.7 % per year. If 24 hours or more of atrial arrhythmias were detected, the event rate was 4 % per year.
However, by adding the patient’s CHADS2 score to the duration of atrial arrhythmia, groups at low risk (0.8 % per year) and at high risk (5 % per year) for thromboembolic events could be better
identified. 62 This is still an uncertain area, however there are several ongoing registries and trials that will report in the next several years and lead to a clarification.
Echocardiography is valuable to define the origin of AF and may add useful information in predicting the risk of stroke. Among high-risk patients, impaired left ventricular systolic function on transthoracic echocardiography, thrombus, dense spontaneous echo contrast or reduced velocity of blood flow in the left atrium appendage and complex atheromatous plaque in the thoracic aorta on transoesophageal echocardiography have been associated with
increased thromboembolic risk.
There has been increased interest in the role of biomarkers for improving stroke risk prediction models. C-reactive protein, D-dimer, fibrinogen, gamma glutamyl transferase, plasminogen-activator inhibitor type 1 and N-terminal pro-B-type natriuretic peptide
(NT-proBNP) are some examples. 66–71 Sub-study analyses of the 18,113- patient Randomisation evaluation of long-term anticoagulation therapy (RE-LY) trial, involving the new oral anticoagulant (OAC) dabigatran assessed the prognostic value of the biomarkers D-dimer and NT-
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proBNP for predicting cardiovascular events in patients with non-valvular AF. 70,71 D-dimer concentration at initiation of treatment with warfarin or dabigatran was strongly associated with the risk of stroke, mortality and bleeding independently of CHADS2 risk factors and baseline anticoagulant treatment. 70 In AF patients with risk factors for stroke, the NT-proBNP level was significantly raised compared with healthy subjects of similar age. A raised NT-proBNP level was associated with an elevated risk of stroke, major haemorrhage and death even after adjustment for the CHADS2 risk factors and study drug.
The assessment of the contribution to improved risk prediction by considering of new risk factors and biomarkers has stimulated examination of optimal statistical techniques for these evaluations.
However, the added value of these markers to current risk stratification schemes is yet to be determined.
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