Stroke is the leading cause of death and permanent disability globally, with an incidence of approximately 80% of cases being of ischemic origin.1,2 About 17% of ischemic stroke (IS) patients are diagnosed with embolic stroke of undetermined source (ESUS), commonly characterized as a non-lacunar brain infarct of >1.5cm.3 Since the initial definition of ESUS by the Cryptogenic Stroke/ ESUS International Working Group criteria in 2014, there has been a growing interest towards ESUS-specific treatment approaches. Although atrial fibrillation (AF) is highly associated with cryptogenic strokes, emerging studies have shown that blood clots were observed during atrial cardiopathy (AC), even before AF occurs.4 As such, the ARCADIA trial was designed to validate AC as a therapeutic target by investigating the benefits of apixaban in comparison to the standard of care, aspirin, for the reduction of stroke recurrence in patients with AC but no known AF.5,6 The potential contribution of apixaban towards predicting the risk of AC, as well as identifying other potential risk predicators, was discussed during the International Stroke Conference (ISC) 2020.
The latest type of IS: Embolic stroke of undetermined source
Embolic stroke of undetermined source (ESUS) is a newly described type of IS with a prevalence rate of 7% to 42% among patients.2 ESUS is more prevalent in African Americans (29%) as compared to Caucasians; with every 10 years of age, the risk for AC is increased by 30%. Besides, the risk for AC is 34% higher for women versus men with ESUS. Also, other risk factors associated with AC in an ESUS population are lower hemoglobin and hematocrit levels, together with the occurrence of non-hypertensive vascular diseases such as heart failure, hypertension, and peripheral artery disease (Figure 1).7
The principal investigator of the ARCADIA trial, Dr. Mitchell Elkind, MD, from Columbia University in New York City, shared, “Modest effects of these associations suggest that all ESUS patients, regardless of underlying demographic and risk factors, may have atrial cardiopathy.”
Characteristically, ESUS is defined as a non-lacunar brain infarct, which is routinely detected by computed tomography or magnetic resonance imaging, in the absence of extracranial or intracranial atherosclerosis with ≥50% of luminal stenosis in arteries supplying the ischemic area. As such, ESUS is a high-risk source of cardioembolism and mainly caused by AF. However, based on recent observational findings, AF is not the leading cause of ESUS. Significantly, several studies have identified thromboembolism as the most likely source.4 Moreover, the risk of IS is determined by a complex interplay of genetic and environmental factors and the rate of recurrent stroke after ESUS may be as high as 5% per year.2
Limitations in the current standard of care for ESUS
The current standard of care (SOC) for treating patients with ESUS relies primarily on aspirin and warfarin. To date, aspirin is recommended for secondary prevention after a transient ischemic attack (TIA) or IS, based on the trials’ results showing a 13% reduction in long-term risk of recurrent stroke. Despite the efficacious short-term benefit of aspirin, long-term outcomes were not sustainable.8
Data gathered from 11 trials, in a sample size of 9,635 patients, investigating aspirin only versus control, indicated that aspirin reduced the 6-weekly risk of recurrent IS by about 60% (HR=0.41; 95% CI: 0.30-0.56; p<0.0001). The benefit was most significant at the first six weeks (Figure 2), and there was no reduction in risk of recurrent IS after 12 weeks (OR=0.97, 95% CI: 0.84-1.12, p=0.67; pint<0.0001 for <12 weeks vs. >12 weeks).8
Real-world data of apixaban for stroke prevention in AF
Recently, treatment with the blood thinner apixaban demonstrated similar overall effectiveness in reducing stroke and any thromboembolic events when compared with warfarin. Also, secondary analysis of real-world data from the AUGUSTUS trial presented at the ISC 2018 indicated a lower risk of bleeding, death, and hospitalization, in comparison to warfarin, regardless of history of prior stroke, blood clot, or thromboembolic events. Furthermore, these data revealed a better safety profile with apixaban compared with warfarin, dabigatran, and rivaroxaban.9
Efficacy of apixaban in the prevention of recurrent stroke in patients with cryptogenic ischemic stroke and AC
Emerging discovery of blood clots occurring during AC, before AF, has established the fact that other factors might be responsible for ESUS. For instance, un-detected thromboembolism in the left atrium of the heart was identified as another possible pathophysiologic mechanism. As such, ARCADIA trial evaluated the effectiveness of apixaban as an anticoagulant therapy to reduce stroke recurrence in patients with AC, but no known AF.5
The ARCADIA study is a biomarker-driven, randomized, double-blinded, active- control, phase 3 clinical trial, consisting of patients ≥45 years of age with ESUS. Moreover, evidence of AC was defined as ≥1 of the following markers: P-wave terminal force >5,000μV*ms in ECG lead V1, serum NT- proBNP >250pg/mL, and left atrial index ≥3cm/m2 on echocardiogram.5
Patients excluded from the trial possessed the following criteria: AF, a definite indication or contraindication to antiplatelet or anticoagulant therapy, or a clinically significant bleeding diathesis. Recruited patients were categorized into two groups, with one receiving apixaban 5mg twice daily versus aspirin 81mg once daily. Subsequently, survival analysis and a log-rank test were used to determine significant differences between the two treatment groups, inclusive of patients requiring open-label anticoagulation for newly detected AF.
Predicting the risk of AC by evaluating the findings from the ARCADIA trial
Additionally, a more in-depth investigation reviewing 924 patients with a mean age of 66 was performed to develop a multivariable relative risk regression model. The aim of this algorithm was to predict for risk factors such as dichotomous outcomes of PTFV1>5,000μV*ms and NT-proBNP>250pg/mL.10
The 924 ESUS patients who met inclusion/exclusion criteria exhibited the multiple risk factors for AC, such as age (RR per decade=1.2095), race (RR for African American=1.20), sex (RR for women=1.22), hemoglobin (RR per unit=0.94), and cardiovascular/peripheral arterial disease (RR=1.48). However, prior history of stroke or TIA, hypertension, diabetes, smoking, cancer, sleep apnea, and time from stroke to consent and blood draw for NT-proBNP were not associated with AC (Figure 3).10
Findings also showed that the black race was a significant predictor of elevated PTFV1 but not NT-proBNP while increasing age was significantly associated with a higher risk of elevated NT-proBNP. Furthermore, increasing hemoglobin showed a differentially significant association with both AC markers, increasing PTFV1 probability but decreasing the probability of NT-proBNP. Finally, patients with a prior history of other vascular diseases did not demonstrate a relationship with either AC marker.5,10
In summarizing the findings, Dr. Elkind stated, “Surprisingly, there was no independent association between the time to the measurement of NT-proBNP and risk, suggesting that this biomarker does not rise simply in response to stroke but reflects a stable condition.”
Increased systolic blood pressure as a stroke risk indicator
Another highlighted stroke risk indicator linked with a worse outcome after acute IS is the increased systolic blood pressure (BPV). Moreover, according to results from previous randomized INTERACT-2 trials, a negative impact after intracerebral hemorrhage was observed in patients with increased systolic BPV.16 Evidently, the Antihypertensive Treatment of Acute Cerebral Hemorrhage II trial (ATACH-II), corroborated the association of increased systolic BPV with worse long-term neurological outcome.11,12
The primary endpoint outcome was a 3-month follow up consisting of a score on the modified Rankin scale 4-6 (which assesses the degree of disability or dependence in daily activities, with scores ranging from 0 [no symptoms] to 6 [death]), followed by a secondary outcome with scores on the European Quality of Life – 5 Dimensions (EQ-5D) utility index and visual analog scale (VAS) at three months. The means of blood pressure and its variability were determined by analyzing the systolic blood pressure from the acute period (2-24 hours post-randomization) and subacute period (days 2, 3, and 7). Furthermore, the five measures of systolic BPV, but not systolic mean, were consistently associated with the primary outcome in both periods (Figure 4).11,12
As a result, a scoring system was created by investigating optimal baseline demographics associated with potential clinical variables. Essentially, findings of the receiver operating curve of 0.772 identified non-Asian, intubation, and female sex as a significant AC risk predictor. Consequently, there is an accuracy of 79% sensitivity and 60% specificity by the predictive risk model for determining the top quintile of SBP, with a score of ≥4.11,12
The ARCADIA trial highlighted that ESUS patients belonging to these groups: Female sex, black race, older age, relative anemia, and with a history of vascular disease, are at a higher risk of being associated with AC. Also, upon the successful completion of ARCADIA trial, improved response rates would confirm apixaban as a superior regimen to aspirin for the prevention of recurrent stroke in subjects with cryptogenic ischemic stroke and AC. Likewise, the secondary analysis of ATACH-II trial also discovered several clinical variables related to the highest levels of BPV following IS. These secondary findings have urged the importance of having an alternative therapy to reduce BPV for managing stroke patients.